A Phase Ib Study of Neoantigen Vaccine (NeoVax Plus Montanide) in Combination With Nivolumab and Locally Administered Ipilimumab in Patients With Advanced Melanoma
Phase: PHASE1
Conditions: Cutaneous Melanoma
Sponsor: Dana-Farber Cancer Institute

Title: A Phase Ib study of Neoantigen Vaccine (NeoVax plus Montanide) in 
combination with Nivolumab and locally administered Ipilimumab in patients 
with melanoma 
 
NCT Number: NCT03929029 
 
IRB Approval Date: 08/30/2018 

DF/HCC Protocol#: 18-279 
BMS Protocol #: CA184-590 
DF/HCC Protocol#: 18-279 
Version 8.0 / November 20, 2023 
TITLE: A Phase lb study ofNeoantigen Vaccine (NeoVax plus Montanide) in combination 
with Nlvolumab and locally adntlnlstered Iplllmumab In patients with melanoma 
Coor<Unatlng Center: 
Dana-Farber Cancer Institute 
Principal Investigator (Pl): 
Pabick A. Ott, MD, PhD; 
Dana-Farber Cancer Institute 
Agents: 
I) Personalized neoantigen peptides IND# 15703 Dana Farber Cancer Institute
2) Poly-ICLC (Hiltonol®) DMF # BB-MF 14,266 and BB-MF 14,302 Oncovir Inc.
3) Montanide"' ISA-51 VG, Seppic
4) Nivolumab, Bristol Myers Squibb
5) Ipilimmnab, Bristol Myers Squibb
IND#: 15703 
IND Sponsor: Pabick A. Ott, MD PhD 
Protocol Type/ Version#/ Venlon Date: 
Version 8.0 / November 20, 2023 
CONFIDENTIAL 
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SCHEMAA 
Vaccine Manufacture 
Nivolumab 
5 
♦(B1) Tumor Biopsy
♦(L1) leukapheresis
Vaccine site biopsy 
·tt m•IAnoma ts unrutcta.l>lt
SCHEMAB 
O or1 
Treat Cohort 3 
Dose Level i-
N • 10 
0 or1 
Treat Cohort 2 
Dose level i­
llo S 
Vaccine + local lpilimumab 
l
l 
{ 
! 
! 
15 
20 
♦ (B2')
♦ (B3')
♦L2
>=2 
♦ 
Treat Cohort 1 
Dose Level 1 • 
ti = 5 
Treat Cohort 3 
Dose Level1" 
N • 10 
♦L3
♦ 
O or1 
Treat Cohort 3 
Oo:se level .1a 
N • 1 
2 
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DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
! 
25 
Treat Cohort 2 
Do.se level. 1 ff 
N•S 
'> PD
♦(B4')
• 2.5 mg lpiinumab 
per .,jeeton site
0 1.25 mg lpirrumab
peri"ljection site
-S mg lpli01Jmab
peri'ljection site
>=2 
¹ 
111is document is confidential. Do not disclose or use except as authorized. 

TABLE OF CONTENTS 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
SCHEMA A ..................................................................................................................................... 2 
SCHEMA B ..................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ .3 
I. 
OBJECTIVES ...................................................................................................................... 5 
1.1 
Study Design ............................................................................................................ 5 
1.2 
Primaiy Objectives ................................................................................................... 5 
1.3 
Seconda1y Objectives ............................................................................................... 5 
2.
BACKGROUND ................................................................................................................. 5 
2.1 
Study Disease(s) ....................................................................................................... 5 
2.2 
Computational and immm1ological infrastructure for NeoVax plus 
Montanide ................................................................................................................ 6 
2.3 
IND Agents .............................................................................................................. 7 
2.4 
Rationale ................................................................................................................ 21 
2.5 
Hypothesis .............................................................................................................. 23 
2.6 
CotTelative Studies Background ............................................................................ 23 
3.
PARTICIPANT SELECTION ........................................................................................... 25 
3. l
Eligibility Criteria .................................................................................................. 25 
3.2
Exclusion Criteria .................................................................................................. 26 
3.3
Inclusion o f  Women and Minoiities ...................................................................... 28 
4.
REGISTRATION PROCEDURES ................................................................................... 28 
4.1 
General Guidelines for OF/HCC Institutions ........................................................ 28 
4.2 
Registration Process for DF/HCC Institutions ....................................................... 29 
5.
TREATMENT PLAN ........................................................................................................ 29 
5.1 
Preparation ofNeoVax plus Montanide ................................................................ 30 
5.2 
Agent Administration ............................................................................................. 33 
5.3 
Pretreatment ciiteria ............................................................................................... 36 
5.4 
Dose schema and staggering ofparticipants .......................................................... 36 
5.5 
Defmition of Dose-Limiting Toxicity .................................................................... 38 
5.6 
General Concomitant Medication and Suppo1tive Care Guidelines ...................... 38 
5.7 
Duration of Therapy/ Criteria for Taking a Participant Off Protocol 
Therapy .................................................................................................................. 39 
5.8 
Duration of Follow Up ........................................................................................... 40 
5.9 
Nivolumab treatment beyond progression ............................................................ .40 
5.10 
Criteria for Taking a Participai1t Off Study ......................................................... .41 
6.
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIF1CA TIONS ......... 42 
6.1 
Anticipated Toxicities ........................................................................................... .42 
6.2 
Toxicity Mai1agement ............................................................................................ 42 
6.3 
Dose Modifications/Delays .................................................................................... 45 
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6.4 
Criteria to Resume Treatment ............................................................................... .49 
6.5 
Discontinuation criteria.............................................................. 
. .. 50 
7.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
... 51 
7.1 
Adverse Event Definition and Characteristics ....................................................... 51 
7.2 
AE and SAE Recording and Reporting ................................................................. 52 
7.3 
Reporting to the Food and Drug Administration (FDA) ....................................... 55 
7.4 
Reporting to Study Sponsor ................................................................................... 55 
7.5 
Reporting SAEs to BMS ........................................................................................ 56 
7.6 
Reporting to the Institutional Review Board (IRB) ............................................... 58 
7.7 
Reporting to Hospital Risk Management. ............................................................. 58 
7.8 
Expected Toxicities ................................................................................................ 58 
8.
PHARMACEUTICAL INFORMATION .......................................................................... 62 
8.1 
Nivolmnab .............................................................................................................. 62 
8.2 
Ipilimumab ............................................................................................................. 63 
8.3 
Poiy-lCLC (Hiltonol®) ........................................................................................... 65 
8.4 
Personalized neoantigen peptides .......................................................................... 66 
8.5 
Montanide .............................................................................................................. 68 
8.6 
Preparation ofNeoVax + Montanide ................................................................... 70 
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................ 75 
9.1 
Phannacodynamic Studies ..................................................................................... 75 
9.2 
Future Analyses . 
. .. 76 
10.
STIJDY CALENDAR ...
... 77 
11.
MEASUREMENT OF EFFECT
... 80 
11. l 
Antitumor Effect- Solid Tumors .......................................................................... 80 
11.2 
Other Response Parameters ........................................... 
. .. 86 
12.
DATA REPORTING I REGULATORY REQUIREMENTS ........................................... 88 
12.l 
Data Reporting ....................................................................................................... 88 
12.2 
Data Safety Monitoring .......................................................................................... 88 
13.
STATISTICAL CONSIDERATIONS ............................................................................... 88 
13.l 
Study Design/Endpoints ........................................................................................ 88 
14.
PUBLICATION PLAN ..................................................................................................... 91 
REFERENCES .............................................................................................................................. 92 
APPENDIX A 
APPENDIXB 
APPENDIXC 
PERFORMANCE STATUS CRITERIA .................................................. 99 
ADVERSE EVENT MANAGEMENT ................................................... 100 
REGULATORY CONSIDERATIONS ................................................... 108 
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1.
OBJECTNES
1.1 
Study Design 
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The sn1dy is an open label, phase lb/II tiial in which patients with stage III B/C/D or stage IV 
melanoma will be treated with NeoVax plus Montanide® ISA-51 VG in combination with 
Nivolmnab and locally administered Ipilirmunab. Tumor from a sm-gical resection specimen or 
core needle biopsy of a melanoma metastasis will be used to prepare DNA and RNA for 
sequencing. Patients will begin treatment with Nivolmnab and vaccine will be prepared during 
the initial 12 weeks of Nivolumab therapy. At week 12, patients will begin vaccination with up 
to 20 neoantigen peptides. These peptides are encoded by non-silent mutations that are identified 
through DNA and RNA sequencing. Up to 20 peptides - 20 amino acids in length will be 
prepared for each patient and will be administered together with the immune adjuvant poly-lCLC 
and Montanide® ISA-5 I VG, a mineral oil based inunune adjuvant analogous to incomplete 
Fretmd's adjuvant (IFA). 
ConcmTently with the vaccine and Nivolumab, lpilinmmab will be delivered via subcutaneous 
injection in proximity to each vaccination site in order to I) direct anti-CTLA-4 activity to the 
vaccine-draining lymph nodes and 2) limit systemic toxic effects. This approach is effective in 
aniinal tumor models and is expected to result in significantly reduced levels of systemic 
Ipilimumab compared to the approved dose/schedule in advanced melanoma (3 mg/kg q3wks for 
four doses in the metastatic setting). The lpiliiuumab dose will be escalated/de-escalated from 
2.5 mg flat dose per injection in coho11 l. Serial tumor biopsies and vaccine site biopsies will be 
performed. (Schema A) 
1.2 
P1imary Objective 
•
To evaluate the safety of administering Neoantigen Vaccine (Neoantigen Peptides plus
Hiltonol and Montanide® ISA-51 VG) in combination with Nivolumab and locally
administered lpilimumab
1.3 
Sec.ondary Objective 
•
To assess the induction of neoantigen-specific cellular immune responses following
administration of NeoVax plus Montauide in combiiiation with Nivolumab and locally
administered Ipilimmnab
•
To estimate rates of disease progressiou/recun-ence depending on whether the patient had all
melanoma resected or has measurable disease per RECIST 1.1
2.
BACKGROUND
2.1 
Study Disease(s) 
Advanced melanoma has the highest per-death loss of years of potential life expectancy except 
for adult leukemia. The incidence of melanoma continues to rise worldwide at approximately 3% 
per year. It is estimated that in the United States 100,350 ii1dividuals will be diagnosed with 
melanoma and 6,850 will die from the disease ii1 20201. According to SEER data, roughly 4% of 
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DP/HCC Protocol #:18-279 
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melanomas are already metastatic at the time of diagnosis. The tendency for melanoma to spread 
through the lymphatic system and the bloodstream is in stark contrast to most other skin cancers. 
Thin melanoma (<1-2 mm) without lymph node involvement is curable in most cases by 
surgical removal with sufficient margins and adequate staging, which includes assessment of 
sentinel lymph node involvement if necessary. In contrast, thicker melanomas, ulcerated tumors, 
or lymph node involvement, although initially mostly amenable to complete surgical resection, 
confer a much poorer prognosis due to the risk of systemic recwTence, with 5-year swvivals 
ranging from 25% to 75%. Disseminated, locally advanced, or rectn1·ent melanoma is notoriously 
unresponsive to standard treatment, and is associated with a dismal prognosis, with 5-year 
smviva.ls of the order of 10-25%. Recent advances with targeted agents that block d1iver 
oncogenic mutations such as BRAfV600 have shown significant but transient clinical efficacy in 
patients with advanced melanoma2•6, whereas immunotherapy using co-stimulatory molecule 
blockade with monoclonal antibodies such as anti-CTLA-4, PD-1, or PD-Ll can lead to dmable 
responses in 15-40% of melanoma patients 7-10.
2.2 
Computational and immunologic.al infrastructure for NeoVax plus Montanide 
Over the last several years, we at DFCI have developed a computational infrastmcture and 
conceptual framework for trnnslating sequencing infonuation into a therapeutic vaccine through: 
(1) Pre.diction of mutated peptides that can bind to personal HLA molecules. Efficiently choosing
which pa1ticular mutations to utilize as immw1ogens requires identification of the patient HLA type
and the ability to predict which mutated peptides would efficiently bind to tl1e patient's HLA alleles.
Recently, neural network based learning approaches with validated binding and non-binding peptides
have advanced the accuracy of prediction algorithms for the major HLA-A and -8 allelesl1_ In a pilot
study, Sidney et al prepared seventy-four 9-mer and sixty-three 10-mer peptides predicted by the
algorithm NetlvlHCpan to have affinities to p&ticular HLA alleles below 1000 nM, with most being
below 500 nM. Binding of these peptides to their cognate HLA alleles was expe1imentally
detemlined using a well-established competitive binding assay12. Seventy-five percent of 9-mer
peptides predicted to have an affulity below 150 nM were expe1imentally ve1ified to be below 150
nM &1d 90% of these peptides were shown to have an affulity below 500 nM, a generally accepted
tlueshold. Fifty percent of 9-mer peptides predicted to have an affi1lity between 150 lllld 500 nM
were shown to have &1 affinity below 500 nM. Ten-mer peptide predictions were slightly less
precise. For predicted high affinity JO-mer peptides (below 150 nM), 70% were shown to have
an affinity below 500 nM. However, only 35% of 10-mer peptides predicted to have an affinity
between 150 and 500 nM were shown to have an affnlity below 500 nM. Thus, 10-mer peptides
with predicted affinities above 150 nM will not be utilized. These predictions provide
a reliable tool, when co11ectly applied, to assist in the selection of potentially immunogenic
peptides.
(2) Evaluating spontaneous human T cell responses to neoantigens. We have analyzed the
predicted HLA-binding prope1ties of 40 different neoepitopes representing both missense
mutations &1d neoORFs identified following an extensive literature review for reports of
spontaneous CDS+ T cell responsesl3_ Tllis analysis allowed us to conclude that the NetlvlHCpan
algo1ithm would have accurately predicted ea.ch epitope and to detennine that a. majoiity of
missense epitopes was due to mutations that affected the interaction with the T cell receptor and
not the MHC molecule.
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DP/HCC Protocol #:18-279 
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(3) Fonnulating the drug as a 11111/ti-epitope vaccine of long peptides. For each patient, multiple
neoantigens will be targeted. Targeting as many mutated epitopes as practically possible takes
advantage of the eno1mous capacity of the inumme system, prevents the oppommity for
illllllunological escape14 by down-modulation of a particular inumme targeted gene product, and
compensates for the known inaccuracy of epitope prediction approaches. Synthetic peptides provide
a particularly usefol means to prepare multiple illlllltmogens efficiently and to rapidly translate
identification of mutant epitopes to an effective vaccine. Peptides can be readily synthesized
chemically and easily pmified utili2ing reagents free of contaminating bacteiia or animal substances.
The small size allows a clear focus on the mutated region of the protein and also reduces inelevant
antigenic competition from other components (tmmutated protein or vii-al vector antigens). "Long"
peptides, ~20-30 amino acids in length (as opposed to "short" peptides, ca 8-10 amino acids)
have recently been shown to produce a more robust and more durable immune responses15,16. 
( 4) Combination with po?y-/CLC, a strong vaccine adj11va11t. Efective vaccines requil'e a strong
adjuvant to initiate an illlllltme response. As described in Section 2.3.3, poly-ICLC, an agon.ist of
1LR3 and the RNA helicase domail1s ofMDA5 and RIG3, has shown several desirable properties
for a vaccine adjuvant. These prope1iies include the induction of local and systemic activation of
ilmnune cells in vivo, production of stilnulatory chemokines and cytokines, and stiluulation of
antigen-presentation by DCs. Furthe1IDore, poly-ICLC can induce durable CD4+ and cos+ 
responses il1 humans. Imponantly, strikillg similarities in the upregulation of transcriptional and
signal transduction pathways were seen in subjects vaccinated with poly-ICLC and in volunteers
who had received the highly effective, replication-competent yellow fever vaccil1e17.
Fruthennore, >90% of ovarian carcinoma patients immunized with poly-ICLC in combination
with a NY-ESO-1 peptide vaccine (in addition to Montanide) showed il1duction ofCD4+ and CDs+ 
T cell, as well as antibody responses to the peptide in a recent phase 1 study18. Moreover, poly-ICLC
has been extensively tested in more than 25 clilrical tiials to date and exhibited a relatively benign
toxicity profile.
2.3 
IND Agents 
2.3.1 
Personalized Ne0Anti2en Peptides 
Sequencing technology has revealed that each n1mor contains multiple, patient-specific 
mutations that alter the protein coding content of a gene-!2. Such mutations create altered 
proteins, ranging from single amino acid changes ( caused by missense mutations) to addition of 
long regions of novel amino acid sequence due to frame slrifts, read-through of tennination 
codons or translation of intron regions (novel open readil1g frame mutations; neoORFs). l11ese 
mutated proteins are valuable targets for the host's inunune response to the tumor as, unlike 
native proteins, they are not subject to the illlllltme-dampening effects of self-tolerance. 
Therefore, mutated proteins are more likely to be ilmnunogenic and are also more specific for the 
tumor cells compared to nomial cells of the patient20. 
There have been several reports indicating that tumors expressil1g missense mutations or 
neoORFs can be prevented, and in some cases eradicated, by i.tmnllllization with peptides 
correspondil1g to the mutated protein21•25. For example, cos+ cytotoxic T lymphocytes (CTLs)
directed at missense mutations in the RNA helicase proteŝ or tl1e 02-spectrin proteiI122 fotmd in 
particular murine tumors have been identified. Expression of these mutated proteins by the ttnnor 
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was found to co1Teiate with tumor control or progression. 
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Co1respondingly, several human studies of spontaneous regression and long-te1m smvival have 
shown that powerful cos+ T cell responses against mutated epitopes coffelate with good clinical 
responses13. These studies began with the first identification of human immunogenic 
neoantigens2l2l!, and the seminal study by Lennerz demonstrating the strength and durability of 
neoantigen response compared to native protein responses22, and now have included the 
obse1vations of an increase in neoantigen-specific CDS-> T cells in a patient responding to anti­
CTLA4 therapy30 and tmnor regression following infusion of a tumor infiltrating lymphocyte
(TIL) population highly emiched in a neoantigen directed CD4+ T celJil. These obse1vations 
were made in multiple cancer types for multiple HLA alleles and have been widely observed in 
nunor infiltrating T cell populations, suggesting that there may be an association with CDs+ T cell 
activity and productive clinical responses211 32-36. Most of these CD8., T cell responses show a high 
degree of specificity toward the mutated inissense epitope compared to the native epitope, 
represent a high propo1tion of circulating T cells, and result in cells that are more abtmdant and 
active than cos+ T cell responses in the same patients directed toward over-expressed native 
antigens. 
Thus, in anirnals and in hmnans, immune responses to both discrete, mutated antigens (such as 
missense mutations) and expansive novel antigens (neoORFs) are observationally con-elated with 
regression and long-term remission. Extending that con-elation among a large set (11=468) of 
patients found in the Cancer Genome Atlas (TCGA) database, a recent meta-analysis of six 
nunor types revealed a significant smvival advantage (hazard ratio = 0.53; p=0.002) for patients 
with at least one predicted irmum10geuic neoepitope compared to patients with no predicted 
iimuunogenic epitopes37.
Four studies in humans have directly assessed the immtmotherapeutic potential of mutated 
antigens. First, because follicular lymphoma is charactelized by uncontrolled growth of a B cell 
expressing reananged immunoglobulin, many groups purified the rea1Tanged irmmmoglobulin 
for use as a vaccii1e. The induced cos+ T cells showed reactivity to the reananged, mutated 
po11ion of the irnmunoglobulin molecule (the idiot),pe) and not the gelTnline fran1ework38, and
this personalized vaccii1e approach revealed highly encouragii1g results in Phase I/II trials. 
However, only one of three Phase ill trials demonstrated prolonged disease-free survival (but this 
tJial failed to achieve its p1ima1y clinical end points )12. The observed failures have been 
att1ibuted to flaws in tr-ial design, such as imbalances iii standard prognostic scores between 
n·eated and control anns as well as enrollment of patients lacking sustained partial or complete 
remissions. Thus, the value of idiotype vaccines in conjunction with cmrent rituximab­
containing reginlens remains to be detennined. Second, a mix of peptides conesponding to the 
oncogenic proteins of HPV (a neoORF for humans) has been shown to result in significant 
remission of premalignant lesions induced by HPv1s,1•,
40_ Moreover, immunization with a 
synthetic version of an in-frame junctional deletion vaiiant of the epidennal growth factor 
receptor (EGFRviii) iii glioblastoma patients, a population known to frequently contain this 
mutation, provided encouraging phase 2 results41•42. lmpo1tantly, in these glioblastoma studies, 
evaluation of tumors in patients with tmuor recmrence showed that the recurrent tmuors almost 
unifonnly (20 of 23) lost expression of EGFRviii. This was interpreted as clear evidence of 
itmnunoediting due to inllllune pressure against an inllllunogenic neoantigen it1 humans. Finally, 
very recently, a personalized dendritic cell-based vaccine targeting melanoma neoantigens 
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promoted a diverse neoantigen-specific T cell receptor repe1ioire along with an increase in 
endogenous neoantigen-specific immune responses in a small Phase I triaĨ. Thus, in animals and 
in humans, immune responses to both discrete mutated antigens (such as missense mutations) and 
expansive novel antigen (neoORF) are observationally coITelated with regression and Jong-term 
remission and, in tv,o clinical studies, have been shown to control disease following therapeutic 
vaccination. The direct and comprehensive identification of the many mutated epitopes fotmd in 
cancer genomes creates the opo1tunity to use this class of immunogen to improve the immune 
response and efficacy of cancer vaccines. 
Most cancer vaccines employing peptides as immunogens have utilized "sho1t" peptides. These 
peptides are typically 9 - IO amino acids in length and capable of direct binding to the HLA 
molecule on the Sllrface of HLA-expressing cells. "Long" peptides, -20-30 amino acids in 
length, have recently been shown to produce a more robust and more durable inllllune 
responseW-6. Long peptides require intemalization, processing and cross-presentation in order to 
bind to HLA molecules; these functions only occur in professional antigen-presenting cells, such 
as dendritic cells, which can induce strong T cell responses. 
Many studies in hmnans have demonstrated the safety of peptide vaccines. These include studies 
with multiple short peptides33 as well as multiple long peptides, including neoORFs. In 
pa1iicular, two studies have been conducted with a mixture of 10 overlapping Jong peptides 
derived from p5328,29 and tluee separate studies with a mixtme of 13 Jong peptides derived from 
the oncogenic proteins of HPV17•19. In these studies, no toxicity higher than grade 2 was 
obse1ved and most adverse events were of limited dmation and severity. Additionally, many 
heterologous antigen preparations have been tested in humans. Such preparations include 
inadiated cell vaccines44•45 and tumor cell lysateĩ. These heterogeneous vaccines contain
mutated antigens, in the fo1m of intact proteins, partially degraded intracellular protein, and 
peptides found on the smface bound to MHC I. Moreover, they contain over-expressed and 
selectively-expressed molecules as well as many additional native proteins. In addition, pmified 
heat shock protein (HSP) 96 peptide complexes have been used as antigen47; such complexes 
also contain many mutated peptides. None of these studies have reported significant safety issues 
directly attributable to the immunogens of the vaccines. 
GMP peptides 
Clinical grade peptides will be prepared by synthetic chemistty, purified UPLC, mixed in stnall 
groups (see Sect 5.1.3) and combined with both the immune adjuvant poly-ICLC (a stabilized 
double-stranded RNA) and Montanide®ISA-51 VG (see Section 5.1.3). 
The mixtures of peptides, poly-ICLC, and Montanide® ISA-51 VG will be used for vaccination 
with the intention to induce cellular immune responses directed at tl1ese patient/tmuor specific 
mutations. Each patient will receive the full complement of peptides at each illlllltmization. 
2.3.2 
Poly-lCLC 
2.3.2.1 
TLR agonists as adjuvants for cancer vaccines
Toll like receptors (TLRs) are impotiant members of the faniily of pattem recognition receptors 
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DP/HCC Protocol #:18-279 
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(PRRs) which recognize conserved motifs shared by many micro-organisms, tenned "pathogen­
associated molecnlar pattems" (P AMPS). Recognition of these "danger signals" activates 
multiple elements of the innate and adaptive imnume system. TLRs are expressed by cells of the 
innate and adaptive illllllune systems such as dendritic cells (DCs ), macrophages, T and B cells, 
mast cells, and granulocytes and are localized in different cellular compartments, such as the 
plasma membrane, lysosomes, endosomes, and endolysosomes:!1!. Different TLRs recognize 
distinct P AMPS. For example, TLR4 is activated by LPS contained in bacterial cell walls, TLR9 
is activated by unmethylated bacte1ial or viral CpG DNA, and TLR3 is activated by double 
stranded RNA.!12. TLR ligand binding leads to the activation of one or more intracellular 
signaling pathways, ultimately resulting in the production of many key molecules associated 
with inflammation and illllllunity (pa11icularly the transcription factor NF-KB and the Type-I 
interferons). 
TLR mediated DC activation leads to enhanced DC activation, phagocytosis, upregulation of 
activation and co-stimulation markers such as CD80, CD83, and CD86, expression of CCR7 
allowing migration of DC to draining lymph nodes and facilitating antigen presentation to T 
cells, as well as increased secretion of cytokioes such as type I interferons, IL-12, and IL-6. All 
of these downstream events are c1itical for the induction of an adaptive inumme response. 
Among the most promising cancer vaccine adjuvants cun-ently in clinical development are the 
TLR9 agonist CpG and the synthetic double-stranded RNA (dsRNA) TLR3 ligand poly-ICLC. 
In preclinical studies poly-ICLC appears to be the most potent TLR adjuvant when compared to 
LPS and CpG due to its induction of pro-inflammatory cytokines and lack of stimulation of IL­
I 0, as well as maintenance of higl1 levels of co-stimulatory molecules in DCĿ. Furthermore, 
poly-lCLC was recently directly compared to CpG in non-human p1imates (rhesus macaques) as 
adjuvant for a protein vaccine consisting of hmnan papillomavims (HPV) I 6 capsomers. Poly­
ICLC was found to be much more efective in inducing HPV specific Thl imnnme responsesll. 
2.3.2.2 
Poly-lCLC - a synthetic TLR3 agouist with strong vaccine adjuvaut properties 
Poly-ICLC is a synthetically prepared double-stranded RNA consisting of poly! and polyC 
strands of average length of about 5000 nucleotides, which has been stabilized to the1mal 
denaturation and hydrolysis by serum nucleases by the addition of polylysine and 
carboxymethylcellulose. The compound activates TLR3 and the RNA helicase-domains of 
MDA5 and RIG3, both members of the PAMP family, leading to DC and natural killer (NK) cell 
activation and production of a "nan1ral mix" of type I inte1ferons, cytokioes, and chemokioes. 
Fm1hennore, poly-ICLC exe11s a more direct, broad host-targeted anti-infectious and possibly 
anti-tumor effect mediated by the two IFN-inducible nuclear enzyme systems, the 2'5' -OAS and 
the Pl/elF2a kinase, also known as the PKR (4-6), as well as RIG-I helicase and MDA5. 
In rodents and non-hU111an primates, poly-lCLC was shown to enhance T cell responses to viral 
antigensŀ, cross-priming, and the induction of truuor-, vims-, and autoantigen-specific cos+
T-censs6-ss. In a recent study in non-human primates, poly-ICLC was f0tmd to be essential for
the generation of antibody responses and T-cell immunity to DC targeted or non-targeted HIV
Gag p24 protein, emphasizing its effectiveness as a vaccine adj11vant.
JO 
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DP/HCC Protocol #:18-279 
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In human subjects, trnnsc1iptional analysis of serial whole blood samples revealed similar gene 
expression profiles among 8 healthy lnunan volunteers receiving one single s.c. administration of 
poly-ICLC and differential expression of up to 212 genes between these 8 subjects versus 4 
subjects receiving placebo!l. Remarkably, compaiison of the poly-ICLC gene expression data to 
previous data from vohmteers immunized with the highly effective yellow fever vaccine 
YF 17Dĥ showed that a large number of transc1iptional and signal transduction canonical 
pathways, including those of the innate inunune system, were similarly upregulated at peak time 
points. 
1\vo studies of poly-ICLC in conjunction with long peptides have been published. An 
illllllunologic analysis was repo11ed on patients with ovarian, fallopian tube, and p1imaiy 
peritoneal cancer in second or thfrd complete clinical remission who were treated on a phase I 
study of subcutaneous vaccination with synthetic overlapping long peptides (OLP) from the 
cancer testis antigen NY-ESO-1 alone or with Montanide-ISA-51, or with 1.4 mg poly-ICLC and 
Montanide. The generation of NY-ESO-1-specific CD4+ and cos+ T-cell and antibody
responses were markedly enhai1ced with the addition of poly-ICLC and Montanide compai·ed to 
OLP alone or OLP and Montanidelll. In a second human sn1dy, poly-ICLC was combined with a 
MUC! synthetic Jong peptide in patients with pre-malignant adenomas. Robust antibody 
responses were detected in nearly half the patients which inversely coffelated with the 
preexisting circulating myeloid de1ived suppressor cell leveJ<"'· 
Poly-ICLC has also been utilized as an adjuvant for imm1mization with minimal epitope-loaded 
patient-de1ived dend1itic cells. Both CD4+ and CD8+ T cell responses to multiple peptides were 
obse,ved in the majority of patients21. 
2.3.2.3 
Pre-clinical toxicology or poly-ICLC 
Complete information on the pre-cli11ical toxicology srudies can be found in the poly-ICLC 
(Hiltonol<I>) Investigator Brochure (IB). The results of these toxicology studies are summarized m 
brief below: 
Single dose toxicitv: 
All administrations of poly-ICLC were intravenous (IV). 
Rodents. The median lethal dose (LDso) values for single dose poly-ICLC were approxilnately 
15-18.3 mg/kg in rats and 25-30 mg/kg in ,nice. No necropsies were conducted.
Dogs. In beagle dogs, the lethal dose of single dose poly-ICLC administration was 4.0 mg/kg.
Necropsy indicated toxic effects in the gastrointestinal, hepatic, cardiovascular, renal, endocrine,
and lymphatic systems. Sublethal doses caused reversible nephrotoxicity and hepatotoxicity. The
non-toxic dose for dogs was 0.25 mg/kg.
Primates. In rhesus monkeys, single-dose administration of poly-ICLC was non-toxic at a dose
of .5 mg/kg, but lethal at 20 mg/kg. Toxic effects were seen in the gastrointestmal, hepatic,
cardiovascular, renal, endocrine, and lymphatic systems.
Repeated dose toxicity: 
Rodents. Mice treated with four daily IV doses of up to 3.66 mg/kg poly-ICLC exhibited no 
toxicity. 
Ca1s. One of two cats treated with the same regimen at 3.33 mg/kg poly-ICLC demonstrated 
JI 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 

vomiting, an episode of dian-hea, and moderate weight loss. 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Non-human Primates. Three rhesus monkeys and 6 macaque monkeys were treated with 5 mg/kg 
IV of poly-ICLC over 2 days and 3 mg/kg 3 times weekly for 16 weeks, respectively; no 
significant toxicity was obse1ved other than a single instance of emesis and shivering. Necropsy 
of the macaques showed no dn1g-related changes by gross or microscopic pathology of all 
organs. In two additional studies, macaque monkeys were treated daily with up to 3 mg/kg IV 
for 12 days and chimpanzees were treated daily with 3 mg/kg IV for two 6-day periods, then 
eve1y other day for a total of 7 weeks. At the 3 mg/kg doses, a decrease in hematoc11t was seen in 
both studies. No change in hematocrit was seen at 0.3 mg/kg. In the chimpanzee study, in 
addition to a decrease in hematoc11t, leukocytosis and elevations in alanine aminotrasferase 
(ALT) and aspa1tate aminotrasferase (AST) were obse1ved and no1malized after te1mination of 
dosing. No other significant toxicity was obseived in these studies. 
2.3.2.4 
Cllolcal toxicology of poly-lCLC 
Poly-ICLC is the TLR3 agonist fonnulation most extensively tested in patients with infectious 
diseases and in subjects with a variety of different tumor types. 
Prior to the availability of recombinant interferon, poly-ICLC was used clinically at high doses 2: 
6mg/m2 (about 170 ftg/kg) in patients with a va1iety of solid tumors and leukemia£!. Fever, often 
above 400C, was a common adverse event and the prima1y dose-limiting factor. Other common 
adverse events were flu-like symptoms (nausea, vomiting, arthralgia. myalgia and fatigue) and 
hypotension, thrombocytopenia and leukopenia. Once recombinant interferon became clinically 
available, the need to pursue high dose poly-ICLC was eliminated, and it became recognized that 
lower doses (IO - 50 µg/kg) were highly effective at stimulating host defense and as an inuuune 
adjuvant. 
By now, more than 400 patients with malignant gliomas have been entered on 7 clinical trials 
using low dose (1-2 mg total dose) poly-lCLC either as monotherapy or in conjunction with 
chemotherapy, radiation, or vaccine (Table 1). Fwthennore, patients with various other solid 
nunors (prostate, colorectal, pancreatic, hepatocellular, breast, and ova1ian cancers), in addition 
to patients with HIV/AIDS and multiple sclerosis have been treated on more than 10 additional 
clinical phase I and phase II sn1dies. Overall, the d11.1g has been well-tolerated across a.II sn1dies 
and spectnun of diseases. The most common adverse events attributed as at least possibly related 
to poly-ICLC have included: 
- bone man-ow toxicity {leukopenia, neutropenia, thrombocytopenia, and anemia) 
- reversible liver toxicity (AST/ALT elevations, LDH and alkaline phosphatase elevation)
-
transient discomfort at the injection site
- transient fatigue/malaise
-
transient flu-like symptoms
In a recently published phase I clinical Ilia!, 11 patients with ovarian, fallopian tube, or p1imaiy 
peritoneal cancer were treated with poly-lCLC at a total dose of 1.4 mg in combination with 
Montanide-ISA-51 and synthetic over-lapping long peptides from NY-ESO-1. The vaccine was 
generally well-tolerated with grade 1-2 injection site reactions and fatigue as the only adverse 
12 
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
events that were considered possibly or definitely drng-related!l!. No grade 3 or 4 adverse events 
were reported. In another clinical study which recently completed accrual (ClinicalTrials.gov 
Identifier NCT01079741) 27 patients with higl1-1isk melanoma received poly-ICLC at a total 
dose of 1.4 mg in addition to NY-ESO-1 protein± Montanide-ISA-51 given s.q. eve1y 3 weeks 
for 4 doses (in addition to 6 patients who received 0.35 mg and 0.70 mg, respectively of poly­
ICLC on coho1is I and 2 of the dose escalation part of the trial). The vaccine was generally well­
tolerated with grade I and 2 injection site reactions and transient 
·ade I or 2, flu-like symptoms 
that resolved after 12-48 hours 
). 
Selected Cllnlcel Trials with Low-Dose PolyZCLC 
Protocol Title 
Phase 
Loug- tem1 IM poly• ICLC in 
1-11
Malismant Glioma -a Pilot Studv 
Poty•ICLC in Recurrent 
1-11
Mali,e,uant Brain Tumors 
Poly-lCLC in Malignant Pediatric 
1-11
Brain Tumo,s 
Poly-JCLC pl\lS Radiation in 
II 
Glioblas.toma 
Poty•ICLC in Recurrent 
II 
Anaplastic Glioma 
Poly-JCLC pl\lS Temodar in 
II 
Newlv Di•rn•osed Glioblastoma 
Pilot Study of !:,;CUC! Vaccine 
plllS poly-JCLC in Advanced 
I-II
Prostate Cancer 
Poly-lCLC plus Dendritic Ce.U 
I-II
vaccine in Recw1·ent Gliomas 
Poly-lCLC plus HSP-HPVE7 
I 
Vaccine in Cenacal Dys-plasia 
ImraTlnnoral (IT) poly•ICLC pltlS 
XRT and TACE in Liver Cancer 
1-11
A Randomized Controlled Phase I 
I 
trial of Nasal Hiltonol 
CDX 130i vaccine wilh poly -
I 
ICLC in metastatic cancers 
Poly- lCLC with gliorua 
1-11
associated peptide vaccine 
MUCI 100-mer and poly-JCLC 
1/11 
Vaccine for Colonic Polyposis 
Hiltonol +NYESOI Protein 
1/IJ 
Vaccine in Ovarian Cancer 
Imranunoral PICLC and DC in 
J/11 
Pancreatic CA 
Protocol Location 
h1dication 
Walter Reed 
Malig nant 
Glioma 
MCV 
Recurrent 
Olioma 
L.A Childrens 
Pediatric 
Ho,-p 
Glioma 
NAB TC 2001-05 
Glioblastoma 
Recurrent 
NABTC 2001 -06 
Anaplastic 
Olioma 
NABTT200S--OI 
OlioblM--toma 
Advanced 
UPMC05·066 
Pro$1ate cancer 
UPMC 
Recurrent 
o:1iowas 
Nventa 
Ceivical 
Dysplasia 
Hepa tom.a, 
żIDNJ 
Metastatic liver 
cancers 
NIAID,NIH: 
Nomial 
volunteers 
Various 
Metastatic 
Cancers 
UPMC 
Grade ll 
Gliomas 
UPMC 
Colonic 
Adeuoma 
MSKCC, 
Ovarian Cancer 
LICR 
MUSC 
Pancreatic 
Cancer 
13 
CONFIDENTIAL 
Status 
N 
Dosing Schedule 
Closed 
67 
IM 10·501g!kg 1·3Xweek 
Closed 
99 
IM 20 µg/kg 
3 Xweek 
Closed 
46 
IM20 µg/kg 
2Xweek 
Closed 
31 
IM 201glkg 
3 Xweek 
IM 20 µg/kg 
Closed 
55 
3Xweek 
Closed 
97 
IM 201glkg 
3Xweek 
IM 25 µg/kg 
Closed 
25 
2Xweek 
Closed 
25 
IM 20 mcglkg 
Closed 
24 
.OS-2mg 
Closed 
24 
I mg IT+ I rug IM 2xweek 
Closed 
50 
0.25-4mg IN 
Closed 
20 
2mg!M 
Closed 
20 
20wcg/kg!M 
2 XWk 
Closed 
45 
.5mg SC 
Closed 
10 
l.4mgSC
Closed 
12 
I mgIT+IM 
This document is confidential. Do not disclose or use except as authorized. 

Selected Cllnlcel Trials with Low-Dose PolyCLC 
lntratumoral PICLC and DC in 
1/11 
Univ. Navarra 
Solid Cancers 
Spain 
Pilot study of iutrattunoral 
1/11 
Mt. Sinai 
and 1M Poly-JCLC 
MC.NY
Poly-lCLC + CDXl401 + FLT3 
1/11 
CITN, 
Ce.Udex 
IMA950 vaccine !Poly-lCLC, 
u. 
1/11 
Oeueva 
Keytruda 
Suist;e 
MAOE A3 + Hiltonol in 
1/11 
Univ. of 
Myelowa 
Maryland 
Rockefell 
DEC205 GAG Protein/ Hiltoool 
II 
e,· 
Univ. 
WT! vaccine/ Hiltonol I 
1/11 
u. 
Basiliximab 
Chic-ago 
ht-Situ, IT Autovacdnation 
1/11 
Mt. Sinai 
Hiltonol, FLT3, aPDI 
MC,NY 
In Situ Autovaccination vdth IT 
II 
Multicemer 
Hiltonol, 
OAPV AC Trial, Europe 
I 
Multicemer 
A Personalized Cancer 
Neoantige,1 vaccine+ Poly-ICLC, 
1/11 
MiĖticemer 
Nivolwuab 
In situ vaccination with 
UVA, 
durvahuuab z trerneli.t1um1ab 
1/11 
+ IT Hiltonol
!SM!,;IS
Pembrolizumab and poly-lCLC 
1/11 
Augm,1a 
u. 
IM Poly-lCLC in Low grade 
UCSD, 
1/11 
Glioma 
EmoryU 
IMHiltonol + aPDI/Ll 
II 
Multicemer 
2.3.3 
Montanlde IS-51 VG 
Solid Cancers 
Closed 
Solid Cancers 
Closed 
Melanoma 
Closed 
Glioblastoma 
Open 
Myeloma 
Closed 
HIV vaccine 
Closed 
AM Leukemia 
Closed 
Lymphoma 
Open 
Solid Tumors 
Open 
OlioblM--toma 
Closed 
Solid Cancers 
Open 
Solid cancers 
Open 
Colon Cancer 
Open 
Pediatric Low 
Grade 
Closed 
Olioma 
Solid cancers 
Open 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
15 
I mg IT 
8 
I mgIT+IM 
60 
I mgIT+IM 
20 
I mg!M 
27 
I mg SC 
40 
1.5 mg SC 
7 
I mg SC 
40 
I mg 
60 
I mgIT+IM 
16 
I mg SC 
90 
2mgSC 
36 
1 mg IT 
45 
I mg IT 
23 
20wcg/kglM 
60 
I mg2Xwk 
Montanide ISA-51 VG {Seppic, Inc.) is a commercially available, mineral oil-based immune 
adjuvant analogous to incomplete Fre\llld' s adjuvant (IF A) that enhances the inumme response to 
vaccination through various mechanisms. The depot effect of this water in oil emulsion results in 
slow release of the antigen from the injection site. The emulsion also protects the antigen from 
rapid degradation by enzymes, and can modify the elecllic charge of the antigen leading to 
enhanced inummogenici¤2. In addition, the emulsion can create inflammation and stimulate the 
recrnitment and possible activation of antigen presenting cells (APC) and even facilitate antigen 
uptake by APCs through interactions between the surfactant and cellular membranes. 
Lymphocyte trapping in draining lymph nodes is an additional mechanism of action of oil 
adjuvants conllibuting to prolonged cell-cell interactions in the lymph node. (Seppic Inc., data, 
14 
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
manufacturer of Montanide). Montanide ISA-51 VG must be mixed in a 1:1 ratio with aqueous 
vacciue preparation to form an emulsion for subcutaneous injection. The compound can be 
administered in repeat doses ranging from 0.5 ml to 2 ml.62 
Montanide has been tested in more than 200 clinical phase 1 - 3 c.aucer vaccine ttials targeting 
melanoma and a number of other solid and hematologic malignancies. The compound has been 
generally well tolerated and induces transient local reactions such as tendemess, erythema, or 
edema at the injection site. Transient general reactions including fever, headache, and flu-like 
symptoms have also been observed. A clinical study of long peptides (-20-mer) derived from the 
HPV-16 E6 and E7 viral oncoprotei.IIS administered in Montanide showed clinical respo11Ses in 
women with vulvar intraepithelial neoplasia; rumor regressions were associated with the 
generation ofHPV-specific, IFN-y-producing CD4+ and CDS+ T cells15.16. 
Montanide-ISA-51 ill combination with poly-ICLC and synthetic over-lappi11g long peptides 
from NY-ESO-1 has been admiI1istered to 11 patients with ovarian, fallopian tube, or primary 
peritoneal cancer ill a phase I clinical trial. This vacciI1e was generally well-tolerated with grade 
1-2 injection site reactio11S and fatigue as the only adverse events that were co11Sidered possibly
or definitely drug-related18. No grade 3 or 4 adverse events were repo1ted. In another clinical
ttial (Clinica!T1ials.gov Identifier NCT01079741} 19 patients with high-risk melanoma received
Moutanide -ISA-51 combined with poly-ICLC and NY-ESO-1 protein given s.q. eve,y 3 weeks
for 4 doses. Toe vaccille was generally well-tolerated with grade 1 and 2 injection site reactions
and trarisient, grade 1 or 2, flu-like symptoms that resolved after 12-48 hoursfil.
2.3.4 
lplllmumab 
Ipilimumab (BMS-734016, MDX0l0, MDX-CTLA4) is a fully humanized monoclonal 
illllllunoglobulin (lg) Gb: specific for human cytotoxic T lymphocyte antigen 4 (CTLA-4, 
CDl52), which is expressed on a subset of activated T cells. CTLA-4 is a negative regulator ofT 
cell activity. Ipilimumab is a monoclonal antibody that biI1ds to CTLA-4 and blocks the 
iI1teraction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to 
augment T cell activation and proliferation, includiI1g the activation and proliferation of tumor 
iilfiltratiI1g T-effector cells. Inhibition of CTLA-4 signalillg can also reduce T-regulato1y cell 
function, which may contribute to a general increase in T cell responsiveness, including the anti­
tumor response. 
Ye1voy TM (lpililnumab) has been approved for use in over 4 7 countries illcludillg the United 
States (US, Mar-2011}, the European Union (EU, Jul-2011} and Australia (Jul-2011}. 
2.3.4.1 
Preclinical Toxicology oflplllmumab 
Complete information on the pre-clinical toxicology studies can be founcl In the Iplllmumab 
Investigator Brochure (ID}. The results of these toxicology studies are summarized in brief 
below. 
Ipilimumab binds to human and cynomologous monkey CTLA-4 with high affinity and blocks 
bindillg of CD80 (B7.l) and CD86 (B7.2) to CTLA-4. The proposed mechanism of action for 
lpilimumab is interference of the interaction of CTLA-4 with its natural ligands, CD80/CD86, 
expressed on antigen presentiI1g cells, which results in blockade of the inhibito1y modulation for 
15 
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
T cell activation. CTLA-4 blockade by lpilimumab resulted in augmentation of antibody 
responses to various T cell dependent antigens and suppression of tmnor growth in mice. 
The cynomologous monkey was selected as the primary toxicology species because lpilinmmab 
binds specific.ally to macaque CTLA-4, but not to homologous CTLA-4 in other traditional 
toxicology specieČ. Administration of lpilimmnab to cynomologous monkeys resulted in 
marked enhancement of the immune response to a viral antigen (hepatitis B surface antigen), a 
cell-based vaccine (SK-mel) and to keyhole limpet hemocyanin. 
In IV repeat-dose toxicology studies in monkeys, Ipilimumab was tolerated without adverse 
effects at doses up to 30 mg/kg/day administered every 3 days for 3 doses (peak serum 
concentrations S 682 č•g/mL)65-67 at 10 mg/kg (equivalent to hmnan dose on a body-weight basis) 
administered weekly for 1 month68 (mean area under the concentration-time cmve 0-168h) and 
AUC (0-63days) of 31.6 mg·h/mL and 90.6 mg·h/mL respectively), at 1 mg/kg administered 
weekly for 10 weeks69 and at doses up to 10 mg/kg/day administered approximately monthly for 
up to 6 months6668 7o,n In the pivotal 6-month toxicity study (10 mg/kg administered on days 
0,28,56,84 and 140), treatment-related fmdings were linlited to decreases in absolute and relative 
thyroid (44% to 50%) and testicular (27% to 50%) weights. 
In an explorato1y pha1macology study, severe colitis occu!l'ed after the second dose in 1 of 5 
monkeys receiving Ipilimmnab at 10 mg/kg approximately monthly in combination with 3 
vaccines. The binding of Ipilimumab to CTLA-4 expressed on gut-associated lymphoid tissue 
was confamed in human and monkey tissue-binding studies64 n,73 and suggests that these
lymphocytes exist in an activated state, making them susceptible to CTLA-4 blockade. Two 
gastrointestinal toxicities ( dianhea and colitis) have emerged as significant inllllune related 
adverse events in the clinical studies with Ipilimmnab (See 2.4.2.2 below) 
The effects oflpilimlUllab on reproduction and development were studied in an enhanced pre and 
postnatal development study in cynomologous monkeysĎ. Pregnant monkeys received 
lpilimumab eve1y 21 days from the onset of organogenesis through partmition at doses of2.6 or 
7.2 times the clinical exposure at a dose of 3 mg/kg or 0.9 to 2.1 times higher than the clinical 
exposure at a dose of 10 mg.kg eve1y 21 days of Ipilimumab. Beginning in the third trimester, 
the Ipilimmuab groups experienced increased maternal weight decrements; higher incidences of 
abortion, stillbirth, prematm·e delivery and higher incidences of infant mo11ality in a dose-related 
manner. Infants exposed to 30 mg/kg/q3w had a lower mean body weight at bil1h that persisted 
for multiple months. Based on the results for the monkey reproductive system, Ipililumnab is not 
recommended for use during pregnancy unless the potential benefit justifies the potential risk to 
the fetus. 
In summa1y, other than the events desc1ibed above, lpilimumab did not result in any adverse 
toxicities in any other monkeys in general toxicity studies when adnlinistered IV at doses up to 
30 mg/kg for 1 week, 10 mg/kg weekly for 1 month, 1 mg/kg weekly for 10 weeks, or 10 mg/kg 
monthly for 6 months. 
16 
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2.3.4.2 
Clinical Toxicology of lplllmumab 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Except for pediatric patients, all the clinical studies reported in the Investigator Brochure utilized 
Ipilimumab delivered intravenously at doses of 3 mg/kg to IO mg/kg, usually q3weeks X 4. As 
desc1ibed in Section 6.1.3, the staiting dose level utilized in this protocol results in 
approximately one thirtieth (1/30) the exposure compared to the 3 mg/kg i.v. dosing. Thus, the 
safety events obse1ved with Ipilimumab delivered intravenously may be significantly greater 
than following limited local delive1y, a hypothesis of this study. 
Complete infonnation on the clinical safety of lpilimumab delivered intravenously at doses of 3 
mg/kg and IO mg/kg can be found in the Ipilimrnnab Investigator Brochure (IB) and are 
sununaiized in brief below. 
Blockade of CTLA-4 by Ipilimumab leads to T cell activation with the potential for clinical 
inflammatory AEs primarily involving the skin (dennatitis, pruritis), GI tract (diai1hea/colitis), 
liver (hepatitis), endocrine glands (e.g., hypophysitis, adrenal and thyroid abnormalities) and 
other less frequent orga!IS (e.g., uveitis/episcleritis). The majority of the infla111111ato1y AEs are 
reversible with the guidance issued below. In rare cases, these inflammato1y AEs may be fatal. 
Patients should be assessed for signs and symptoms of enterocolitis, dennatitis, neuropathy and 
endocrinopathy, and clinical chemistlies (including liver fonction and thyroid ftmction tests) 
should be evaluated at baseline and before each dose oflpilimumab. GI (dian-hea and colitis) and 
skin (rash and pruritis)-related toxicities are the most common inflammato1y events reported in 
studies with Ipilimrnuab. Suggested evaluation procedures for suspected GI, liver, skin, 
endocrine, neurological and ocular toxicities are described below. Early diagnosis and treatment 
intervention for inflammatory events can help prevent the occrn1·ence of complications, such as 
GI perforation. 
During evaluation of a suspected inflammatory AE, all efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin or other etiologic causes. Serological, in1munological, 
imaging, a11d biopsy with histology (e.g. biopsy-proven lymphocytic) data should be used to 
support the diagnosis of an immune-mediated toxicity or support an alternative cause of the AE. 
In general, for severe inflammatory AEs, Ipilimumab should be pennanently discontinued and 
systemic high-dose corticosteroid therapy should be initiated. For moderate i.nnmme-mediated 
AEs, Ipilimumab should be held or delayed and moderate dose corticosteroids should be 
considered. Upon improvement, co11icosteroids should be tapered gradually over at least I 
month. 
Based on limited cm1ent clinical experience, co1ticosteroids do not appear to adversely affect the 
antittunor response. For exainple, disease control was maintained in subjects with objective 
responses who received co1ticosteroid administration for concomitant se1ious inflaiumato1y AEs. 
The management guidelines for general inflammato1y GI, liver, skin, endocrine, and 
neurological toxicities are provided in detail in Appendix 3 of the Investigators Brochure. 
17 
CONFIDENTIAL 
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DP/HCC Protocol #:18-279 
Versioll 8.0 / November 20, 2023 
2.3.4.3 
Clinical Toxicology oflplllmumab in combination with a peptide vaccine 
A number of clinical trials have evaluated the combination of systemic Ipilinuunab with a variety 
of different vaccines, including peptide vaccines as outlined in the table below. In all cases, no 
qualitatively or quantitatively different toxicities were obse,ved other than those typically 
obse1ved with Ipilimumab alone. 
Vaccine 
Dose and schedule 
Reference 
3 mg/kg lpilimtunab: iv: q3weeks 
2010: Hodi et aJll 
gp I 00 peptide vaccine 
I mg peptide: sc: 
q3weeks (2 peptides) 
GM-CSP transdnced allogelleic prostate 
0.3 - 5 mg/kg lpilimumab; iv; q4weeks 
2012; Van den 
cancer cells (GV AX- prostate) 
GV AX-nrostate id; q2weeks for 24 weeks 
Eertwegh et aJZ§ 
Prostate-specific antigen and three co-
I - 10 mg/kg lpilimumab; iv; q4weeks 
2012; Madan et aJlZ 
stimulato1y molecules (CD58, CDS0 and 
Prostvac; sc; q4weeks 
!CAMI) in a nnxviral vector (Prostvac)
GM-CSP transdnced allogelleic pancreatic 
IO mg.kg lpilimumab: iv: q3weeks 
2013: Le et aJZll. 
dnctal ade!locarcilloma cells (GVAX-
GV AX-pancreatic: id; q3weeks 
pancreatic) 
3 or 10 mg/kg lpilimumab: iv' q6-8weeks 
2011: Samaik et aJ.li 
gp!00, MART-I and Tyrosinase peptide 
I mg each peptide: sc: q2weeks x6 then 
vaccine 
less frequently 
2.3.4.4 
Clinical Efficacy oflpilimumab as Mouotb,rapy in Advnoc,d M,lanoma 
In a large, double-blind, double-dwnmy randomized phase 3 study involving 676 patients, 
Ipilimumab was delivered at 3 mg/kg in patients who had received 1 or more prior therapies. 
Patients were randomized (3: I: I) to receive Ipilimwnab in combination with a peptide vaccine, 
Ipilimumab alone or the peptide vaccine alone. All patients were HLA A *02:0 l. Overall stnvival 
was compared in the Ipilimumab + vaccine arm vs the vaccine-alone arm. Treatment with 
Ipilimumab +vaccine resulted in a 32% reduction of risk of death (HR 0.68; 95% CI 0.55-0.85) 
versus vaccine alone (p = 0.0004). There was no apparent difference between the Ipilimmuab + 
vaccine arm compared to Ipilimrnnab alone (HR 1.04; 95% CI 0.83-1.30). The median survival 
of patients on the Ipilimumab + vaccine anu was improved by 4 months (10 months vs 6 
months). 
One of the hallmarks of Ipilimumab efficacy is long-te1m survival. A large meta-analysis of 
1861 advanced melanoma subjects treated with Ipilinuunab as patt of clinical trials demonstrated 
a plateau in OS Kaplan-Meier curve at Year 3, which remained flat through Year 108....Q. 
2.3.5 
Nivolumab 
Nivolumab (also refe1Ted to as BMS-936558 or MDX-1106) is a fully human monoclonal 
illllllunoglobulin G4 (IgG4-S228P) antibody that targets the progranuued death-1 (PD-1, cluster 
of differentiation 279 [CD279]) cell stu-face membrane receptor. PD-1 is a negative regulatory 
molecule expressed by activated T and B lymphocytes. l Binding of PD-1 to its ligands, 
programmed death-ligand I (PD-LI) and 2 (PD-L2), results i.!1 the down-regulation of 
lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes 
itmnune responses and antigen-specific T-cell responses to both foreign antigens as well as self-
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
antigens. Nivolumab is expressed in Chinese hamster ova1y (CHO) cells and is produced using 
standard mammalian cell cultivation and chromatographic pmification technologies. The clinical 
study product is a ste1ile solution for parenteral administration. 
2.3.5.1 
Preclinic,,J Toxicology of J\ivolumab 
Complete Information on the pre-clinical toxicology studies can be found In the Nlvolumab 
Investigator Brochure (ID). The results of these toxicology studies are summuizecl in brief 
below: 
Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to related 
members of the CD28 family such as CD28, inducible co-stimulator (ICOS), cytotoxic T­
lymphocyte antigen 4 (CTLA-4) and B and T lymphocyte attem1a.tor (BTLA). Nivolumab 
inhibits the interaction of PD-I with its ligands, PD-LI and PD-L2, resulting in enhanced T-cell 
proliferation and interferon-gamma (IFN-y) production in vitro. Fluorescent-activated cell sorter 
(F ACS) analysis confnmed that Nivolumab could bind to transfected CHO and activated human 
T-cells expressing cell surface PD-I and to cynomolgous monkey PD-I, but not to rat or rabbit
PD-I molecules. Nivoltl!llab has also been shown to bind to PD-I on vims-specific CD8+T-cells
from chronically infected hepatitis C virns (HCV) patients. PD-I inhibition in a mixed
lymphocyte reaction (MLR) resulted in a reproducible concentration dependent enhancement of
IFN-y release in the MLR up to 50 ftg/mL. No effect was observed with a human lgG4 isotype
control or CD4+ T-cells and dendritic cell (DC) controls.
The potential ofNivolumab to react with non-target tissues was investigated with cryosections of 
nonnal hmnan tissues. Nivolumab demonstrated reactivity with rare to occasional lymphocytes 
in the majority of tissues at both concentrations. At a concentration of 1 11glmL, there was no 
unexpected binding in any tissue. At a concentration of 10 ftg/mL, there was moderate to strong 
cytoplasmic staining of rare to occasional endocrine cells in the adenohypophysis ( < 25% of the 
endocrine cells). The staining of these endoc1ine cells is considered to be an unexpected cross 
reactivity because expression of PD-I has not been reported in this cell type. In addition, the 
binding can be reduced by the addition of PD-I to the assay and binding to these cells is not seen 
with a commercial anti-PD-I antibody. Although this reactivity is not expected, it is unlikely to 
result in physiological effects due to the limited exposure of cytoplasmic compa11ments to 
Nivolumab in humans. Sintilar staining pattems were observed in cynomolgus monkey tissues 
indicating that this is an appropriate animal species to evaluate the potential toxicities of 
Nivolumab. 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, Nivolrnnab was well 
tolerated at doses up to 50 mg/kg administered weekly for 5 weeks and at doses up to 50 mg/kg, 
administered twice weekly (Q2W) for 27 doses. Drng-related findings were limited to a 
reversible decrease of 28% in tJiiodothyronine (T3) among the females administered 27 doses of 
50 mg/kg. No conesponding changes in the level ofthyroxin (T4), thy
roid stimulating ho1mone
(TSH), or histologic changes in the thyroid were observed. There were no clinical signs of 
toxicity or effects on body weight, food consumption, blood pressure, hea1t rate, respiration rate, 
ophthalmic and electrocardiographic parameters, or clinical or anatomic pathology related to the 
administration ofNivolumab. 
No drng-related findings were observed in standard clinical evaluations of cardiovascular, 
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DP/HCC Protocol #:18-279 
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respirato1y, and neurologic fimction conducted in cynomolgus monkeys as pa1t of the repeat dose 
toxicity studies for up to 3 months with Nivolmnab. In addition, the potential cardiovascular 
effect of Nivolumab when administered as a single IV dose was examined in conscious 
cynomolgus monkeys. The single IV bolus administration ofNivolumab at doses of 10 mg/kg or 
50 mg/kg was well tolerated. There were no effects on clinical signs, body weights, body 
temperatures, mean arterial blood pressures, electrocardiograms or cardiovascular parameters 
during the study. 
While Nivolumab alone was well tolerated in cynomolgus monkeys, combination studies have 
highlighted the potential for enhanced toxicity when combined with another inummostimulatory 
agent 
2.3.5.2 
Clinical Toxicology ofNlvolurnab 
Tue overall safety experience with Nivolmnab, as a monotherapy or in combination with other 
therapeutics, is based on expe1ience in approximately 1500 subjects treated to date. In general, 
for monotherapy, the safety profile is similar across tmnor types. l11e one exception is 
pulmonary inflaIWnation AEs which may be nume1ically greater in subjects with NSCLC 
because in some cases it can be difficult to distinguish between Nivolumab-related and umelated 
causes of pulmonary symptoms and radiographic changes. Tue safety profile is generally 
consistent across completed and ongoing clinical 11-i.als with no MID reached at any dose tested 
up to IO mg/kg. There was no pattem in the incidence, severity, or causality of AEs to 
Nivolumab dose level. Most AEs were low-grade (Grade l to Grade 2) with relatively few 
related high-grade (Grade 3 to Grade 4) AEs. Most high-grade events were manageable with use 
of co1ticosteroids or honnone replacement therapy (endoc1inopatbies). Nivoltlillab should not be 
used in subjects with active autoimmune disease given the mechanism of action of the antibody. 
A total of 306 subjects with selected recunent or treatment-refractory malignancies have been 
treated in an ongoing, Phase I multi-dose study (NCT00730639), respectively.IQ. There was no 
pattem in the incidence, seve1ity, or causality of AEs related to the dose ofNivolumab, between 
1 and 10 mg/kg, in MDXI 106-03. Of the 306 treated subjects in MDXI 106-03, 303 (99.0%) 
subjects have at least 1 repo1ted AE regardless of causality. Tue most frequently repo1ted AEs 
were fatigue (54.9%), decreased appetite (35.0%), dianhea (34.3%), nausea (30.1%), and cough 
(29.4%). Treallnent-related AEs were reported in 230 (75.2%) of the 306 subjects. The most 
frequently repo1ted treatment-related AEs were fatigue (28. 1 %), rash (14.7%), dian-hea (13.4%), 
and pmritus (10.5%). Most treallnent-related AEs were low grade. Treallnent-related high grade 
(Grade 3-4) AEs were reported in 52 (17.0%) of subjects. Tue most frequently reported 
n·eatrnent-related high-grade AE was fatigue (6.5%). 
2.3.5.3 
Clinical Toxicology of Nlvolumab In combination with a peptide vac.clne 
In a phase I trial (NCT0ll 76474), 49 HLA-A02:0l positive patients received Nivolmnab at 
doses of l mg/kg, 3 mg/kg, and 10 mg/kg in combination with a 4-peptide vaccine consisting of 
gpl00209.211 (2101\1), gpl00280.288 (288V), MART-12c;.35 ( 27L), and NY-ESO-1157.165 (165V) 
emulsified in Montanide ISA 51 VGfil. One patient who received Nivolmnab at 3 mg/kg 
expe1ienced dose-limiting toxicity (grade-3 bilateral optic neuritis), which resolved with a 60-mg 
prednisone taper over 4 weeks and topical c01ticosteroids. Two other patients discontinued 
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treatment seconda1y to toxicity beyond the DLI period of 12 weeks: One patient receiving 
Nivolmnab at l mg/kg had grade-3 fevers in cycle 2 that required 4 weeks of a prednisone taper 
from 60 mg for resolution, and one patient receiving Nivolumab a.t l 0 mg/kg had grade-3 
pneumonitis after completion of two cycles of therapy requiring a prednisone taper from 120 mg 
over 2 months for resolution. No dose-limiting imnume-related colitis was seen in the study. The 
rates or severity of AEs in this trial were not different from those seen in trials with Nivolumab 
alone (such as MDX-1106-03, [NCT00730639]), although the nmuber of patients is smaller. 
2.3.5.4 
Cllolcal Efficacy orNlvolumab as Mouotlterapy In Melanoma 
In a large phase I study (NCT00730639), the clinical activity of Nivollllllab was demonstrated in 
a va1iety of tumor types and across a range of doses (0. l mg/kg, 0.3 mg/kg, I mg/kg, 3 mg/kg, 
IO mg/kg).L!!. As of the clinical cut-off date of 05-Mar-2013, a total of 306 subjects with 
melanoma, RCC, and NSCLC have been treated with Nivoltrmab. All subjects initiated treatment 
at least one year p1ior to analysis. A response of either CR or PR, as determined by investigator 
assessed tmnor evaluations based on modified RECIST 1.0, bas been repo1ted at all dose levels. 
Among 107 patients with advanced melanoma who received Nivolumab, the prelimina1y 
objective response rate was 33/I07 (31 %) Responses occmTed at each dose level, with 6/17 
(35%), 5/18 (28%), 11/35 (31%), 7/17 (41%), and 4/20 (20%) melanoma subjects responding at 
0.1, 0.3, 1, 3, and 10 mg/kg, respectively. Duration of response range from 24.1 to 48.7+, 18.4 to 
66.3+, 32.4 to 108.l+, 40.l+ to 115.4+, and 73.9 to 117.0+ months in melanoma subjects treated 
at 0.1, 0.3, 1, 3, and 10 mg/kg, respectively. An additional 7% of melanoma subjects had stable 
disease for 24 weeks or longer. Across dose levels, melanoma subjects achieved a median overall 
smviva.l of 16.8 months (95% CI: 12.5, 31.6), with a 2-year overall stuvival rate of 43%. 
Nivolmnab demonstrated improved overall survival in patients with advanced melanoma when 
compared to IpilimU1Uab and chemotherapy, respectively _.22,si 
Nivolmnab was approved by the FDA for adjuvant ti-eatment of patients with melanoma who 
have undergone complete resection but are at high 1isk of recmTence based on involvement of 
regional lymph nodes or metastatic disease. The CbeckMate 238 study compared nivolumab 3 
mg/kg with ipilimumab JO mg/kg as a.djt1vant treatment for patients with high-risk resected stage 
IIIB-C or stage IV melanoma100. At a median follow-up of 19·5 months, nivolumab
demonstrated longer rectll1'ence-free survival than did ipilimumab (HR for disease rectuTence or 
death 0·65; 97·56% CI 0·51--0·83; p<0·00l), with 12-month recmTence-free smvival of 70·5% 
(95% CI 66· l -74·5) in the nivolumab group versus 60·8% (56·o-65·2) in the ipilimumab group 
(3-year rectuTence-free survival was subsequently repo1ted at 58% vs 45%, respectively).
Treatment discontinuation due to treatment-related adverse events was reported in 3 5 (7 • 7%) of 
452 patients who received nivolumab compared with 189 (41 ·7%) of 453 patients who received 
ipilimumab. At a mininurm follow-up of 4 years, nivolumab demonstrated sustained recurrence­
free survival benefit versus ipili.Jmunab i.J1 resected stage illB-C or IV melanoma 1°1.
2.4 
Rationale 
2.4.1 
Melanoma Is responsive to lmmunotberapy 
Multiple imnrnnotherapeutic approaches including cytokines such as interleu.kin-2 and 
i.J1terferon-alpha, vacci.J1es, adoptive T cell therapy and inhibition of i.Jmnune cbeckpoi.J1ts 
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(CTLA-4 and PD-I/PD-LI) have shown anti-tumor activity in melanoma. Several immime­
modulating therapies have been approved including interleukin-2, interferon-alpha, the anti­
CTLA-4 monoclonal antibody IpilimumaŤ, and the anti-PDl monoclonal antibodies 
Pembrolizumab and Nivolumab. The combination of Nivolumab and Ipilimumab is also 
approved by the FDAť. 
Despite the encouraging activity and relative safety of imnume checkpoint blockade, many 
advanced melanoma patients lack responses or do not respond robustly to CTLA-4 or PD-1/PD­
Ll inhibition. The objective tmuor response rates seen in patients with advanced melanoma 
treated with concuITent Ipilimumab and Nivolumab st1ggest that significant improvements are 
achievablŦ, but this regimen is associated with significant illllllune-related toxicities. For 
resected stage III or IV melanoma, treatment with nivolmnab bas demonstrated i.Iuproved 
rectUTence-free stnvival over ipilimumab, however a substantial proportion of patients still 
experience recmTences. Alternative methods to Improve the anti-tumor activity of 
NIYolumab without Increasing toxicity are therefore highly desirable. 
2.4.2 
Checkpoint blockade may be limited by size and specificity of the existing T ceU population 
Anti-CTLA-4 and anti-PD-I/LI di.I'ected therapy alone may help relieve local inumme 
suppression and overcome I-cell exhaustion or anergy, but may be constrained by the size and 
specificity of the existi11g T cell population - T cells arising from the normal physiological 
presentation of the evolving tumor to the host inunune system. The lack of coincident, focused 
ilmnune stimulation may thus be a critical factor that is limitiI1g the maximal efficacy of 
checkpoint inhibition therapy - a deficit that may be overcome by an effective vaccine. Indeed, in 
many animal studies, including the studies suppo1tiI1g the initial development of Ipilimmnab, the 
effect of CTLA4 illhibition alone was dramatically enhanced when combined with a vaccineŧ 
and this improvement has been obse1ved or suggested in several hmnan studies78 88 89. In 
addition, recent precliI1ical studies in mice have demonstrated the improved efficacy of anti-PD I 
treatment in combination with a vaccine90.
2.4.3 
NeoVax is a novel personalized cancer vaccine utilizing the exquisitely tu.mor-specific neonnfigens 
created by the pe.-sonal mutations found in each patient's tumor= 
While novel, potent illlllltmotberapies such as checkpoint inhibitors mlleasb T cell killing in a wide 
variety of cancers, their efficacy is thot1ght to rely upon amplification and reinvigoration of a pre­
e.xisti11g T cell infiltrate that recognizes tumor neoantigens9>-95. Thus, resistance to these therapies 
may be driven by a lack of T cells that recognize tumor neoantigens. A c.ancer neoantigen vacciI1e 
offers the possibility of i11d11ci11g novel tumor neoantigen-specific T cell responses as well as 
expanding pre-existing ones; and tints, iinproviI1g outcomes for patients who may have not have 
benefited from other inummotherapeutic approaches. 
As described iii 2.3, over the last several years, we at DFCI have developed a computational 
infrastrncture and conceptual framework for tnmslating sequencing information iI1to a therapeutic 
vaccine. Cunently, two Phase I studies exammiI1g tl1e safety, feasibility and preli.Inina1y efficacy 
of Neo Vax (Neoantigen peptides plus Hiltonol) are approved and accrning patients at the Dana­
Farber Cancer Institute. DFHCC 13-240 and 14-362 both study NeoVax iii the adjuvam setting 
of surgically resectable, advanced melanoma or after adjuvant radiotherapy for resectable 
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glioblastoma multifo1me, respectively. 
DP/HCC Protocol #:18-279 
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2.4.4 
NeoVax is immunogenic iu melanoma and can be effectively combined with anti-PD-I therapy li
On the melanoma tiial, we enrolled 12 patients, 8 of whom completed dosing. We have focused 
our testing of the induction of neoantigen-specific responses on 6 patients with available samples 
at the time of data cutoff in March of 2016. Across all 6 subjects, we unifo1mly identified strong, 
polyfonctional CD4+ a.nd CDS+ T cell responses against multiple neoepitopes. Four of 6 patients 
remain free of disease while 2 progressed. The 2 patients who progressed were subsequently 
treated with the anti-PD-I antibody Pembrolizumab and both achieved a complete radiographic 
response (CR) after 4 doses of Pembrolizumab which are ongoing, now for> 22 months (CR rate 
of Pembrolizumab as first-line treatment for meta.static melanoma only 6% 97. In both patients, 
we detected persistence and broadening of neoantigen-reactive T cell responses that wet·e 
Induced by vaccination and then following CPB, conslGtent with epltope spreading. In the 
first patient, we detected CD4+ T cell responses against 25 of 49 assay peptides (with 4 novel 
responses) and CDS+ T cell responses against 2 of 18 predicted class I epitope peptides. 
Sinlilarly, for the second patient, CD4+ T cell responses were detected against 15 of 61 assay 
peptides (with 2 novel responses) a.nd CDS+ T cell responses against 4 of 32 class I epitope 
peptides (with 2 novel responses) 96. These data suppo11 the hypothesis that vaccination with 
neoantigens can both expand pre-existing neoantigen-specific T cell populations and induce 
a broader repertoire of new T cell specificities In cancer 1>atlents. 
2.5 
Hypothesis 
We hypothesize that combining the immtme stinmlating effects of this neoa.ntigen-targeted 
vaccine (NeoVax + Montailide® ISA-51 VG) with enhanced priming through the addition of 
locaJly administered Ipili.Jmunab and the relief of immune suppression by systemically 
admi.Jlistered Nivolumab will be safe and will enhance the anti-n1mor activity of monotherapy 
with nivoltunab. We propose that this effect occurs by qualitatively broadening the repertoire of 
T cell targets as well as strengthening the activity of extant and newly-induced neoantigen­
specific T cells, both pai·ameters that can be accurately monitored. 
2.6 
Conelatlve Studies Background 
2.6.1 
Testing the inummogeniciry ofNeoVax
In our first tiial in patients at high risk for recunence, testing has focused on the induction of 
neoantigen-specific responses on the 6 patients enrolled in that study. Per protocol, PBMCs for 
the melanoma study were collected by leukapheresis (pre-vaccination and at week 16 [4 weeks 
after 1st boost]), and by monthly venipm1cture for the dmation of the study. Across all 6 
melanoma subjects, we have unifomlly identified strong, polyfunctional CD4+ and CD8+ T cell 
responses agai.J1st multiple neoepitopes. 
As shown in 2 representative examples (Figure 1, Panel A), we have obse1ved high ex vivo 
responses in PBMCs across multiple peptide pools of overlapping l 5-l 6mers cotTespondi.J1g to 
the pools of immunizing SLPs. By deconvolution of the peptide pools, we have identified CD4+ 
and CDS+ T cell responses against 18% (19 of 103) of the inuntmizing peptides and 19% (16 of 
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DF/HCC Protocol #:18-279 
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83) predicted epitopes, respectively. The vast majority of T cell lines were specific for the
mutated but uot cones nding wildt e (Panel B, Fi¨1u-e below).
0 
;t 8 12 t6 20 2, 
Ill 
I 
I 
Pnrne 
Boost 
Weeks followin vax 
8 
CD4 
COB 
-
{]PS16 
•• CIT 
 
1 
MUT 
o O 
0) 
 24 
02 
f2 
01 
U .,. 
WT 
Q. 0 
LMN 
VJ -
o ,o210• 1tfl 
. .  o .o2, ,oe 
pg/ml
pg/ml 
C 
COS+ neoant,,g81Hpeclt'ic T cells+ 
Aulok>gous 
tumor 
Autologous lumor + 
dass rblocklng al> 
Irrelevant tumor 
PHA 
Figure 1: Detection of immune responses to ueoeptopes folloniog 
NtoVax ror lDt'lanoma patients. 
A. Ex vivo analysis of PBMCs against pools of peptides (A. B, C, D) 
encompassing the SLPs forou1 lating the personal vacdoes across the 
duration of vaccine delivery. B. Deconvolution against peptide pool 
responses 
reveals 
reactiviry 
against 
specific 
u1nated but 
not 
corresponding wild type epitopes. C. For s0011? neoantigen•specific T cells. 
reactivity is directed against autologous tmmrbut not irrelevant tu(JX)r. 
2.6.2 
Sample collection for co1Telative studies
Peripheral blood as well as tumor and vaccllle site biopsy sample collection includes 
procurement of: 
(i) Peripheral blood mononuclear cells (PBMCs): Leukapheresis samples will be obtained from
study subjects prior to initiation ofNivolumab (LI), prior to initiation of vaccination (L2) and
after the 3,d vaccine at week 20 (L3). PBMCs will also be obtained by venipuncture on weeks 4,
13, 15, 18, 24 and eve1y 4 weeks thereafter until disease progression.
(ii) Tumor samples will be obtained from study subjects with unresectable melanoma prior to
initiation of Nivolumab (BI), prior to initiation of vaccination (B2), after the 3'd vaccine at week
20 (B3), and at the time of progression (B4). B2 and B3 biopsies will be perfonned provided that
biopsiable disease is present.
(iii) Vaccine site biopsies will be obtained within 24 hours prior to the 3,d vaccine. One of the 2
vaccines sites will be biopsied as per investigator discretion.
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DP/HCC Protocol #:18-279 
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3. PARTICIPANT SELECTION
3.1 
Eligibility C1iteria 
Eligibility to paiiicipate will be assessed at two timepoints: prior to initial core needle/surgical 
biopsy (Initial Registration) and prior to the first vaccination (Secondary Registration). 
3.1.1 
Inrlnslon CJ·lterla 
3.1.1.l 
3.1.1.2 
3.1.1.3 
3.1.1.4 
3.1.1.5 
3.1.1.6 
Pa11icipant is willing and able to give w1itten info1med consent 
Pa1iicipants must have histologically confirmed stage IIIB/C/D or stage IV cutaneous 
melanoma (mucosa! melanoma or uveal melanoma are excluded) tha.t is surgically 
resected, is deemed surgically resectable, or is unresectable; rumor tissue for 
sequence analysis must be available from either previous melanoma resection/biopsy 
or at least one site of disease must be amenable to surgical or core biopsy 
Age 2:: 18 years 
ECOG performance status of O or l 
Recovered from all toxicities associated with prior treabll.ent, to acceptable baseline 
status (as to Lab toxicity see below liniits for inclusion) or a National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, Grade 
of 0 or 1, except for toxicities not considered a safety 1isk, such as alopecia or vitiligo 
Pa11icipants must have nomial organ and maiTow function as defined below: 
-
WBC
-
ANC
-
Platelets
-
Hemoglobin
-
Total Bilirnbin
-
AST(SGOT)/ALT(SGPT)
-
Creatinine
-
Creatinine clearance
2:;3,000/µL 
2::l,500/11L 
2:: I 00, OO0htL 
> 9.0 g/dL
:;; 1.5 x ULN
(except subjects with Gilbett Syndrome, who can have
total bilirubin < 3.0 mg/dL)
::; 3 x ULN 
:S 1.5 x ULN 
OR 
2:;40 mL/niin/1.73 m2 for participants with creatinine 
levels above institutional nonnal (if using the 
Cockcroft-Gault fonnula below): 
Female CrCJ = (140 • age in vears) x weight in kg x 0.85 
72 x senun creatinine in mg/dL 
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DP/HCC Protocol #:18-279 
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Male CrCI = 040 • age in years) x weight in kg x 1.00 
72 x senim creatinine in mg/dL 
3.1.1.7 
Women of childbearing potential (WOCBP) should have a negative serum pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior 
to the start of Nivolumab, because the effects of NeoVax plus Montanide and 
Nivolumab on the developing human fetus are unknown 
3.1.1.8 
Because there is an unknown but potential risk for adverse events in nm-sing infants 
seconda1y to treatment of the mother with study agents, breastfeeding should be 
discontinued if the mother is treated with Ipilimmnab, Nivolmnab and NeoVax + 
Montanide. 
3.1.1.9 
Female pa1ticipants enrolled in the study, who are not free from menses for >2 yea1-s, 
post hysterectomy / oophorectomy, or smgically sterilized, should be willing to use 
either 2 adequate barrier methods or a barrier method plus a hormonal method of 
contraception to prevent pregnancy or to abstain from sexual activity throughout the 
study, starting with visit 1 through 5 months after the last dose of study therapy. 
Approved contraceptive methods include for example: intra uterine device, 
diaphragm with spermicide, ce1vical cap with spermicide, male condoms, or female 
condom with spermicide. Spermicides alone are not an acceptable method of 
contraception. Should a woman become pregnant or suspect she is pregnant while she 
is participating in this study, she should inform her ti-eating physician 
immediately.The investigational product will be penuanently discontinued in an 
appropriate manner. 
3.1.2 
Exclusion C1ite1ia 
Pat1icipants who exhibit any of the following conditions will not be eligible for admission into 
the study: 
3.1.2.1 
3.1.2.2 
3.1.2.3 
3.1.2.4 
Prior innnunotherapy except for aiiti-CTLA-4. Patients with tmresectable melanoma 
who have received PD-1 inhibition therapy as adjuvant therapy and stopped receiving 
PD-1 inhibition for a pe1iod of 2. 6 months before starting treatment with Nivolumab 
are allowed to participate. 
> 24 weeks between surgical resection of stage IIIB/C/D or IV melanoma and
initiation of study ti-eatment
Concomitant therapy with any anti-cancer agents, other investigational anti-cancer 
therapies, or innnunosuppressive agents including but not limited to methotrexate, 
chloroquine, azathioprine, etc. within six months of study participation 
Active brain metastases or leptomeningeal metastases 
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3.1.2.5 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Use of a non-oncology vaccine therapy for prevention of infectious diseases (with the 
exception of vaccination against the SARS-Co V-2 vims for the prevention of 
COVID-19 disease) during the 4 week period prior to first dose of Nivolumab. 
Participants may not receive any non-oncology vaccine therapy dw·ing the period of 
Nivolumab or NeoVax plus Montanide ad1ninistration and until at least 8 weeks after 
the last dose of study therapy. 
Given the severity of the COVID-19 pandemic, vaccination specifically against the 
SARS-Co V-2 vims for the prevention of COVID-19 is ALLOWED in this study. 
3.1.2.6 
History of severe allergic reactions attributed to any vaccine therapy for the 
prevention of infectious diseases. 
3.1.2.7 
Active, known or suspected autoinunm1e disease. Subjects are pennitted to enroll if 
they have vitiligo, type I diabetes mellin1s, residual hypothyroidism due to 
autoinunune condition only requiring honnone replacement, psoriasis not requiring 
systemic treatment, or conditions not expected to recur in the absence of an extemal 
nigger. 
3.1.2.8 
A condition requi.iing systemic treatment with either corticosteroids(> 10 mg daily 
prednisone equivalents) or other i.imnw1osuppressive medications withill 14 days of 
study drug administration. Inhaled or topical steroids and adrenal replacement doses> 
10 mg daily prednisone equivalents are permitted in the absence of active 
autoi.imnm1e disease. Co1ticosteroids used as pre-medication for i.inaging studies are 
allowed. 
3.1.2.9 
Test positive for hepatitis B vi.ius smface antigen (HBV sAg) or hepatitis C vi.i1.1s 
ribonucleic acid (HCV antibody) indicating acute or chronic infection. 
3.1.2.10 
Known history of testing positive for human i.inmm1odeficiency vm1s (HIV) or 
known acqufred i.imnunodeficiency syndrome (AIDS). 
3.1.2.11 
Known sensitivity or allergy to Nivolumab and/or Ipilinuunab. 
3.1.2.12 
Uncontrolled intercunent illness including, but not limited to ongomg or active 
infection requiring treatment, symptomatic. 
3.1.2.13 
Any m1derlyillg medical condition, psychiatric condition or social situation that in 
the opinion of the investigator would compromise st11dy administration as per 
protocol or compromise the assessment of AEs. 
3.1.2.14 
Pla1med major surgery (excluding surgery for resection of melanoma if applicable). 
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DP/HCC Protocol #:18-279 
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3.1.2.15 
Pregnant women are excluded from this study because Nivolumab, personalized 
neoantigen peptides and poly-ICLC are agents with unknown risks to the developing 
fen1s. Because there is an unknown but potential risk of adverse events in nursing 
infants seconda1y to treatment of the mother with Nivolumab, personalized 
neoantigen peptides and poly-ICLC, nursing women are excluded from this study. 
3.1.2.16 
Individuals with a histo1y of an invasive malignancy are ineligible except for the 
following circumstances: a) individuals with a h.isto1y of invasive malignancy are 
eligible if they have been disease-free for at least 3 years and are deemed by the 
investigator to be at low risk for rect11Tence of that malignancy; b) individuals with 
the following cancers are eligible if diagnosed and treated - carcinoma in si111 of the 
breast, oral cavity or ce1vix, localized prostate cancer, basal cell or squamous cell 
carcinoma of the skin. 
3.1.2.17 
P11soners, or subjects who are compulso1y detained are not eligible to participate. 
3.2 
luclusioo of Women and Miu.01ities
Both men and women of all races and ethnic groups are eligible for th.is trial. 
4. REGISTRATION PROCEDURES
Eligibility will be confumed prior to the initial biopsy to obtain tumor for sequencing. Prior to 
initial biopsy, the patient is screened for eligibility using the eligibility checklist. Once overall 
tJial initial eligibility is confirmed, the patient is registered, undergoes core needle or surgical 
biopsy and preparation of the participant's vaccine is initiated (while the patient is receiving 
Nivolumab). 
Before the fust dose of the vaccine plus ipili.mumab the patient will be registered to the 
conespondent dose level vaccine plus ipilimumab . 
4.1 
General Guidelines for DF/HCC Institutions 
Institutions will register eligible pa1ticipants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occm prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
For registration, an investigator will confirm eligibility criteria and a member of the study team 
will complete the appropriate protocol-specific eligibility checklist. 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall P1incipal Investigator (PI). If a pa1ticipant 
does not receive protocol therapy following registJ·ation, the participant's registration on the 
study must be canceled. Registr·a.tion c.ancellations nmst be ma.de in OnCore as soon as possible. 
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4.2 
Registntion Process for DF/HCC Institutions 
The Registration procedures are as follows: 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
To be eligible for registration to the study, the pa1ticipant nmst meet each inclusion and 
exclusion criteria listed in protocol section 3. 
Reminder: Confum eligibility for ancilla1y sn1dies at the same time as eligibility for the 
treatment study. Registration to both treatment and ancillary studies will not be completed if 
eligibility requirements are not met for all studies. 
1. Confirm w1itten infonned consent from the participant has been obtained p1ior to the
pe1fonnance of any protocol-specific screening procedmes or assessments.
2. Complete the E/ig;b;/iry Checkhst
3. Pe1fo1m subject registration per DF/HCC SOP REGIST-101
4.
Verify the success of the subject registration in all DF/HCC systems.
5. TREATMENT PLAN
Overall Treatment admlnlstratlon 
Treatment will be administered on an outpatient basis. Expected toxicities and potential risks as 
well as dose modifications for Nivolumab and NeoVax plus Montanide and locally administered 
Ipilimumab, respectively, are described in Section 6 (Expected Toxicities and Dosing 
Delays/Dose Modification). No investigational or commercial a.gents or therapies other than 
those described below may be administered with the intent to treat the patient's malignancy. 
PaI1icipants will be identified and enrolled on the study if they meet all eligibility criteria. After 
confinnation of adequate tumor content in the surgical resection/core biopsy specimen (at least 
30% tumor in specin1en), each pa1ticipant will start receiving Nivolumab as described in section 
Section 5 .2.1, while vaccine is being prepared. If there is no adequate rumor content in the 
specin1en, the patient will be removed from protocol and replaced. Treatment with NeoVax plt1s 
Mont:anide plus local lpiliummuab will begin within 12 weeks after initiation of Nivolumab. 
Days will not be counted continuously on protocol therapy. If a toxicity results in a hold of study 
vaccine administration, counting of days will hold until treatment resumes (e.g. should a patient 
not be able to receive his/her second vaccine at Week 15 due to a toxicity, collllting is held; if the 
toxicity has resolved a week later, the ad1ninistration of tha.t second vaccine becomes the 
participant's new Week 15). Following a dose delay, those day's assessments should be repeated 
in order to restart participant's vaccinations. 
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5.1 
Pl'eparatiou ofNeoV,l.'I: plus Moutauide 
5.1.1 
Tumor and normal tissue harvest 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Patients with resectable or unresectable melanoma will undergo surgical resection, surgical 
biopsy, or core needle biopsy of a melanoma metastasis. For patients with melanoma that bas 
alieady been completely resected, archival tissue can be used for assessment of tumor content by 
a staff pathologist at Brigham and Women's Hospital (in an H&E stained tmuor specimen) as 
well as wbole-exome and transcri tome sequencing. Dr. Patrick Ott, the principal investigator 
) should be contacted at the time of the initial consent to 
ensure at anc1 ruy stu 1es are coor nated. 
For patients with resectable or umesectable melanoma who Ulldergo surgical resection, surgical 
biopsy, or core needle biopsy of a melanoma metastasis, the study investigators and members of 
the study team will coordinate tissue acquisition with the interventional radiology or surgical 
staff of the Brigham and Women's Hospital and the staff of the BWH-SHL, and TIGL. After 
adequate ttunor for pathological assessment has been harvested as deemed by the inte1ventional 
radiologist or smgeon, some or all of the remaining ttuuor tissue will be placed in sterile media 
in a ste11le container and transfened to the Specialized Histopathology Core at BVlH. A staff 
pathologist at Brigham and Women's Hospital will assess H&E stained tumor specimen for 
tumor content. Portions of the tumor tissue will be used for whole-exome and transcriptome 
sequencing. Cell line and tumor infiltrating lymphocyte generation (if adequate tissue) will be 
pe1formed in the Translational Immunogenomics Laborato1y (TIGL). 
In the event that sequence analysis yields no results or sub-optimal results, tumor cell line cells 
or paraffin embedded n1mor sections from the recently resected n1mor (if available) may be used 
to prepare additional nucleic acid for sequencing. No saved samples will be used to prepare 
cellular products for future clinical use. Peripheral blood mononuclear cells from a blood draw 
will be utilized for a normal tissue sample. 
5.1.2 DNA/RNA S<.'(Juenciog 
Nucleic acid will be extracted from the tissue samples and sequencing will be conducted at either 
the CLIA-certified laborato1y at Broad Institute/Clinical Research Sequencing Platfom1 (CRSP) 
---- Samples will be de-identified before being shipped to either the Clinical 
Ėtfonu (CRSP) and Broad Genomics Platfonu research lab at the Broad 
Institute----. 
Sequencing at the B1·oad Institute 
Whole-exome sequencing will be conducted in the Clinical Reseru·ch S uencin<> Platfonn, LLC 
(CRSP) at the Broad Institute. CRSP is CLIA licensed 
) and CAP 
accredited - and one of tests offered by CRSP is Somatic • o e Exome sequencing, 
which willė for these trials. CRSP will extract total DNA from blood and tumor tissue 
using standru·dized procedures. The DNA srunples will be processed through the CLIA Somatic 
WES test. For ttunor and nonnal DNA samples, whole exome capttu·e will be conducted p1ior to 
sequencing on Illrnnina HiSeq or NovaSeq. RNA sequencing is completed at the non-CLIA 
Broad Genomics Platfonn research lab. For n1mor RNA, a cDNA libra1y will be prepared and 
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DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
may be enriched by transcriptome capture prior to sequencing on Illumina HiSeq or NovaSeq. If 
the quantity or quality of DNA or RNA isolated from t11e tissue sample is inadequate for exome 
or cDNA library preparation and sequencing, then DNA or RNA may be extracted from the 
patient-specific tumor cell line (if generated). 
5.1.3 
Prep.,·otlon ofpersonallud neoantlgen peptides 
I 
I 
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I 
5.1.3.1 
5.1.3.2 
P•ptid• syothosis 
Pr•p•rntiou of Neonutigeo peptide pools 
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CONFIDENTIAL 
DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
111is document is confidential. Do not disclose or use except as authorized. 

52 . 
A•ent Administration 
T1·tat1ntu1 
Agent 
phase 
Schedule**
Nivolumab 
Entire Durntion 
Every 4 weeks 
Ncoantie:en 
Vaccine-
(peptide, + poly-
ICLC+ 
VaccioatlOn 
Weck 12, IS, 
Mou1anide* !SA-
Phase 
18. and 21
51 VO)'·''' 
lpilinuuuab 
Vaccinatjon 
Week 12, 15. 
Phase 
18, and 21 
Allowable 
Treatment 
Adm.in ,Vindow 
"'3 days 
"'3 days 
± 3 days 
DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Dose 
480 me flat dose 
Poly-JCLC: 
2 x 0.5 mg (0.25ml eacll) 
peptides: 
2 X 300)'g per 
pep1ide/0.75ml 
Montanide*ISA-51 VO: 
2 X Jml 
Total Ncoantigco Vaccine 
VoJume•: uo 10 2 x 1.6 1111 
2 x 1.25 mg (0.25ml), 2.5 
mg (0.5 ml) or 5 mg (1.0 ml) 
dcpcudint on the eohon 
Route 
1.v.
Neoaurigcn Vaccine 
s.c. injections into up co
2 different anatomic 
sites 
s.e injection \vithin 1
cm of cach Neoauciget1
Vaccine injection
*Doring NeoVax (pet"sonalized oeoantiien peptides+ Hiltonol) and 1\1ootanide mixin.g preparation there is a loss of0.4 mL
**PltaŰe rtfe..- to section 5.2,1.2 1·egardfog delays on ,•uciualfon therapy stsu·t
***It emulsion of tither t>ool A 01· pool B or both pools A and B is unsutC't"'i.'iful aftt1· two attempts, the ntoantignn vacdue will bt
prepared ·without l\Iontauidt as stated iu s«tiou 8.6.3.
If one of lhe initial vaccine doses is not successfully emulsified with monlauide afler two 
attempts, the vaccine will be prepared without the Montanide (see table below and section 8.6.3). 
During the vaccination treatment period if any of the two vaccine doses is not successfully 
emulsified with montanide after two attempts, the vaccine will be prepared without tJ1e 
Montanide. 
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CONFIDENTIAL 
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Treatment plan if emulsion NeoVax -Montanide fails: 
Treatment 
Allow•ble 
Agent 
phase 
Schedule** 
Tnatment 
Admlo Window 
Nivoltnnab 
Entire DlJl'atiOO 
Every 4 weeks 
±3 days 
NeoVax 
(peptides + poly-
Vacdn.1rion 
Week 12, 15, 
ICLC) ... 
Pllase 
18, and 21 
:t 3 days 
Ipilimumab 
Vacci:nat.ioo 
Week 12, 15, 
±3 days 
Pllase 
18, and 21 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Dose 
Route 
480 mg fiat oose 
i.v.
Polv-ICLC: 
2 x 0.5 mg (0.25ml each) 
NeoVax 
s.c. injections into up ,o
Peptides: 
2 different anatomic
2 X 30011g per 
sites
peptide/0. 75ml 
Toca! NeoVax Vollllle: up
to 1.0 ml(+/- 0.1 ml) 
2 X 1.25 mg (0.25ml), 2.S 
s.c injection within 1
mg (0.5 ml) or 5 mg (1.0 ml) 
cm of each NeoVax
depending ou the coho11 
injection
***If emubiou of eithu pool A or pool B 01· both pools A a.ud Bis unsuc.ces.sful aftel' two attempts the vaccme will be prepared 
n1thout Mont>oldt as stated tn sert1on 8.6.3 
5.2.1 
Nlvolumab 
5.2. 1. l 
Nivolumab Run-in Period 
Rtm in pe1iod will begin within 2 weeks of metastatic tissue biopsy or within 4 weeks of 
enrollment if the patient has resected melanoma, once the following crite1ia have been met: 
l) Histopathologic confinnation of melanoma
2) Confirmation of adequate tmnor content in resection specimen for DNA sequencing
Patients will receive Nivohunab at a flat dose of 480 mg as a 30-minutes (+/- JO min.) i.v. 
infusion every 4 weeks (28 days). 
5.2.1.2 
Nlvohunab plus neoantlgeu vaccine (NeoVax plus Moutanlde) / Iplllmutnab Period 
Patients will begin therapy with neoantigen vaccine (NeoVax plus Montanide) /Ipilimumab once 
the vaccine has been prepared and testing completed at week 12. Patients will receive Nivolumab 
at a flat dose of 480 mg as a 30 minutes (+/- JO min.) i.v. infusion every 4 weeks (28 days). 
Nivolumab will be given 60 minutes ( +/- l O min) following local lpilimumab administration. 
If therapy with neoantigen vaccine (NeoVax plt1s Montanide) / Ipilimumab gets delayed, 
vaccintation timepoints will be modified as follows: 
Neoantigen vaccine (NeoVax plus Montanide) / lpilimumab vaccination timepoints #2 (week 
15), #3 (week 18), and #4 (week 21) will be moved accordingly so there is a window of three 
weeks (+/- 3 days) between each vaccination timepoint. If any of the vaccine adminstrations 
coincide with Nivolumab treatment, neoantigen vaccine (NeoVax plus Montanide) / local 
Ipilimumab will be administrated first and Nivolumab will be given 60 minutes (+/- 10 min) 
following local lpilimumab administration. 
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5.2.1.3 
Nlvolumab Continuation Period 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
After neoantigen vaccine (NeoVax plus Montanide) / lpilimumab treatment has been completed, 
patients with unresectable stage illB/C/D or IV melanoma will continue to receive Nivoltunab 
alone at a flat dose of 480 mg as a 30 minutes(+/- 10 min.) i.v. infusion every 4 weeks (28 days), 
until disease recm1·ence or progression, Ullacceptable toxicity, or withdrawal of consent, for a 
maximum duration of up to 2 years from the first study treatment in the Run in Period. 
Pat1icipants with completely resected melanoma will receive nivolumab for a maximum period 
of one year (13 doses) 
5.2.2 
Neoantlgeu Vaccine (NeoVax + Montaulde ISA-51 VG) 
5.2.2.1 
Injectlons 
5.2.3.1.1 Nroaoligen Vaccine (N•oVax + Monlauide"ISA-51 VG) 
Each of the Neoantigen Vaccine syringes will be assigned to one of two extremities. At each 
illllllunization, each NeoVax plus Montanide syringe will be administered s.c. to the assigned 
exti-emity (i.e., NeoVax + Montanide A will be injected iI1to left arm week 12, 15 etc.; NeoVax +
Montanide B will be injected into right aim week 12, 15). For participants who have undergone a 
complete axilla1y lymph node dissection, alternative anatomical locations are the left and/or right 
thigh or left and/or right mid1iff. The arms or left and/or 1ight midriff can also be used for 
pa11icipants who have undergone a complete inguinaVfemoral lymph node dissection (or other 
contraindications that prevent injections to a pa1ticular extremity). The personalized neoantigen 
vaccine (peptide + poly-ICLC + MontanideĞ ISA-51 VG) should be a.dmillistered witllin 6 
hours after preparing the peptide+ poly-ICLC + Montanide® ISA-51 VG mixture, and injection 
sites may be shifted in order to a.void a.dnliniste1ing injections to areas with evidence of 
persistent local reaction. 
NOTE: If emulsion of either pool A or pool B or both pools A and B is unsuccessfol after two 
attempts, the vaccine will be prepared without Montanide (please see section 8.6.3). 
5.2.3.1.2 Ipilimumab 
Within 30 nlinutes (+/- 10 nun) following NeoVax plus Montanide admimstration, lpilimumab 
will be iI1jected within I cm of each neoantigen vaccine administration. 
5.2.2.2 
Twaunent window 
Neoantigen vacciI1e (NeoVax plus Montanide) and IpilimtuUab may be administered withiI1 3 
days of the scheduled admimstration date. (See Section 10; Study Calendar). 
Days will not be counted continuously on protocol therapy. If a toxicity results in a hold of study 
vaccine and nivolumab administration, collllting of days will hold until treatment resumes. (e.g. 
should patient not be able to receive his/her second vacciI1e at Week 15 due to a toxicity, 
counting is held; if the toxicity has resolved a week later, the admimstration of that second 
vaccme becomes the pa1ticipant's new Week 15) Following a dose delay, those day's 
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
assessments should be repeated in order to restart participant's vaccinations. 
5.2.2.3 
Obser,,atioo post vaccination
Pat1icipants should be observed in the clinic for at least 60 minutes after the last of the 4 
injections and vital signs should be checked at 30 minutes(+/- JO min) and 60 minutes(+/- JO 
min) after the last injection for each clinic visit. Monitoring for immediate adverse events should 
include attention to possible injections site reaction or a systemic reaction. In the absence of the 
occtuTence of an adverse event, pa1ticipants will be discharged from the outpatient clinic at 
DFCI. 
5.3 
Prelrenhoeot criteria 
Preparation of the final Nivolumab, lpilimumab, and/or Neoat1tigen vaccine product will begin 
upon confirmation that the participant is medically cleared to undergo treatment ( continued 
an·ivaJ in the clinic, stable vital signs, no new acute medical issues or laboratory abnonnalities 
potentially inte1fering with vaccine or Nivolumab administration). 
5.3.1 
Day 1
Laborato1y parameters must be reviewed prior to administration of the study agents. No specific 
prophylactic or supportive care is necessa1y p1ior to administration of the study agents. 
Pat1icipants who have developed flu-like symptoms after NeoVax plus Montanide that are 
controlled with acetatninophen or non-steroidal anti-inflammato1y drngs dming previous 
treatments may be pre-treated with acetaminophen (650 mg PO) or ibuprofen (400-600mg PO) 
as per the investigator's discretion. 
5.3.2 
Subseqoent treatment days
Tue following must be reviewed and confirmed within thl'ee days prior to subsequent treatment 
administrations: 
I. Stable vital signs
2. ECOG perfonnance status
3.
No new acute medical issues that would require a dose hold or delay as noted in dose
modification section 6.3
No specific prophylactic or supportive care is necessa1y prior to administration of the snidy 
agents. 
5.4 
Dose schema and staggering of partkipants 
5.4.1 
DLT and expan.slon cohorts
Adverse events classified as dose-limiting toxicities (DLn and the assessment tin1e for DLTs are 
sullllllarized in Section 5.5. Five patients will be treated with NeoVax plus Montanide plus local 
Ipilimumab plus Nivolumab (starting at week 12) for the initial safety evaluation (Cohort I). We 
have chosen dose escalation cohorts of 5 patients, rather than a more traditional 3+3 design, 
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
because the detennination of whether to treat at a different dose in this trial is made over a longer 
period of time due to the time required for vaccine preparation and the extended period for safety 
evaluation. These larger cohort sizes help us avoid having to pause and then restart enrollment to 
a dosing coho11 several months later. 
If none or only 1 patient in Coho1t 1 experiences a dose limiting toxicity (DLI ) during the first 7 
weeks of treatment (NeoVax plus Montanide plus local Ipilinuunab plus Nivolumab) of Coh01t 
1, 5 patients will be treated as Cohott 2 Dose Level 2. If two or more patients in Coho1t l 
experience a DLT during the first 7 weeks of treatment, then 5 patients will be treated as Coh01t 
2, Dose Level -1. 
If none or only 1 patient experiences a DLT on Coho1t 2 Dose Level 2, then Dose Level 2 will be 
the maxinmm tolerated dose (MID) and an additional 10 patients will be treated at that dose 
level (Coho1t 3, Dose Level 2) to increase the likelihood of detecting serious toxicities, to 
complete biologic coll'elative endpoints and to gain preliminary experience with clinical tumor 
activity. If two or more patients in Coho1t 2 Dose Level 2 experience dose limiting toxicity 
(DLI ), then Dose Level l will be the MID and an additional 10 patients will be treated in an 
expansion coho1t at this dose (Coho1t 3 Dose Level 1). 
If none or only l patient experiences a DLI on Cohort 2 Dose Level -1, then Dose Level-I will 
be the maximmn tolerated dose (MfD) and an additional JO patients will be treated in an 
expansion coho11 at that dose level (Cohort 3 Dose Level-I). If two or more patients in Coho11 2 
Dose Level -1 experience dose limiting toxicity (DLT), then the study will be stopped. 
Dose Escalation schedule 
Starting Dose --> 
5.4.2 
Staggering or patten ts 
Dose Level 
-1 
1 
2 
Dose ofipilimumab 
1.25 mg (0.25 mL) 
2.5 mg (0.5 mL) 
5 mg (1.0 mL) 
The first three patients will be emolled in a staggered fashion: Patients 2 and 3 will not sta1t 
treatment until the previous patient has completed 4 weeks after the first dose of the NeoVax 
vaccme. 
5.4.3 
Definition of evaluable pru1ldpants 
All pa1ticipants receiving at least one dose of Nivolmnab will be evaluable for tox1c1ty. 
Pa11icipants will be evaluable for immunologic activity if they have received all vaccinations 
dming the p1iming phase and the fnst boost vaccination. 
Pai1icipants with unresectable a.nd measurable disease who have received at least one dose of 
study vaccine therapy will be considered evaluable for determination of tttlllor response. 
A minimum of 2 vaccinations and absence ofDLTs are required for a participant to complete the 
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6-week DLT obse1vation period successfolly.
5.5 
Definition of Dose-Limiting Toxicity 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Dose-limiting toxicity (DLT) is based on the CTEP Active Version (version 5.0) of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE). DLT refers to toxicities 
expeiienced within 42 days (6 weeks of Neoantigen Vaccine treatment initiation i.e. 2 
vaccinations "DLT window"). If treatment has to be delayed because of a toxicity that does not 
fulfill the c1iteria of a DLT, the DLT window should be extended by that time period of delay. A 
DLT will be defined as follows: 
1. Grade 3 or 4 toxicity that is definitely, probably, or possibly related to the
administration of vaccine, excluding:
- Transient(::; 72 hours) flu-like symptoms
- Grade 3 nausea, vomiting, diarrhea, or constipation that returns to grade 2 (or lower)
level within 48 hours
- Any grade 3 rash that resolves to grade 2 or grade I within::; 14 days
• Any grade 3 endocrine abnomiality that is coll'ected with honnonal therapy within 4
weeks
2. Grade 3 or 4 abnormal laboratory value that is defmi.tely, probably, or possibly
related to the administration of vaccine if it persists for more than 7 days, or requires
bospitalization or medical inteivention excluding:
-Any grade 3 electrolyte abno1mality that:
o
lasts ::; 72 hours,
o
is not clinically complicated,
o
and resolves spontaneously or responds to conventional medical
intervention
3. Any grade 3 or grade 4 toxicity that is considered, in the opinion of the Principal
Investigator, to be dose-limiting.
4. Any death related to study treatment.
Management and dose modifications associated with the above adverse events are outlined in 
Section 6 (Expected Toxicities and Dosing Delays/Dose Modifications). 
5.6 
Gi>neral Concomitant Medlcallon and Supporllve Care Guldellnes 
Pa11icipants who have developed flu-like symptoms that are controlled with acetaminophen or 
non-steroidal anti-inflammatory drugs during previous treatments may be pre-treated with 
acetaminophen (650 mg PO) or ibuprofen (400-600mg PO) as per the investigator's discretion. 
Pat1icipants may not receive any non-oncology vaccine therapy (with the exception of 
vaccination against the SARS-Co V-2 vims for the prevention of COVID-19 disease) during the 
4-week pe1iod to fust dose of Nivolumab and lllltil at least 8 weeks after the last dose of
Neoantigen Vaccine administration.
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Given the severity of the COVID-19 pandemic, vaccination specifically against the SARS-Co V-
2 vin.1s for the prevention of COVID-19 is ALLOWED in this study. 
Investigators may presc1ibe all other concomitant medications or treatments deemed necessary to
provide adequate patient care. 
Management of more serious tox.ic11tes will be directed by a sn1dy investigator following
discussion with srudy PI and will be in accordance with standard of care clinical practice. 
5. 7
Duration of Therapy/ Criteria for Taking a Pa111clpant Off Protocol Therapy 
Duration of therapy will depend on tolerability of the immunizations and evidence of disease
recunence or progression as judged by the treating investigator. In the absence of treatment
delays due to adverse events, treatment will be given for two years in patients with
tmresectable melanoma and for one year (13 doses) for pa11icipants with stage III/B/C/D or
IV completely resected melanoma, respectively, or until one of the following criteria applies: 
• Disease progression or recunence, if it is deemed by the treating investigator to be in
the best interest of the participant to discontinue study treatment. If there is clinical or
radiographic disease progression or recunence prior to initiation of vaccine at week 12
or at the week 12 scan, treatment as per protocol (Nivolumab plus NeoVax +
Montanide + local Ipilimumab) should be given unless deemed not in the best interest
of the patient by the investigator. 
•
Intercurrent illness that prevents fu1ther administration of treatment
•
Unacceptable adverse event(s) 
•
Pa11icipant demonstrates an inability or unwillingness to comply with protocol
requirements 
•
Pa11icipant decides to withdraw from the study, or
•
General or specific changes in the participant's condition which render the pa11icipant
unacceptable for further treatment in the opinion of the treating investigator. 
Pa11icipants will be removed from the protocol therapy when any of these c11te1ia apply. The
reason for removal from protocol therapy, and the date the pa1ticipant was removed, must be
docmnented in the case repo1t fonn (CRF). Alternative care options will be discussed with the
participant. 
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off­
Treatment/Off-Study information will be updated in OnCore. 
In the event of unusual or life-threatening complications, participating inveÛ
-fy the Principal Investigator, Patrick Ott, MD, PhD at DFCI--
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5.8 
Duration of Follow Up 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Participants removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. All participants will be followed until resolution 
or stabilization of any serious adverse events occuning during treatment or starting within 100 
days of last study drug. 
Accrual duration is expected to be around 2 years. The overall study duration will be 
approximately 6 years. 
Active Follow-Up: Participants removed from active study treatment will enter active follow-up 
and will be followed at the following schedule until initiation of a new therapy for progressive 
disease, withdrawal of consent, or death (whichever comes first): 
•
At least every 3 months(+/- 2 week) for the first 2 years after initiation of study therapy
•
At least every 4 months(+/- 2 weeks) for the third year after study therapy initiation
•
And at least every 6 months (+/- 4 weeks) thereafter, until 5 years have passed since
study therapy initiation
NOTE: When progression is noted during follow-up, the respective measurements documenting 
progression will be recorded on the appropriate CRF. 
Long-Te1m Follow-Up: Participants removed from active follow-up for progression/initiation of 
a new therapy will enter long-te1m follow-up, where they will be followed via medical record 
review until death for survival. All patients will be followed for survival. Updates to the CRFs 
are to be made roughly eve1y six months. 
5.9 
Nil•olumab treatment beyond progression 
Accmnulatiug evidence indicates a minority of subjects with unresectable melanoma treated with 
i.mmunotherapy may de1ive clinical benefit despite initial evidence of progressive disease (PD).
Subjects with tmresectable stage IIIB/C/D or IV melanoma who show initial evidence of
progression (as defined by modified RECIST 1.1) after or during vaccination will be permitted to
continue or res1m1e treatment with Nivolumab if documented, as long as they meet all of the
following criteria:
•
Investigator-assessed clinical benefit
•
Subject has tolerated prior Nivolurnab
•
Stable or improved perfonnance status
•
Treatment beyond progression will not delay an inte1vention to prevent iniminent serious
complications of disease progression (e.g, CNS metastases)
Subject will be required to sign written informed consent prior to recervmg additional 
Nivolumab treatment, using an ICF describing any reasonably foreseeable 1isks or discomforts 
and other alternative treatment options. The assessment of clinical benefit should take into 
account whether the subject is clinically deteriorating and unlikely to receive further benefit from 
continued Nivolumab treatment. 
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A radiographic tumor assessment must be perfo1med 4 to 8 weeks after the assessment 
docmnenting initial PD. Subjects must discontinue study treatment upon evidence of futther 
progression on the next scheduled n1mor assessment, defined as an additional l 0% or greater 
increase in tumor burden from the time of initial PD (including all target lesions and new 
measurable lesions). If ftu1her progression is not documented on this next tumor assessment, 
then study treatment may continue until there is evidence of ft11ther progression on any 
subsequent tmnor assessment. 
New lesions are considered measmable at the time of initial PD documented if the longest 
diameter is at least 10 mm ( except for pathological lymph nodes, which must have a sho1t axis of 
at least I 5 mm). Any new lesion considered non-measurable at the tin1e of initial PD may 
become measurable and therefore included in the tmnor bmden measmement if the longest 
diameter increases to at least IO lllill ( except for pathological lymph nodes, which must have an 
increase in short axis to at least 15 mm). 
For statistical analyses that include the investigator-assessed progression date, subjects who 
continue Nivolumab treatment beyond initial investigator-assessed progression, as defined by 
modified RECIST I. I, will be considered to have investigator-assessed progressive disease at the 
time of the initial progression event. 
5.10 
Criteria for Taking a Partldpant OIJ Study 
Pa11icipants will be removed from study when any of the following criteria apply: 
•
Dose-limiting toxicity (DLT) as defined in protocol section 5.5
•
Grade 3 or greater skin toxicity (ulcer )
•
Lost to follow-up
•
Failure to produce an adequate supply of acceptable vaccine
•
Withdrawal of consent for data submission
•
Death
The reason for taking a participant off study, and the date the pa11icipant was removed, must be 
documented in the case report fonu (CRF). In addition, the study team will ensure Off 
Treatment/Off Study i.nfo1mation is updated in OnCore in accordance with OF/HCC policy 
REGIST-I0I. 
In the event of mmsual or life-threatening complications, participating inveõ 
immediate! notify the Principal Investigator, Patrick Ott, MD, PhD at DFCI--
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6.
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Tenuinology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
http://ctep.cancer.gov/protocoJDevelopment/electronic applications/ctc.htm. 
If possible, symptoms should be managed as needed. In the case of toxicity, appropriate medical 
treatment should be used. 
All adverse events expeiienced by participants will be collected from the time of the first dose of 
study treatment (first Nivolmnab administration), through the study and until the final study visit. 
Pa11icipants continuing to expe1ience toxicity at the end of treatment visit may be contacted for 
additional assessments lllltil the toxicity has resolved or is deemed irreversible. 
6.1 
Anticipated Toxicities 
A list of the adverse events and potential risks associated with the agents administered in this 
study appears on section 7 .1 and will detennine whether dose delays and modifications will be 
made or whether the event requires expedited repo1ting in addition to routine repo1ting. If one 
<hug is held due to an AE all the 3 drugs will be held until 01iginal AE is resolved. 
6.2 
Toxicity Management 
If treatment needs to be held because of toxicity, all study drug will be held until resolution of 
the adverse event. 
6.2.1 
Nlvolumab 
6.2.1.1 
Dose Modification and Guidelines ror Management of Nlvohunab-related Adverse Events 
Management algorithms (listed in Appendi,x B) have been developed to assist investigators in 
assessing and managing the following groups of AEs: 
•
Gastrointestinal
•
Renal
•
Pulmonruy
•
Hepatic
•
Endoc1inopathies
•
Skin
•
Nem-ological
6.2.1.2 
Twahnent or Nlvolumab Related Inruslou Reactions 
Since Nivolumab contains only human immunoglobulin protein sequences, it is mtlikely to be 
iimuunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
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to occur, it might manifest with fever, chills, rigors, headache, rash, pnnitis, arthralgias, hypo- or 
hypenension, bronchospasm, or other symptoms. 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infosion 
reactions should be graded according to NCI CTCAE (CTEP Active Version (version 5.0) of the 
NCI Common Terminology Criteria for Adverse Events (CTCAE) which is identified and 
located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm guidelines. 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
For Grade 1 symptoms: (Mild reaction; infosion interruption not indicated; intervention not 
indicated) Remain at bedside and monitor subject m1til recovery from symptoms. l11e following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before 
additional Nivolmnab administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion intem1ption but 
responds promptly to symptomatic treatment [ eg, antiliistamines, non-steroidal anti­
inflammatory drngs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours). 
Stop the Nivolmuab infosion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen); 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid or 
bronchodilator therapy may also be ad,ninistered as appropriate. If the infusion is intenupted, 
then restart the infosion at 50% of the original infosion rate when symptolllS resolve; if no fmther 
complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion 
rate. Monitor subject closely. If symptoms recur then no forther Nivolmnab will be administered 
at that visit. Administer diphenbydramine 50 mg IV, and remain at bedside and monitor the 
subject until resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case repo1t fonn (eCRF). The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 
325 to 1000 mg (acetarninophen) should be adininistered at least 30 minutes before additional 
Nivolmnab adiuinistrations. If necessary, colticosteroids (recommended dose: up to 25 mg of IV 
hydrocor1isone or equivalent) may be used. 
For Grade 3 or Gracie 4 sym1itoms: (Severe reaction, Gracie 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief intem1ption of infusion]; recmTence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impaiiment, pulmonary infiltrates]). Grade 4: (life tln·eatening; pressor or ventilatory 
supp011 indicated) 
Immediately discontinue infusion ofNivolumab. Begin an IV infusion of normal saline, and treat 
the subject as follows. Recommend bronchodilators, epiI1ephrine 0.2 to 1 mg of a 1: 1,000 
solution for subcutaneous administration or 0.1 to 0.25 mg of a 1: 10,000 solution injected slowly 
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for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV 
(or equivalent), as needed. Subject should be monitored m1til the investigator is comfortable that 
the symptoms will not recur. Nivollllllab will be pennanently discontinued. Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recove1y from symptoms. In the case of late-occuning hypersensitivity 
symptolllS ( eg, appearance of a localized or generalized pmritis within 1 week after treatment), 
symptomatic treatment may be given (eg, oral antihistamine, or corticosteroids). 
6.2.2 NeoVax plus Montanlde 
6.2.2.1 
Localizecl Reaction 
Treatment with corticosteroids and antihistamines are not recommended for initial treatment, but 
may be instituted at the discretion of the treating physician if clinically necessa1y. Local 
applications of cold compresses and moisturizing creams are preferable over systemic agents for 
the management of local reactions. l11e use of topical or systemic steroids should be rese,ved for 
severe injection site reactions. Topical or systemic non-steroidal anti-inflammatory or 
antihistamine medications may be used as an alternative, however routine use to prevent 
injection site reactions should be avoided, and doses should be the lninimum necessa1y for 
appropriate clinical management. Neoantigen Vaccine injection sites may be shifted in order to 
avoid administe1ing injections to areas with evidence of persistent local reaction. The injection 
will occur on the same extremity ( or flank). 
6.2.2.2 
Systemic Reactions 
Flu-like symptoms: Participants who develop flu-like symptoms that are controlled with 
acetaminophen or non-steroidal anti-inflanuuato1y drugs given at the discretion of the 
investigator may be pre-treated with acetaminophen (650 mg PO) or ibuprofen (400-600 mg 
PO) 
Hypersensitivity reactions: Participants who develop grade 1 or 2 allergic reactions may continue 
to receive NeoVax plus Montanide study injections following discussion with the smdy PI as 
long as: 
1) The patticipant is made aware of the potential risk for future reactions, including
potentially life-threatening reactions, and consents to continue treatment
2) The participant is pre-medicated with an anti-histamine and H-2 blocker. Premedication
with corticosteroids may also be considered, but should be used judiciously in order to
decrease potential ability of these agents to dintinish the vaccine's effectiveness
3) At the next dosing visit, the patient is observed for at least 4 hom-s after the vaccination
Pa11icipants who develop grade 3 or 4 allergic reactions attributable to NeoVax plus Montanide 
administration should not receive fmther vaccination therapy and should discontinue study 
therapy. 
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6.3 
Dose Modifications/Delays 
6.3.1 
Nlvolumab 
Dose Modifications 
Dose reductions or dose escalations are not penuitted. 
Dose Delay Criteria 
DP/HCC Protocol #:18-279 
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Because of the potential for clinically meaningful Nivolumab-related AEs requiring early 
recognition an<l prom1>t lnten•ention, management algorithms have been developed for 
suspected AEs of selected categories (listed in Appendix B). 
•
Gastrointestinal
•
Renal
•
Pulmonruy
•
Hepatic
•
Endocrinopathies
•
Skin
•
Neurological
Dose delay criteria apply for all drug-related adverse events (regardless of whetber or not tbe 
event is a.tbibuted to Nivolumab). All study drugs must be delayed until treatment can resume. 
Dose delay ciiteria apply for all <hug-related AEs. Nivolumab must be delayed until treatment 
can resume 
Nivolumab administration should be delayed fo1· the following: 
Any GradeÌ 2 non-skin, drng-related AE, with the following exceptions: 
•
Grade 2 chug-related fatigue or laborato1y abnonnalities do not require a treatment delay
•
Any Grade 3 skin, ch11g-related AE
Any Grade 3 chug-related laboratory abnonnality, with the following exceptions for 
lymphopenia, lenkopenia, AST, ALT, total bilirnbin, or asymptomatic amylase or lipase: 
•
Grade 3 lymphopenia or leukopenia does not require dose delay.
•
If a subject has a baseline AST, ALT, or total bilirnbin tbat is within nonnal limits, delay
dosing for ch11g-related GradeÍ 2 toxicity.
•
If a subject has baseline AST, ALT, or total bili.rubin within the Grade 1 toxicity range,
delay dosing for drng-related GradeÍ 3 toxicity.
•
Asymptomatic amylase or lipase do not require a treatment delay
Any AE, laborato1y abnonnality, or intercmTent illness which, in the judgment of the 
investigator, wammts delaying the dose of study medication. 
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Criteria to Resume Treatment 
DP/HCC Protocol #:18-279 
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Subjects may resume treatment with Nivolumab when the dmg-related AE(s) resolve to 
Grade ::;1 or baseline value, with the following exceptions: 
•
Subjects may resume treatment in the presence of Grade 2 fatigue
•
Subjects who have not experienced a Grade 3 dmg-related skin AE may resmue
treatment in the presence of Grade 2 skin toxicity
•
Subjects with baseline Grade 1 AST/ALT or total bilimbin who require dose delays for
reasons other than a 2-grade shift in AST/ALT or total bilirnbiI1 may resume treatment in
the presence of Grade 2 AST/ALT OR total biliI11bin
•
Subjects with combined Grade 2 AST/ALT AND total biliI11bin values meeting
discontinuation parameters should have treatment permanently discontinued
•
Drng-related puhuona1y toxicity, dianhea, or colitis, must have resolved to baseline
before treatment is resumed
•
Drng-related endocrinopathies adequately controlled with only physiologic ho1mone
replacement may resume treatment
If the criteria to restnne treatment are met, the subject should restart treatment at the next 
scheduled timepoint per protocol. However, if tile treatment is delayed past tile next scheduled 
timepoint per protocol, the next scheduled timepoint will be delayed until dosing resumes. 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in discontinuation section. 
Discontinuation Criteria 
Treatment should be pennanently discontinued for tile following: 
•
Any Grade 2 drug-related uveitis or eye pain or bluned vision that does not respond to
topical therapy and does not improve to Grade I severity within the re-treatment period
OR requires systemic treatment
•
Any Grade 3 non-skin, drng-related adverse event lasting > 7 days, witll tile following
exceptions 
for 
drng-related 
laborato1y 
abnonnalities, 
uve1t1s, 
pneumonitis,
bronchospasm, dianhea, colitis, neurologic adverse event, hypersensitivity reactions, and
iI1fusion reactions
o
Grade 3 <hug-related uveitis, pneumonitis, bronchospasm, dianhea, colitis,
neurologic adverse event, hypersensitivity reaction, or infusion reaction of any
duration requires discontinuation
o
Grade 3 dJ.·ug-related laborato1y abno1malities do not requfre treatment
discontinuation except tllose noted below
•
Grade 3 drng-related thrombocytopenia > 7 days or associated with bleeding
requires discontinuation
•
Any drng-related liver fi.tnction test (LFT) abno1mality that meets the
following criteria require discontinuation:
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AST or ALT> 8 x ULN 
Total bilirnbin > 5 x ULN 
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ConcmTent AST or ALT> 3 x ULN and total bilirnbin > 2 x ULN 
•
Any Grade 4 drng-related adverse event or laborato1y abno1mality, except for the
following events which do not require discontinuation:
•
Isolated Grade 4 amylase or lipase abno1malities that are not associated with
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4
within 1 week of onset.
•
Isolated Grade 4 electrolyte imbalances/abnonnalities that are not associated with
clinical sequelae and are conected with supplementation/approp1iate management
within 72 homs of their onset
•
Any dosing inte1111ption lasting> 6 weeks with the following exceptions:
•
Dosing intem.1ptions to allow for prolonged steroid tapers to manage drug-related
adverse events are allowed. Prior to re-initiating treatment in a subject with a
dosing intenuption lasting > 6 weeks, the P1incipal Investigator must be
consulted. Tumor assessments should continue as per protocol even if dosing is
inte1111pted
•
Dosing inte1111ptions > 6 weeks that occur for non-drng-related reasons may be
allowed if approved by the Principal Investigator. Prior to re-initiating treatment
in a subject with a dosing inte1ruption lasting > 6 weeks, the Investigator must be
consulted. Tmuor assessments should continue as per protocol even if dosing is
inten11pted
•
Any adverse event, laborato1y abnormality, or intercun-ent illness which, in the
judgment of the Piincipal Investigator, presents a substantial clinical risk to the subject
with continued Nivolmnab dosing
6.3.2 
NeoVax plus Montanide 
6.3.2.1 
If a participant develops grade 3 toxicity attributable to the vaccine, additional 
treatment will be withheld tmtil the toxicity has resolved or improved to grade 1. If 
the toxicity constitutes a DLT as defined in 5.6, the participant will be removed from 
the study. If the toxicity does not fulfill the criteria of a DLT, the nei.1 vaccine 
administration may be delayed for a maximum duration of 14 days. If vaccine dosing 
bas to be delayed more than 2 times because of an attributable toxicity that is not 
considered a DLT, the participant will be removed from the study 
6.3.2.2 
If a pa11icipant develops grade 4 toxicity attributable to the vaccine s/he will be 
removed from treatment 
6.3.2.3 
If two or more grade 4 or greater toxicities attributable to the vaccine are obse1ved, 
the trial will be suspended to investigate the causes of these (rn1expected) toxicities 
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6.3.2.4 
Vaccine dosing may be delayed in the event of unrelated adverse events if it is felt to 
be in the medical best interest of the patient following discussion by the treating 
investigator with the sn1dy Pincipal Investigator or designee. Vaccine dosing may be 
resmued once the treating investigator deems it is medically safe to do so following 
discussion with the sn1dy Principal Investigator or designee as long as the pa1ticipant 
has not developed progressive disease 
6.3.3 
lpilimumab 
6.3.3.1 
Treatment oflpilimumab Related Infusion Reactions 
Since Ipilimumab contains only human inuuunoglobulin protein sequences, it is unlikely to be 
iimuunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pnnitis, artln·algias, hypo- or 
hypenension, bronchospasm, or other symptoms. 
All Grade 3 or 4 injection reactions should be reported as an SAE if c1ite1ia are met. Injection 
reactions should be graded according to NCI CTCAE (CTEP Active Version (version 5.0) of the 
NCI Common Terminology Criteria for Adverse Events (CTCAE) which is identified and 
located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electrnnic applications/ctc.htm guidelines). 
Treatment reco1muendations are provided below and may be modified based on local treatment 
standards and guidelines as approp1iate: 
For Grade 1 symptoms: (Mild reaction; inte1vention not indicated) Remain at bedside and 
monitor subject until recovery from symptoms. The following prophylactic premedications are 
recormuended for future ii1jections: diphenhydramille 50 mg (or equivalent) and/or paracetamol 
325 to 1000 mg (acetaminophen) at least 30 minutes before additional Ipil.inmmab 
administrations. 
For Gracie 2 symptoms: (Moderate reaction requires therapy or injection inte1ruption but 
responds promptly to symptomatic treatment [ eg, antihistamines, non-steroidal anti­
inflammatory clrngs, narcotics, co1ticosteroicls, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours) 
Stop Ipilimumab injections, begin an IV infosion of normal saline, and treat the subject with 
diphenhydrarnine 50 mg IV ( or equivalent) and/or paracetamol 325 to J 000 mg (acetaminophen); 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid or 
bronchodilator therapy may also be administered as appropriate. The followii1g prophylactic 
premedications are recommended for funire injections: diphenbydrarnine 50 mg ( or equivalent) 
and/or paracetamol 325 to l000 mg (acetaminophen) should be administered at least 30 minutes 
before additional Ipiliinumab administrations. If necessa1y, corticosteroids (recommended dose: 
up to 25 mg of IV hydroco11isone or equivalent) may be used. 
For Grade 3 or Gracie 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication; rectm·ence of symptoms following ii1itial improvement; 
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hospitalization indicated for other clinical sequelae [ eg, renal in1pailment, pulmona1y 
il1filtrates]). Grade 4: (life threatening; pressor or ventilatory support il1dicated). 
Stop lpilinmmab il1jections. Begin an IV infosion of nomial saline and treat the subject as 
follows. Recommend bronchodilators, epineplu·ine 0.2 to l mg of a l: 1,000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydra1nine 50 mg IV with methylprednisolone l 00 mg IV ( or 
equivalent), as needed. Subject should be monitored until the investigator is comfortable that the 
symptoms will not recm. Ipilimmnab will be permanently discontinued. Investigators should 
follow their illstitutional guidelines for the treatment of anaphylaxis. Remaill at bedside and
monitor subject tmtil recove1y from symptoms. In the case of late-occuning hypersensitivity 
symptoms (eg, appearance of a localized or generalized prnritis within l week after treatment), 
symptomatic treatment may be given (eg, oral antihistamine, or corticosteroids). 
6.3.3.2 
lpilimumab should be delayed for the foDowing: 
Any Grade 2: 2 non-skin, drug-related AE, with the following exceptions: 
•
Grade 2 drng-related fatigue or laboratory abnomialities do not requil·e a treatment delay
•
Any Grade 3 skin, drug-related AE
Any Grade 3 drng-related laborato1y abno1mality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, total biliI11bin, or asymptomatic amylase or lipase: 
•
Grade 3 lymphopenia or leukopenia does not require dose delay.
•
If a subject has a baseline AST, ALT, or total bilil11bin that is within n01mal lilnits, delay
dosing for drng-related Grade 2: 2 toxicity.
•
If a subject has baseline AST, ALT, or total biliI11bill withill the Grade l toxicity range,
delay dosillg for drug-related Grade 2: 3 toxicity.
•
Asymptomatic amylase or lipase do not requfre a treatment delay
Any AE, laboratory abnonnality, or illterctuTent illness which, ill the judgment of the 
iI1vestigator, wanants delayillg the dose of study medication. 
6.4 
Criteria to Resume Treatment 
Subjects may resmue ti-eatment with Ipililumnab and NeoVax plus Montanide when the drug­
rela.ted AE(s) resolve to Grade ::cl or baselille value, with the following exceptions: 
•
Subjects may resmne ti-eatment in the presence of Grade 2 fatigue
•
Subjects who have not expe1ienced a Grade 3 drng-related skill AE may restlllle
treatment in the presence of Grade 2 skin toxicity
•
Subjects with baseline Grade l AST/ALT or total biliI11bill who requil·e dose delays for
reasons other than a 2-grade shin in AST/ALT or total bilirubil1 may resume treatment ill
the presence of Grade 2 AST/ALT OR total biliI11bill
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•
Subjects with combined Grade 2 AST/ALT AND total bilirnbin values meeting
disconti1mation parameters should have treatment pennanently discontinued
•
Drng-related pulmona1y toxicity, diarrhea, or colitis, must have resolved to baseline
before treatment is resumed
•
Drng-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment 
If the criteria to resume treatment are met, the subject should restaii treatment at the next 
scheduled timepoint per protocol. However, if the treatment is delayed past the next scheduled 
timepoint per protocol, the next scheduled timepoint will be delayed until dosing resmues. 
If treatment is delayed> 6 weeks, the subject must be permanently discontinued from snidy 
therapy, except as specified in discontinuation section. 
6.5 
Discontinuation crite1ia
Treatment should be penuanently discontinued for the following: 
•
Any Grade 2 drng-related uveitis or eye pain or blurred vision that does not respond to
topical therapy and does not improve to Grade l severity within the re-treatment period
OR requires systemic treatment
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following
exceptions 
for 
drng-related 
laborato,y 
abnormalities, 
uverus, 
pnewnonltls,
bronchospasm, dianhea, colitis, neurologic adverse event, hypersensitivity reactions, and
injection reactions
o
Grade 3 drng-related uveitis, pnetunonitis, bronchospasm, diarrhea, colitis,
nemologic adverse event, hypersensitivity reaction, or injection reaction of any
dmation requires discontinuation
o
Grade 3 drng-related laboratory abnormalities do not require treatment
discontinuation except those noted below
•
Grade 3 d11.1g-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation 
•
Any drug-related liver function test (LFT) abno1mality that meets the
following crite1ia require discontinuation:
AST or ALT> 8 x ULN 
•
Total bilirubin > 5 x ULN
•
ConctuTent AST or ALT> 3 x ULN and total bilirubin > 2 x ULN
•
Any Grade 4 drug-related adverse event or laborato,y abnonnality, except for the
following events which do not require discontinuation:
•
Isolated Grade 4 amylase or lipase abno1malities that are not associated with
sympto111S or clinical manifestations of pancreatitis and decrease to < Grade 4
within 1 week of onset.
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DP/HCC Protocol #:18-279 
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•
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with
clinical sequelae and are con-ected with supplementation/approp1iate management
within 72 hours of their onset
•
Any dosing intenuption lasting> 6 weeks with the following exceptions:
•
Dosing intem1ptions to allow for prolonged steroid tapers to manage drug-related
adverse events are allowed. Prior to re-initiating treatment in a subject with a
dosing intenuption la.sting > 6 weeks, the Principal Investigator must be
consulted. Tumor assessments should continue as per protocol even if dosing is
intem1pted
•
Dosing inte1n1ptions > 6 weeks that occur for non-dn1g-related reasons may be
allowed if approved by the Principal Investigator. Prior to re-initiating treatment
in a subject with a dosing intenuption lasting > 6 weeks, the Investigator must be
consulted. Tumor assessments should continue as per protocol even if dosing is
inten11pted
•
Any adverse event, laborato1y abnomiality, or intercun-ent ilh!ess which, in the
judgment of the Principal Investigator, presents a substantial clinical risk to the
subject with continued Ipilimumab dosing
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
7.1 
Adverse Event Definition and Characteristics 
7.1.1 
Denultlons 
ADVERSE EVENTS 
An Adverse Event (AE) is defined a.s any new untoward medical occwTence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign ( such as an abnonnal laboratory finding), symptom, or 
disease temporally associated with the use of investigational product, whether or not considered 
related to the investigational product. 
A non-serious adverse event is an AE not classified as serious. 
SERIOUS ADVERSE EVENTS 
A Serious Adverse Event (SAE) is any Witoward medical occun-ence that at any dose: 
•
results in death
•
is li.fe-tlu·eatening ( defined as an event in which the pa1ticipant was at risk of death at the
time of the event; it does not refer to an event which hypothetically might have caused death
if it were more severe)
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•
requires inpatient hospitalization or causes prolongation of existing hospitalization
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/bi.Ith defect
•
is an impo1tant medical event (defined as a medical event(s) that may not be immediately
life-threatening or result in death or hospitalization but, based upon approp1iate medical and
scientific judgment, may jeopardize the subject or may require i.t1tervention [ eg, medical,
smgical) to prevent one of the other serious outcomes listed in the definition above.)
Examples of such events include, but are not muted to, intensive treatment in an emergency
room or at home for aJlergic bronchospasm; blood dyscrasias or convulsions that do not
result in hospitalization.)
•
Suspected transnussion of an infectious agent (eg, pathogenic or nonpathogenic) via the
study dnig is an SAE.
Adverse event (AE) monitoring and repo1tillg is a routille part of every clinical trial. The 
following list of reported and/or potential AEs (Section 7 .9) and the characteristics of an 
observed AE (Section 7 .1) will detennine whether the event requires expedited reporting in 
addition to routine reporting. 
7.1.2 
Adverse Event Charncte1istlcs 
•
CTCAE term (AE description) an<l grade: The desc1iptions and grading scales found
i.11 the revised NCI Cormnon Temunology Criteria for Adverse Events (CTCAE) version
5.0 will be utilized for AE reporting. All approp1iate treatment areas should have access
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be
downloaded from the CTEP web site:
http://ctep.cancer.gov/protocoJDevelopment/electronic applications/ctc.htm.
•
For expedited reporting purposes only:
-
AEs for the agent(s) that are listed above should be repo1ted only if the adverse event
vaiies in nature, intensity or frequency from the expected toxicity illfo1mation which
is provided.
-
Other AEs for the protocol that do not require expedited repo11ing are outlined in the
next section (Expedited Adverse Event Repo1ting) under the sub-headi.t1g of Protocol­
Specific Expedited Adverse Event Reporting Exclusions.
•
Attribution of the AE:
-
Definite - l11e AE is clearly related to the study ti-eatment.
-
Probable - The AE is likey related to the study treatment.
-
Possible - The AE 111ay be ,·elared to the study treatment.
-
Unlikely - The AE is doubtfully related to the study treatment.
-
Umelated - The AE is clearly NOT related to the study treatment.
7.2 
AE and SAE Recording aod Reporting 
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
The study must be conducted in compliance with FDA regulations, local safety repo1ting 
requirements, and reporting requirements of the principal investigator. 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report fonns. AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must !h2 be reported in routine study data submissions. 
It is the responsibility of each participating investigator to report serious adverse events to the 
study sponsor and/or others as described below. 
7 .2 .1 
Non-Setious Adverse Events 
Non-se1ious adverse events will be reported to the DF/HCC Overall Principal Investigator on the 
toxicity Case Report Fonns. 
Reporting Non-Serious Adverse Events to BMS 
•
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or
final study reports as specified in the agreement or, if a regulat01y requirement [eg, IND
US trial] as part of an allllual reporting requirement.
•
Non-serious AE infonuation should also be collected from following the subject's written
consent to participate in the sn1dy.
The collection of non-serious AE infomiation should begin following the subject's written 
consent to pa1ticipate in the study. All non-serious adverse events (not only those deemed to be 
treatment-related) should be collected continuously during the treatment period and for a 
minimwn of I 00 days following the last dose of study treatment. 
Non-serious AEs should be followed to resolution or stabilization, or repo1ted as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause inte1111ption or 
disconti1mation of study drug and for those present at the end of sn1dy treatment as approp1iate. 
Labot·atory Test Abnormalities 
All laborato1y test results captured as pa1t of the sn1dy should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and repo1ted to BMS as 
such. 
Tue following laborato1y abnonnalities should be documented and repo1ted appropriately: 
•
any laborat:01y test result that is clinically significant: or meets the defmition of an SAE
•
any labora.to1y abnormality that required the participant to have study drug discontinued or 
intenupted 
•
any laboratory abnomiality that required the subject to receive specific con-ective therapy.
It is expected that wherever possible, the clinical rather than laborato1y tenn would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value). 
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7 .2 .2 
Serious Adverse Events 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
All se1ious adverse events that occw· after the initial dose of study treatment, dming treatment, or 
within 30 days of the last dose of treatment must be reported to the OF/HCC Overall Principal 
Investigator on the local institutional SAE fo1m. This includes events meeting the crite1ia 
outlined in Section 11.1.2, as well as tl!e following: 
•
Grade 2 (moderate) and Grade 3 (severe) Events - that are Unexpected and there is a
Reasonable Possibility that the Adverse Event is related to the study inte1vention
•
All Grade 4 (life-threatening or disabling) Events - Repo1t all events that are Unexpected.
Events that are expected and listed within the protocol and /or cwTent consent fo1m do not
need to be repo1ted to the DFCI IRB. Please not, an event that present at a higher severity
than what is cmTently listed within protocol and/or cunent consent as expected would be
considered unexpected and repo,table.
•
All Grade 5 (fatal) Events - When the patient is enrolled and actively participating in the
tiial OR when the event occm·s within 30 days of the last study intervention.
Note: If the patient is in long tenn follow up, repo1t the death at the time of continuing
review.
•
Although pregnancy and potential drng-induced liver injmy (DILi), are not always serious
by regulatory definition, however, these events must be reported within the SAEs timeline.
o
Potential drng induced liver injmy is defined as:
I. AT (ALT or AST) elevation> 3 times upper limit of nonnal (ULN)
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
senun alkaline phosphatase)
AND 
3. No other inllllediately apparent possible causes of AT elevation and
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing
chronic or acute liver disease, or the administration of other drug(s) known to
be hepatotoxic.
•
Any component of a study endpoint that is considered related to smdy therapy should be
reported as an SAE ( eg, death is an endpoint, if death occmTed due to anaphylaxis,
anapbylaxis must be reported).
•
Any significant worsening noted during inte1im or final physical exanlinations,
electrocardiograms, X-rays, and any other potential safety assessments, whether or not
these procedures are required by tl!e protocol, should also be recorded as a non-se1ious or
serious AE, as appropriate, and repo,ted accordingly.
7 .2.3 
DFIHCC Reportable Adverse Events 
•
In the event of an unanticipated problem or life-threatening complications treating
investigators must immediately notify the Overall PI.
•
Investigators must repo11 to the Overall PI any adverse event (AE) that occtu-s after the 
initial dose of study treatment, dming treatment, or within 30 days of the last dose of 
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
treatment on the local institutional SAE form. 
•
Adverse Events Reporting Guidelines
All participating sites will report AEs to the Sponsor-Investigator per DF/HCC
requirements, and the IRB of record for each site as applicable per IRB policies. The table
below indicates which events must be reported to the DF/HCC Sponsor-Investigator:
OF/HCC Reportable Adverse Events(AEs) 
Gr.2&3AE 
Gr.2&3AE 
Gr. 4 AE Expected 
Gr. 4AE 
Gr. 5 AE 
Attribution 
Expected 
Unexpected 
Unexpected 
Expected or 
Unexpected 
Unrelated 
Not required 
Not required 
5 calendar days• 
5 calendar days 
24 hours• 
Unlikely 
Possible 
Probable 
Not required 
5 calendar days 
5 calendar days• 
5 calendar days 
24 hours• 
Definite 
# If listed in protocol as expected and not requiring exped·ed reporting, event does not need to be reported. 
• For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last
intervention, events must be reported w¸hin 1 business da)! of learning of the event.
The following information regarding injection site reaction(s) will be collected during the visits 
belonging to the vaccine treatment period for both peptide pools and ipilimuma.b injections: 
•
Erythema/redness: yes/no. If yes length /width will be provided
•
Induration/swelling: yes/no. If yes length /width will be provided
•
Warmth: yes/no
•
Prnritus: yes/no
•
Other (if applicable)
7.3 
Reporting to the Food aod Drug Administration (FDA) 
The Overall PI, as snidy sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occunence, any serious adverse event 
that meets the FD A's criteria for expedited rep01ting following the repotting requirements and 
timelines set by the FDA. 
7.4 
Reporting to Study Sponsor 
Paiticipating investigators must report each serious adverse event to the DF/HCC Overall 
Principal Investigator and Study Sponsor (Dr Patrick Ott, DFCI) within 24 homs of learning of 
the 
occun-ence 
using 
the 
Medwatch 
3500A. 
The 
form 
can 
be 
found here: 
https://w-ww.fda.e:ov/safetv/medical-product-safetv-infonuation/medwatch-forms-fda-safetv­
reportine:. In the event that the participating investigator does not become aware of the serious 
adverse event immediately (e.g., patient sought treatment elsewhere), the participating 
investigator is to repoit the event within 24 homs after learning of it and docmnent the time of 
his or her first awareness of the adverse event. Report se1ious adverse events by telephone, email 
or facsimile to: 
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D1''/HCC Overall PI/ Study Sponsor 
Patrick 011, MD, PhD 
DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Within the following 24-48 hours, the pa1t1c1pating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the 
event has resolved or continues, if and how the event was treated, and whether the patient will 
continue or discontinue study patticipation. 
Oncovir, Inc. and SEPPIC will be provided with a simultaneous copy of all adverse events filed 
with the FDA. 
7.5 
R,porting SAEs to BMS 
All SAEs that occur following the subject's written consent to participate in the study thrnugh 
100 days of discontinuation of dosing must be repo1ted to BMS Worldwide Safety, whether 
related or not related lo study dmg, including those thought lo be associated with protocol­
specified procedures (eg, a follow-up skin biopsy) within 24 hours\ 1 business day to comply 
with regulato1y requirements. MedWatch 3500A fo1m should be completed and submil1ed to 
BMS to repo11 the SAEs. 
Note: Please include the BMS Protocol number on the SAE form or on the cover sheet uitb the SAE form 
tr11nsmission 
An SAE report should be completed for any event where doubt exists regarding its seriousness; 
if the investigator believes that an SAE is not related to study dmg, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the nanative section of tbe SAE Report Form. 
Investigators should repot1 to the responsible regulatory authority as appropriate. 
All SAEs must be reported by confumed facsimile (fax) transmission or repo11ed via electrnnic 
mail to the below email address and the BMS Protocol number must be included on the SAE 
f01m or on the cover sheet with the SAE fo1m transmission 
SAE Email Address: 
SAE Facsimile Number 
If only limited info1mation is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
be-comes available, a follow-up SAE report should be sent within 24 hours \ I Business Day to 
BMS using the same procedure used for transmitting the initial S . .<\E report. 
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All SAEs should be followed to resolution or stabilization. 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
The causal relationship to sn1dy drug is dete1mined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following: 
•
Related: There is a reasonable causal relationship between study drng administration and
the AE.
•
Not related: There is not a reasonable causal relationship between study drng
administration and the AE.
Tue tenn "reasonable causal relationship" means there ts evidence to suggest a causal 
relationship. 
Adverse events can be spontaneously repo1ted or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occ1m·ence of one or more AEs.) 
Tue Sponsor-Investigator will reconcile the clinical database AE cases 
transmitted to BMS Global Pha1macovigilance 
-
The Investigator will request from BMS GPV &E,
the SAE 
reconciliation report and include the BMS protoco
data base lock or final data smumary
-
GPV&E will send the investigator the repott to verify and confinu all AE and SAEs have
been transmitted to BMS GPV &E.
-
The data elements listed on the GPV &E reconciliation repo1t will be used for case
identification purposes. If the Investigator determines a case was not transmitted to BMS
GPV &E, the case should be sent ll111llediately to BMS
In addition to the Sponsor Investigator's responsibility to report events to their local HA, 
suspected serious adverse reactions (whether expected or llllexpected) shall be repotted by BMS 
to the relevant competent health authorities in all concerned countries according to local 
regulations (either as expedited and/or in aggregate repo1ts). 
In accordance with local regulations, BMS will notify sponsor investigators of all repo11ed SAEs 
that are suspected (related to the investigational product) and unexpected (ie, not previously 
desc11bed in the IB). An event meeting these c1iteria is tenued a Suspected, Unexpected Setious 
Adverse Reaction (SUSAR). Sponsor investigator notification of these events will be in the fo1m 
of either a SUSAR Report or a Semi-Annual SUSAR Report. 
•
Other important findings which may be reported by BMS as an Expedited Safety Rep01t
(ESR) include: increased frequency of a clinically significant expected SAE, an SAE
considered associated with study procedures that could modify the conduct of the study,
la.ck of efficacy that poses significant hazard to sn1dy subjects, clinically significant
safety finding from a nonclinical ( eg, animal) study, impo11ant safety recommendations
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
from a study data monitoring committee, or sponsor or BMS decision to end or 
temporarily halt a clinical study for safety reasons. 
•
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with
the IB. Where required by local regulations or when there is a central IRB/IEC for the
study, the sponsor will submit the ESR to the approp1iate IRB/IEC. The investigator and
IRB/IEC will detenuine if the informed consent requires revision. The investigator
should also comply with the IRB/IEC procedures for reporting any other safety
infonnation.
7.5.1 
Reporting Pregnancy event to BMS 
If it is discovered a patient is pregnant or may have been pregnant at the time of exposure to the 
BMS product associated with this study, including dw·ing at least 5 half-lives after product 
administration, the pregnancy, AEs associated with maternal exposme and pregnancy outcomes 
must be repo11ed and submitted to BMS on a BMS Pregnancy Smveillance Fonn or the 
MedWatch or approved site SAE fonn, and repo11ed to BMS within 24 hours/I business day by 
confumed fax or repo1ted via electronic mail t 
If only limited 
infonnation is initially available, follow up reports may e requu:e . our ongmal fonns are to 
remain on site. Protocol-required procedmes for study discontinuation and follow-up must be 
perfonned on the pa11icipant. 
Follow-up info1mation regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring infonnation must be repo11ed on the MedWatch, BMS 
Pregnancy Stu:veillance Form, .!!!..approved site SAE form. ABMS Pregnancy Swveillance Form 
may be provided upon request. 
7.6 
Reporting to lb• Iustitulioual Rrview Board (IRB) 
Investigative sites within DF/HCC will report all serious adverse events directly to the DFCI 
Office for Hwuan Research Studies (OHRS). 
7. 7
Repo111ug to Hospital Risk Management 
Pa11icipating investigators will report to their local Risk Management office any pa1ticipant 
safety reports, sentinel events or unanticipated problems that require reporting per institutional 
policy. 
7 .8 
Expect eel Toxicities 
A list of the adverse events and potential risks associated with the agents administered in this 
study appears below and will detenuine whether dose delays and modifications will be made or 
whether the event requires expedited reporting in addition to routine repo1ting. 
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7.8.1 
Adverse Events List 
7.8.1.1 
Adverse Event List for poly-ICLC 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Poly-ICLC is an investigational agent; however there has been significant experience in previous 
clinical trials as discussed in 2.3. The safety profile has been acceptable.These reactions have 
been generally mild to moderate and transient for most patients in previous studies. 
Localized reactions: 
•
Transient ( <24 h) injection fluid accumulation
•
Erythema
•
Bruising
•
Induration
•
Prnritus
•
Edema
•
Localized rash
•
Peri.oral nmnbness
Systemic reactions: 
Flu-like symptoms, including: 
•
Malaise
•
Fatigue
•
Myalgia/arthralgia
•
Headache
•
Fever
•
Chills
•
Dizziness
•
Elevated blood pressure
•
Elevated pulse rate
•
Shortness of breath
7.8.1.2 
Adverse Event List for Personalized NeoAutigeo Pepti,les 
Localized reactions or systemic reactions are expected but they are anticipated to be mild to 
moderate in the majority of cases: 
Localized reactions: 
•
Elythema
•
Bruising
•
Induration
•
Prnritus
•
Edema
•
Localized rash
•
Perioral numbness
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Systemic reactions: 
Flu-like symptoms, including: 
•
Malaise
•
Fatigue
•
Myalgia/a11bralgia
•
Headache
•
Fever
•
Chills
•
Arthralgia
•
Dizziness
•
Flushing
•
Elevated blood pressure
•
Elevated pulse rate
•
Shortness of breath
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Hypersensitivity reactions represent allergic reactions. Hypersensitivity reactions typically occur 
in an inunediate fashion (i.e. within the same day as the vaccination) although they may be 
delayed with onset of symptoms from one day to weeks after vaccination. Symptoms typically 
include mild to moderate pmritns, erythema, flushing, rash, perioral munbness, lightheadedness, 
shortness of breath, myalgia and increased pulse, blood pressure and temperature. Precautions 
should be taken to prepare for the possibility of hypersensitivity reactions after Neo Vax plus 
Montanide administration. Patients should be observed for a mininnun of one hour following 
vaccination in order to evaluate and treat any immediate hypersensitivity reactions. The use of all 
routine supportive medication is permitted for hypersensitivity reactions, although routine use of 
prophylactic antihistamines, non-steroidal anti-inflanunato1y agents and concomitant 
co1iicosteroids are to be avoided if at all possible. If used, doses of co1iicosteroids should be the 
minimum necessa1y for appropriate clinical management. If any new administration or increased 
dose of systemic corticosteroids is necessary, every effo1i should be taken to taper, and 
preferably discontinue treatment with them as quickly as clinically feasible. 
Autoimmune diseases: In principle, the mechanisms that allow the immune system to recognize 
nunor antigens could also lead to breakdown of tolerance to native or self-antigens, generating 
an autoinmume reaction. Thus, symptoms that mimic autoinmume diseases or other autoinunune 
reactions are a theoretical possibility for which pa1iicipants will be monitored. 
7.8.1.3 
Adverse Event List ror Montanlde 
Monatnide has been generally well tolerated and induces transient local reactions such as 
tenderness, erythema, or edema at the injection site. Transient general reactions including fever, 
headache, and flu-like symptoms have also been obse,ved. 
7.8.1.4 
Adverse Event Li.st for Nlvolumab 
Immuno-oncology agents such as Nivolumab are associated with AEs that can differ in severity 
and duration from AEs caused by other therapeutic classes. Early recognition and management 
of AEs associated with Nivolumab may mitigate severe toxicity. Immlille related AEs have been 
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observed in the following organ systems: 
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathies
•
Skin
•
Nem-ological
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
In a previous large phase I study, the most frequently repo1ted AEs were fatigue (54.9%), 
decreased appetite (35.0%), dianhea (343%), nausea (30.1 %), and cough (29.4%)10. Treatment­
related AEs were repo11ed in 230 (75.2%) of the 306 subjects. The most frequently reported
treatment-related AEs were fatigue (28.1%), rash (14.7%), dia□-hea (13.4%), and prnritus 
(10.5%)10. Most treatment-related AEs were low grade. Treatment-related high grade (Grade 3-
4) AEs were repo1ted in 52 (I 7.0%) of subjects. The most frequently reported treatment-related
high-grade AE was fatigue (6.5%).
7.8. l.5 
Adverse Events ro,· lplllmumab 
Localized reactions: 
•
Eiythema
•
Iuduration
•
Prnritus
•
Edema
•
Localized rash
The systemic exposure of patients to Ipilimuma.b will be significantly lower than the exposure 
according to approved dosing reginien for melanoma (3 mg/kg q3weeks x4) as shown in the 
Table below. 
Table 1. Dose Le,-,e.t Descdption and Comparison to Appro,-,ed lpilimnmab Dosing Regimen* 
Yaecination Phase 
Cohort Dose Lerel Loca.lized Ipilimwna.b ... 
Approred 
Relative 
IDilimumab*** 
I T'IM'ISure.**** 
Cohort -1 Dose 
015 ml per injection site 
630mgonr 
I 60 
Lenl-1 
10 m11. onr first 63 davs 
63 davs 
Cohort l Dose 
0.5 ml per injection site 
630mgoYer 
lf30 
Lerel l 
20 mg onr first 63 davs 
63 days 
Cohort 2 Dose 
I ml per injection site 
630 mg o,·er 
1115 
Le,·el 2
40 m2 over first 22 davs 
63 davs 
•Tue Neoantigen Vaccine dose is identical for all injections: 300 µg of each ofup to 10 peptides per injection site+ 0.5 mg
Poly•ICLC (Hiltonol®) + I ml.. Montanide per injection site
•• Localized Ipiliwwuab dosing: 5 mg/ml dosage form; 4 injection sites/day; 5 injection days
•n Approved Ipilimumab dosing: 3 mglkgi q3weeks X4 
••••Relative exposure is calctdated as the mass oflpifunumab delivered subcutaneously divided by that delivered systemically 
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
The dose of lpilimumab will va1y between 1.25 and 5 mg per injection site dming the MTD 
detenuination phase. At the highest dose of Ipilimumab planned (5 mg Ipilinuunab at each 
vaccination site with the vaccine), the maximal exposure would be 140 mg over 20 weeks, about 
I I-fold lower than the approved regimen (840 mg for a 70 kg patient given over 10- 16 weeks]. 
Thus, systemic reactions are not expected, but may occur: 
•
Gastrointestinal
•
Renal
•
Pulmonruy
•
Hepatic
•
Endoc1inopathies
•
Skin
•
Neurological
8. PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this stlldy can be found in Section 7.1. 
8.1 
Nlvolumab 
8.1.1 
Oescl'lpttou 
Nivolmnab is a fully hmnan monoclonal innmmoglobulin G4 (IgG4-S228P) antibody that targets 
the programmed death (PD-1) cell surface membrane receptor. 
8.1.2 
Forrn 
Nivolmnab Injection Dmg product is a sterile, non-pyrogenic, single-use, isotonic aqueous 
solution fo1mulated at 10 mg/ml. The solution is a clear to opalescent, colorless to pale liquid 
and may contain pru1icles. It is supplied in I 00mg, I 0mg/ml vials stoppered with butyl stoppers 
and sealed with altuninmn seals. 
8.1.3 
Storage and Stablllty 
Nivolumab must be stored at 2°-8°C (36°-46°F) and protected from light and freezing. IV bags 
containing m1diluted and diluted solutions ofNivolmnab prepared for dosing may be stored up to 
20 hours in a refrigerator at 2°-8°C (36°-46°F) and used within 8 hom·s at room temperanu·e and 
tmder room light. The maximmn 8-hour period tmder room temperature and room light 
conditions for tmdiluted and diluted solutions of Nivolumab injection in the IV bag should be 
inclusive of the product administration period. 
8.1.4 
Compatibillty 
Nivolumab will not be mixed with any other st11dy agents. 
8.1.S 
Availability 
Nivolmnab is an FDA-approved dmg for the treatment of metastatic melanoma and will be 
supplied by Biistol Myers Squibb to the pa11icipating instit11tion's pharmacy. 
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
At the end of the study period, Bristol-Myers Squibb Company will not continue to supply 
Nivolmnab to subjects/investigators unless the Sponsor-Investigator chooses to extend their 
study. Toe investigator is responsible to ensure that you receive approp1iate standard of care or 
other appropriate treatment in the independent medical judgement of the Investigator to treat the 
condition tmder study. 
8.1.6 
Handling and Preparation 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-rnicron 
pore size, low-protein binding (eg, polyethersulfone membrane) in-line filter at the protocol­
specified doses and infosion ti.mes. It is not to be administered as an IV push or bolus injection. 
When the dose is based on patient weight (ie, mg/kg), nivoltunab injection can be infosed 
tmdiluted (10 mg/tnL) or diluted with 0.9% sodium chlotide injection or 5% dextrose injection to 
protein concentrations as low as 0.35 mg/mL. When the dose is fixed (eg, 240 mg, 360 mg, or 
480 mg flat dose), nivolumab injection can be infused undiluted or diluted so as not to exceed a 
total infosion volume of 160 tuL. For patients weighing Jess than 40 kg, the total volume of 
infusion must not exceed 4 mL per kg of patient weight. 
Dming dmg product preparation and handling, vigorous mixing or shaking is to be avoided. Care 
must be taken to ensure sterility of the prepared solution as the product does not contain any 
antimicrobial presetvative or bacteriostatic agent. Nivolumab infusions are compatible with 
polyvinyl chlotide or polyolefin containers and infusion sets, and glass bottles. 
8.1. 7 
Admlnlstratton 
Nivolumab injection is to be administered as an IV infusion, using a volumetric pump with a 0.2 
I 0.22 micron ore size, low-protein binding polyethersulfone membrane in-line filter at the 
protocol-specified doses. 
8.1.8 
Ordering 
Nivolumab will be obtained from Bristol Myers Squibb (BMS) as an Investigator Initiated 
Study. Nivolumab can be ordered from BMS by providing a completed Drng Shipment Fonn. 
8.1.9 
Accountability 
Tue investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drng Accountability Record 
Form (DARF) or another comparable drng accom1tability fonn. (See the NCI Investigator's 
Handbook for Procedures for Drug Accountability and Storage.) 
8.1.10 Destl'uclion and Returu 
At the end of the study, mmsed supplies of Nivolumab should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record 
Fom1. 
8.2 
lpilimumab 
8.2.1 
Descl'iption 
Ipili.rnumab is a fully human monoclonal irnmunoglobulin G he antibody that targets the human 
cytotoxic T lymphocyte antigen 4 (CTLA-4) cell surface membrane receptor. 
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8.2.2 
Form 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Ipilimumab Injection Dn1g product is a ste11le, non-pyrogenic, single-use, isotonic aqueous 
solution formulated at 5 mg/ml (0.9% sodium chloride injection; USP, or 5% dextrose injection). 
Tue solution is a clear to slightly opalescent colorless to pale yellow liquid and may contain a 
small amount of translucent-to-white pa11icles. BMS will provide 50mg/10ml or 200mg/40mL 
vials for this srudy. 
8.2.3 
Storage and Stability 
Ipilimumab must be stored at 2°-8°C (36°-46°F) and protected from light and freezing. Partially 
used vials should be discarded after single use. 
8.2.4 
Compatibility 
Ipilimumab will not be mixed with any other s!lldy agents. 
8.2.5 
Handling 
Vials containing Ipilimumab should not be shaken and should be discarded if cloudy. 
8.2.6 
Availability 
In this protocol, Ipilimumab is an investigational product and will be supplied by Bristol Myers 
Squibb to the participating institution's pharmacy. 
At the end of the study period, Bristol-Myers Squibb Company will not continue to supply 
Ipilimumab to subjects/investigators unless the Sponsor-Investigator chooses to extend their 
study. The investigator is responsible to ensw-e that you receive appropriate standard of care or 
other appropriate ti-eatment in the independent medical judgement of the Investigator to treat tlte 
condition tmder study. 
8.2.7 
Preparation 
Ipilimumab will be used directly from the supplied vial; no fiuther dilution will be required. 
8.2.8 
Admlnlstratlon 
The specified volume of Ipilimumab will be drawn directly into a syringe from the supplied vial. 
Tue needle for witltdrawal from tlte vial will be removed and replaced witlt a needle for 
subcutaneous injection. Filled syringes should be used for injection as soon as possible after 
preparation. 
8.2.9 
Ordering 
Ipilimumab will be obtained from Bristol Myers Squibb (BMS) as an Investigator Initiated 
Study. Ipilimumab can be ordered from BMS by providing a completed Drng Shipment Form. 
8.2.10 Accountability 
The investigator, or a responsible pa11Y designated by the investigator, should maintain a. careful 
record of the inventory and disposition of the agent using the NCI Drng Accountability Record 
Fo1m (DARF) or another comparable chug accountability fo1m. (See the NCI Investigator's 
Handbook for Procedw·es for Drug Accountability and Storage.) 
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DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
8.2.11 Desu·u,Hon and Retw·u 
At the end of the study, unused supplies of lpilimlllllab should be destroyed according to 
institutional policies. Destrnction will be documented in the Drng Accountability Record 
Form. 
8.3.2 
Form 
8.3 
Poly-lCLC (Blltonol'} 
Poly-lCLC is supplied by Oncovir in single-dose vials containing 1 mL of l.8 mg/mL opalescent 
white suspension. Each mililiter of poly-ICLC for injection contains 1.8 mg/mL poly-IC, 1.5 
mg/mL poly-L-lysine, and 5 mg/mL sodium ciuboxymethylcellulose in 0.9% sodium chloride 
solution, adjusted to pH 6-8 with sodium hydroxide. 
8.3.3 
Sror•g• •nd St•bility 
Poly-ICLC is normally shipped or stored refrigerated at about 40°F (2-8°C) but should not be 
frozen. Based on extended fonnal stability data at +5°C ± 3°C and at +25°C ± 2°C, it is 
justified to accept temperattu·e excursions during tt·ausport, shipment and storage of Hiltonol® 
at clinical sites up to +2 7°C for up to 5 days. Likewise, temperat11re deviations between 0°C 
and +2°C are acceptable and have no effect on prnduct quality. 
8.3.4 
Com1»tlbUlty 
Poly-lCLC will be mixed with personalized ueoantigen peptides just p1ior to use to prepare the 
final product (NeoVax plus Montanide). 
8.3.5 
Handling 
There are no specific handling instrnctions for poly-ICLC. 
8.3.6 
Availability 
Poly-ICLC is an investigational agent and has been purchased from Oncovir, Inc. under a 
Clinical Trials Agreement between DFCI and Oncovir, Inc, dated May 2012. Under that 
agreement Oncovir, Inc will grant access to the Drng Master File for poly-ICLC for 
regulatory purposes and provides DFCI infonnation necessa1y to pm·sue the clinical use of 
poly-ICLC. Vials of poly-ICLC sufficient for this clinical trial will be shipped from the 
Hiltonol® storage facility (Bellwyck Packaging, Mississauga, Ontario, Canada) to the DFCI 
Pbarrnacy. Poly-ICLC can be ordered directly from Oncovir, Inc, by submitting a purchase 
order to: 
Oncovir, Inc. 
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8.3. 7 
Preparation 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Poly-ICLC is supplied as an opalescent white suspension. It will be directly withdrawn from 
the vial under sterile conditions and mixed with the personalized neoantigen peptides (see 
Section 8.4. 7). 
Upon allowing the vial to reach room temperature (approximately 1-2 hours), the vial should be 
gently inve11ed about IO times to insure suspension of the fonnulation. Gently tap the vial to 
gather the liquid Sllspension to the bottom of the vial to aid in extracting the required volume for 
dose preparation. If visible particulates or aggregates are present when measured against a black 
background and are not resuspendable or the settled material fails to re-suspend, the vial should 
be placed in quarantine and not used for clinical administration. Obtain a new vial of Poly-ICLC 
for dosage preparation. 
8.3.8 Administration 
Following mixing with the personalized neoantigen peptides, the vaccine (peptide + poly­
ICLC + Montanide) is to be administered subcutaneously. 
8.3.9 
Accountability 
The investigator, or a responsible pa1iy designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drng Accountability Record 
Fo1m (DARF) or another comparable chug accountability fo1m. (See the NCI Investigator's 
Handbook for Procedw·es for Drug Accountability and Storage.) 
8.3.10 Destruction and Returu 
At the end of the study, unused supplies of poly-ICLC will be held by the IND holder for funire 
use until they are out of date at which point they will be destroyed according to institutional 
policies. Destrnction will be docwnented in the Drng Accountability Record Fonn. 
8.4 
Personallzed neoanllgen peptides 
8.4.1 
Oescl'lpllon 
Personalized neoantigen peptides are comprised of up to 20 distinct peptides unique to each 
pa11icipant. Each peptide is a linear polymer of -20 - -30 L-amino acids joined by standard 
peptide bonds. The amino terminus is a primaiy amine (NHz-) and the carboxy te1minus is a 
carbonyl group (-COOH) Only the standard 20 amino acids commonly fotmd in manunalian 
cells are utilized (ala.nine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, 
glycine, histidine, isoleucine, leucine lysine, methionine, phenylalanine, proline, se1ine, 
threonine, tryptophan, tyrosine, valine). The molecular weight of each peptide varies based on 
its length and sequence and is calculated for each peptide. 
8.4.2 
Form 
The two peptide pools, each containing up to 10 peptides, will each be provided in one bulk 
aliquot for use in Drng Product prepai·ation; they will be packaged with a tamper evident seal, 
labelled and shipped under appropriate temperatUl'e controlled conditions to DFCI Phannacy 
dept. 
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DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Bulk aliquots for up to 2 different peptide pools will identified with the patient's Study ID 
number (i e. 18279-101). Final sterile filh·ation will be perfom1ed by the Pharmacy department 
prior to aliquoting into vials. The vials containing peptide pools are to be stored at -70°C or 
colder until use. 
8.4.3 
Stor•ge and Stability 
Personalized neoantigen peptides are to be stored at lhe DFCI Pharmacy al a temperature of -
700C or colder. The thawed vials and the final mi.xture of personalized neoantigen peptides, 
poly-ICLC, and Montanide can be kept at room temperature but should be used as soon as 
possible after preparing the peptide + poly-ICLC + Montanide mixture. 
8.4.4 
Compatibility 
Personalized neoantigen peptides will be mixed with poly-ICLC just prior to use to prepare the 
final product (NeoVax plus Montanide). 
8.4.5 
Handling 
There are no specific instrnctions for handling personalized neoantigen peptides. 
8.4.6 
Availnbillty 
The personalized neoantigen peptides are prepared by a GMP facility under contract with DFCI 
and will be supplied directly to the DFCI. No other institutions will be involved in delivering 
personalized neoantigen peptides tmder this protocol. 
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DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
8.4.8 
Admlnisll'ation 
Following mixing with personalized neoantigen peptides, the personalized neoantigen vaccine 
is to be administered subcutaneously. 
8.4.9 
Ol'dering 
Tue order for personalized neoantigen peptides to the peptide vendor will be placed by the DFCI 
separately for each individual pa1ticipant. Delive1y time is anticipated to be 4 - 8 weeks. 
8.4.10 Accountability 
Tue investigator, or a responsible patty designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Fonn (DARF) or another comparable drug accountability fo1m. (See the NCI Investigator's 
Handbook for Procedures for Drug Accountability and Storage.) 
8.4.11 Desn·ucllon and Retw·n 
At the end of the study, after a patient finishes treatment, or after a patient discontinues 
treatment early, unused supplies of personalized neoantigen peptides will be released to the 
sponsor for further research or destroyed according to institutional policies. If tumsed 
personalized ueoantigeu peptides are destroyed, this will be documented in the Drug 
Accountability Record Form. 
8.5 
Monlnnide 
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8.5.2 
Fo,m 
DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Montauide ISA-51 VG is supplied by Seppic in 2R3 amber vials filled with 3 ml containing 
Montauide ISA-51 VG. 
8.5.3 
Storage and Stability 
Montauide ISA-51 SG is stable at room temperanu·e for 3 years from the date of manufacllrre. It 
is preferable to keep unused vials in the original styrofoam box at standard room temperalllfe. 
8.5.4 
Compatibility 
Montanide ISA-51 SG will be mixed with personalized neoantigen peptides and poly-ICLC just 
p1ior to use to prepare the final product (neoantigen vaccine). 
8.5.5 
Handling 
There are no specific handling instructions for Montanide ISA-51 VG. 
8.5.6 
Availability 
Montauide ISA 51 VG is au investigational agent and will be sourced as commercially available 
product from Seppic. 
I-connectors (luer lock adapters) used to facilitate emulsion preparation will also be supplied by
the study.
8.5.8 
Administration 
Following mixing with the personalized neoantigen peptides, the vaccine (peptide + poly-ICLC 
+ Montauide® ISA-51 VG) is to be administered subcutaneously.
8.5.9 
Accountability 
The investigator, or a responsible pru1y designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Fonn (DARF) or another comparable dJug accountability f01m. (See the NCI Investigator's 
69 
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Handbook for Procedures for Drug Accountability and Storage.) 
8.5.10 Destrurllon and Return 
DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
At the end of the study, unused supplies of Montanide will be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record 
Form. 
8.6 
P1·epa1·ation of NeoVax + Moulauide 
8.6.1 
Pnpa,;ug NP.oVax A+ Mont11nide vaccine 
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I 
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DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
111is document is confidential. Do not disclose or use except as authorized. 

8.6.2 
Preparing Pool B NeoVax + Montanlde vaccine 
I 
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Version 8.0 / November 20, 2023 
111is document is confidential. Do not disclose or use except as authorized. 

I 
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Version 8.0 / November 20, 2023 
111is document is confidential. Do not disclose or use except as authorized. 

-
I 
8.6.3 
NeoVa.x v11criue prepHratiou without using Montan.ide 
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DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
111is document is confidential. Do not disclose or use except as authorized. 

DF/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1 
Pharmacod}11•mi< Studies 
liwntme monitoring will be perfo1med in a step-wise fashion as outlined below to characterize 
the intensity and quality of the elicited immune responses. Peripheral blood and tumor will be 
collected serially al different time points as specified in the study calendar. 
If sufficient tumor tissue is available, a portion of the flunor will be used to develop autologous 
melanoma cell lines for use in cytotoxic T -cell assays. 
9.1.1 
Scrffnlng ex vh•o IFN1 ELISPOT 
For each participant, a set of screening peptides will be synthesized. The screening peptides will 
be 15-17 amino acids in length, overlapping by 11 amino acids and covering the entire length of 
each peptide or the entire length of the neoORF for 11eoORF-de1ived peptides. The set of 
pa11icipant-specific screening peptides will be pooled together (either as a single pool or in four 
sub-pools conesponding to the immunizing peptide pools) at approximately equal concentration 
and a po11ion of each peptide will also be stored individually. In addition, the predicted 9mer or 
I Omer epitope for each inmnmizing peptide will be synthesized and pooled. Purity of the peptide 
pools will be asce1tained by testing PBMC from 5 healthy donors with established low 
backgrotmd in ex vivo IFN-r ELISPOTs. Initially, PBMC obtained prior to Nivolumab, prior to 
Vaccination, and at week 20 (the primary immunological endpoint) will be stimulated for 18 
hours with the overlapping 15-l 7mer peptides (11 amino acids overlap) and with the 
9mer/10mer epitopes to examine the global response to the peptide vaccine. Subsequent assays 
may utilize PBMC collected at other time points as indicated. If no response is identified at the 
primary immunological endpoint using the ex vivo IFN-y ELISPOT assay, PBMC may be 
stimulated i11 vitro with the peptide pool for a longer time period (up to 10 days) and re-analyzed. 
9.1.2 
Doconvolution ofepitopes in follow-up ex vivo IFN--y ELISPOT assays 
Once an IFN-y ELISPOT response elicited by an overlapping or epitope peptide pool is observed 
(defined as at least 55 spot forming tmits / 106 PBMC or increased at least 3 times over baseline), 
the particular immunogenic peptide eliciting this response will be identified by de-convoluting 
the peptide pool into sub-pools based on the immunizing peptides and repeating the ex vivo IFN­
'Y ELISPOT assays. 
In some cases, it may be necessary to synthesize additional peptides to precisely characterize the 
stimulating epitope. 
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
9.1.3 
Additional assays to be conducted on a case-by case basi* for appropriate samples
•
The entire l 5-l 7mer pool or sub-pools will be used as stimulating peptides for intracellular
cytokine staining assays to identify and quantify antigen-specific CD4+, CD8+, central
memory and effector memory populations.
•
Similarly, these pools will be used to evaluate the pattern of cytokines secreted by these cells
to detenuine the TH 1 vs T H2 phenotype.
•
Fluorescent-labeled tetramers may be prepared for direct flow-cytmoeti-ic characterization of
responding CD8+ T cells to directly track and measure the size of T cell populations
responding to neoantigens.
•
If a melanoma cell line is successfully established from a responding participant and the
activating epitope can be identified, T-cell cytotoxicity assays will be conducted using the
mutant and coITesponding wild type peptide reactive T cells against the autologous tumor
cell line.
•
Single cell RNA-Seq analysis from pre- and post-treatment tumor samples to assess the
activation states of T cells and other immm1e cells.
•
Single cell sequencing of both TCR Va and VÏ subunits in serially collected peripheral blood
and tumor samples collected before and after Nivolumab and vaccination, to characterize the
global changes in TCR repe1toire following vaccination as well as to track individual T cell
clones over time in relation to vaccination.
9.1.4 
Immunohistochemlstry 
Immunohistochemislly of tumor samples will be conducted to assess PD-Ll expression by tumor 
cells and tumor infiltrating immune cells and to quantify inunune infiltrates such as CD4+, 
CD8+, ÐIDSC, and Treg infiltrating populations. 
9.2 
Future Annlyses 
We may amend this protocol at a future date should we decide to conduct additional analyses 
utilizing futme-generated samples from study pa1ticipants ( e.g. additional surgeries and autopsy 
tissue). Patients consenting to this trial agree to allow access to these future-generated samples. 
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10. STUDY CALENDAR
Procedare1
JVe,k 
Wonned Con.set 
Medllx 
Coocomitant Medication 
PE/Vitals/Pulse Ox 
ECOGPS 
Siagingscans
3 
CBCw/dif 
SerumChem4 
12-lead EKG
Prc,nancy T csti11..5 
Thiroid Stinula!ilg Honnooe6 
Infectious Panel' 
Urinalysis 
Blood draw for vaccine mamifacturill..S 
HI.A class I and 11 ryp·r,_9 
Nivobnab administtalion lO
lpaimumab adminislralion' 
Neoa!lligen \'accine Administration• 
Tumor bioo.v 11' •
L •
• esisu,• 
Blood dra £ . 
. . !).• 
w or mttmme response momtormg 
Vaccine biopsy• 
Adverse fa'Cll!S 
Scree.
Z 
NIA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-
Pre--Varcination Treatment 
Trelllmeur3 
0 
4 
s 
10 
12 
13 
IS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vaccination Treatwent 
16 
18 
19 
20 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Post Vaccination 
21 
22 
24 
Q4weeks 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xll
•please see Vaccine + lpaimumab administration and vaccine-related assessmellls
Xll
xu 
X 
X 
X 
Xll 
X 
X 
X 
77 
CONFIDENTIAL 
table below 
X 
X 
X 
X 
X 
l11is docmnent is confidential. Do not disclose or use except as authorized. 
X 
X 
X 
X 
X 
X 
Follow Up14 
X 
X 
X 
X 
X 
X 
X 
Xll 
Xll 
X 

All study procedures should be performed wilhin +/- 3 day window unless specified olhetwise 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
2 
Saeeoing assessments mu,t be oompleted within 30 di)'õ of. and prior to the first dose ofNivohtmab oo Week O Day t. AD additional JS days is allowed for a repeat biopsy. if needed, to ootain adequate 
tissue for sequmc:ing. T1lis initial biopsy sample should have approx.imately 30% tumor cellularity and a minimwn of 5-8 cores or I 00 nun3 in order for sequencing to be completed 
3 
.,.,_ 14 day window for staging scans. CT or MRI of other areas of disease (e.g. neck) sbotlld be obtained as clinically indicated. If IV cootrast is contraindicated, a ooo-contrast CT and MRI may be used to 
evaluate sites of disease wbere a CT without contrast is 001 adequate. Tue imaging ruodali1y should remain coosistent througbool the Sllidy and should be the same modality used at ScreeoiIJS. Pllo1ographs 
sbotlld be W:eo of ooe nou-biopoied representitive skin lesion, if feasible, oo the same day lhat radiographic scaus are obtained. The 100-day CT/MRI can be oblained within a ±30-day window. Ji a 
patient bas Wldergone a procedw'e (CT or MRI) that is wiUtin the allotted timefnune for evaluation, then the patient does not hsve to wulergo an additional procedure. OinicaJ assessments must be based 
on REC!Sf vi.I. After Ille week 24 limepoinʥ staging seans sbould be perfonned e\'ery 12 weeks 
4 
Glucose, urea nitrogen, creatinine, sodium, potassium, calcium, total and direct bilirubi.n, AST, ALT, alkaline phosphatase 
5 
Women of child-bearing potential (WOCBP) must have a negative serum or urine ʦHCG pregnancy testʧ Urine or serum pregnancy test should be at screening, within 24 hours prior to receiving the firsl 
dose of study medication and therl every 4 weeJ3 while. on tre.atmeot 
6 
Thyroid stimulating hormone with reflex T4 
7 
HBsAg, HB<Ab, HCV, HIV 1/11 Ab 
8 
Al least two IOmLEDTA tubes "'ill be collected fon,accineproduction ptUl)<)<eS .  The tubes will be keptfroz:eo at theCRLuutiJ the day of shipment for DNA sequencing 
9 
Molecular HLA typing to be perfomied by Tissue Typing Laboratory (HLA-A, HLA-B, HLA-C, and HLA-DR) 
JO 
Nivolwnab treatment will start wiUtin 2 weeks of tumor biopsy and once h.istopalhology report confinns melanoms and the biopsy sample is confinned to have adequate tumor content for DNA 
sequencing. Nivolumab dosing every 4 weeks(-,./. 3 days) until disease p<ogression or intolerable toxicity (minimum 26 di)'õ between dosing). Nivolwnab will be •dministered until intolerable toxicity. 
disease progres;:ion (unless treatment beyond progression is deemed to be beneficial for the patient) for a msximum duration of24 months 
11 
Tumor biopsies will be collected in patients with unresectab1e melanoma who have metastatic sit.es acce.ssib1e to seriaJ tumor biopsies urithin two weeks prior to Nivoltun.1b treatment iuiti..,tion. Tumor 
biopsy must contain 2:30% of tumor cells. 
A1 a millinnun, Sc-ore biopsies or a surg:ic-al nunor specimen of 100ium3 v.'ill be obtained. Skill pur.i.cb biopsies of a skin lesion are also allowed. The collection of lunot biopsies for research purposes do 
not apply for patients "i.th stage m melanoma 
12 
Leukapheresis procedure will be performed within 14 days before slruting Nivolumab 
Ai each Leukapberesis collection timepoim 2xl O mL IDTA tubes will be collected. These tubes should be dropped off at the lAL upon collection 
If Laoolpberesis cauuot be perfonned a 101al of 200UlL of blood should be drawn. If startillg of ,'ll«ille adUliJlistraJiou g,ts delayed, week 20 leukapberesis will be collected before vaeciJlaliou timepoiut 
114. 
A Leukapberesis during lhe Post-Vaccillatiou ""'tmetlli Followu up period may be perfonned 
J 3 
Unless otherwise specified, 80 ml of blood will be drawn for immune monitoring. 
14 
Active Follow-Up: Participants removed from active study treatment will be foUO\ved at the following schedule until initiation of a new therapy for recurrent disease, tvitbdrnw.d of oonseot, or deatb 
(whichever comes first): 
• At least every 3 months (tt- 2 week) for the first 2 years after initiation of study therapy, 
• At lea.st every 4 months(+/-2 weeks) for the third year after study therapy initiation, 
• At least every 6 lllOUths (+/- 4 weeks) tberealler, until 5 years ba,•e passed since study therapy initiation 
Long-Term FoUmv-Up: Participants removed from active follow-up for prog,ressiolll'iuitiatioo of a ne.v therapy v.-ill eut.er long-term follow-up, where they will be followed \o-i.a medical record review uotil
death for survival. Updates to the CRFs are to be made approximately every six months 
• 
Please see table below 
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Neoanth!en vaccine+ Inilimumab administration calendar and assessments ,·elated to vaccination tlmeooints 
Pi·e--,-accine 
Neoa••• 
Procedure1 
as.ses.sments 
PE.,vitals Conc.om.itant Medications ECOG, 
CBC w/ cliff, SttUm Chtm.istrv, 
leukaphue.sis 
}< 
.. 
Twnor biopsy 
x• 
Blood dr3w for imm.wie response monitoring 
Neoantigen vaccine administration 
fpil:imlumab administration 
Vaccine site skin biopsy 
•
r...ilmpberesis proc:roure will be performed a11he following tiJllepoints:
• witbio 14 days before first vaccination timepoint #1
• within 7 days before vaccination tiutepoint #4
\'otdno 
Dose #le
X 
X 
X 
Posrnccine 
Neoanticen Post 'Olccine --r1c ..
,·-· 
,.Hdne 
dose I ,i.sit 
Dosel?c 
dose 2 Tisir 
ɎIJ' 
X 
X 
X 
X 
X" 
J<"' 
X" 
X 
X 
X' 
At each Leukapberesis collection tunepoiot 2xl0 mL EDTA lubes "'ill be collected. These tubes shoold be dropped off at the IALopon collectioo
Post -race.LIie Neoa•fict'• 
,·-· 
do.se 3 visit 
Dose#-tlc 
X 
X 
X' 
x• 
X 
X 
Post l'accine 
dose 4 risir 
X 
X" 
!'liOTE: If Leukapberesis cannot be performed a total of 200mL of blood should be drawn. lf starting of vaccine administration gets delayed, week 20 leulcapberesis "i.11 be collected before
vaccination timepoin.1 #4.
b Tumor biopsies will be collected at the following ti.mepoints: 
• within t\vo weeks before starting: the oeoanligeu vaccine Dose Iii
• within two weeks prior to neoontigen vaccine Dose 114 
• at 1he time of progressioo
At a minimum, 5 core biopsies or a surgical tumor specimen of 100mm3 v.-ill be obtained. Skin puocb biopsies of a skin lesion are also allowed
c 
Expected neoantigen vaccine administratioo timepoints (see. below). If there is a delay in vaccine p,-eparatiOll, Dose #I should be administered as soon as 1he neoantigen vaccine is available. 
Dc,ses #2, #3, aod #4 sboold be schedtlled every 3 weeks ofter Dose #1: 
• ueoantigen vaccine Dose #1: Week 12
• neoant:igeo vaccine Dose #2: Week 15
• neoantigen vaccine Dose 113: Week 18
• ueoantigen vaccine Dose #4: Week 21.
If oeoantigeo vaccioe administration coincides with nivolumab administration, neoant:igeo vaccine + lpilionunab will be administered before Nivolumab
d 
Unless otherwise specified, 80 ml of blood will be dr.m11 for ioumtoe monitoring. Blood collections "'ill be perlonned ,t the following timepoiots: 
• one week(+/-3 days) after neoontigen vaccine Dose #1 
• before ueoantigen va<:<ine Dose #2 
• before neoant:igeo vaccine Dose #3
• within 3 weeks (+/- 3 days) after neoantigen vaccine Dose #4
• before each ui\•ohunab administration during the post \'aecinatioo period
e 
Skin biopsies oear v,ccine injection sites (two 5 mm punch biopsies) should be penonned ,t the following tunepoints: 
• prior to neoontigen vaccine Dose #3, 
• betweeo 48-n hours after neoontigeu vaccine Dose #3
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Additionally. if a different vaccine site appears to clinically have a higher degree of inflammation, additional punch biopsy (N.·o 5mm) of that s.ite may be taken. 
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11. MEASUREMENT OF EFFECT
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Although response is not the prima1y endpoint of this trial, pa1ticipants with measurable disease 
will be assessed by standard criteria. For the purposes of this study, pa1ticipants should be re­
evaluated every 12 weeks. In addition to a baseline scan, confinnato1y scans will also be 
obtained 4 weeks following initial docmnentation of an objective response. 
11.1 
Antitumor Effect - Solid Tumors 
For the pmposes of this study, participants should be re-evaluated for response eve1y 8 weeks. 
In addition to a baseline scan, confumato1y scans should also be obtained 4 weeks following 
initial documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (REC!S1) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional measmement) of 
the tumor lesions and the sho1test diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
11.1.1 Defuritions 
Evaluable for Target Disease response. Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response. l11ese 
participants will have their response classified according to the definitions stated below. 
(Note: Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaltiable.) 
Evaluable Non-Target Disease Response. Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measmable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaltiable for non-target disease. The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions. 
11.1.2 Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as 2'. 20 mm by 
chest x-ray or ð10 mm with CT scan, MRI, or calipers by clinical exam. All tumor 
measmements must be recorded in millimeters (or decimal fractions of centimeters). 
Note: Tmnor lesions that are situated in a previously in-adiated area might or might not be 
considered measurable 
Malignant lymph nodes. To be considered pathologically enlarged and measmable, a 
lymph node must be ñ15 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 
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the sho1i axis will be measured and followed. 
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Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 llllll or pathological lymph nodes with e::10 to <15 mm sho1t axis), 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
plemal/pe1icardial effosions, lymphangitis cutis/puhnonitis, inflannnato1y breast disease, 
abdominal masses (not followed by CT or MRJ), and cystic lesions are all considered 
non-measurable. 
Note: Cystic lesions that meet the c11teria for radiographi.cally 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 pa1ticipant, these are prefened for selection as 
target lesions. 
Target lesions. All measurable lesions up to a maxi.Jmun 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, sho11 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 stllll, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
fiuiher chai-acterize 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. Measmements of these lesions are not required, but 
the presence, absence, or in rare cases m1equivocal progression of each should be noted 
throughout follow up. 
11.1.3 Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation using a rnler, calipers, 
or a digital measurement tool. All baseline evaluations should be performed as closely as 
possible to the beginning of tJ:eatment and never more than 4 weeks before the beginning 
of the treatment. 
The same method of assessment and the same technique should be used to characterize 
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each identified and reported lesion at baseline and dming follow-up. Imaging-based 
evaluation is prefe1Ted to evaluation by clinical examination tmless 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 Ć10 nllll in diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, docmnentation by 
color photography, including a niter 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 smTotmded by aerated lung; however, CT is preferable. 
Conventional CT and MRI. This guideline has defmed measurability of lesions on CT 
scan based on the assmnption that CT thickness is 5nllll or Jess. If CT scans have slice 
thickness greater than 5 mm, the mini.mum size of 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 iniage quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globaUy. 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. Fmthennore, 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 p1ior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
FDG-PET. \Vhile FDG-PET response assessments need additional study, it is sometimes 
reasonable to incoq>orate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (pa1ticularly possible 'new' disease). New lesions on the basis 
ofFDG-PET imaging can be identified according to the following algorithm: 
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of
PD based on a new lesion.
(b) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive
FDG-PET at follow-up conesponds to a new site of disease continued by CT, this
is PD. If the positive FDG-PET at follow-up is not continued as a new site of
disease on CT, additional follow-up CT scans are needed to detenuine if there is
tndy progression occmTing at that site (ifso, the date of PD will be the date of the
initial abnonnal FDG-PET scan). 
If the positive FDG-PET at follow-up
conesponds to a pre-existing site of disease on CT that is not progressing on the
basis of the anatomic images, this is not PD.
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(c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a
biopsy in cases where a residual radiographic abnormality is thought to represent
fibrosis or scaning. 
Tue use of FDG-PET in this circumstance should be
prospectively described in the protocol and supported by disease-specific medical
literature for the indication. 
However, it must be acknowledged that both
approaches may lead to false positive CR due to limitations of FDG-PET and
biopsy resolution/sensitivity.
Note: A 'positive' FOG-PET scan lesion means one which is FOG avid with an uptake 
greater than twice that of the s111Tounding tissue on the attenuation con·ected image. 
PET-CT. At present, the low dose or attenuation cofection CT pottion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measmements. However, if the site can docUI11ent that the CT pe1formed as part of a 
PET-CT is of identical diagnostic qtiality to a diagnostic CT (with IV and oral contrast), 
then the CT po1tion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET po11ion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed. 
11.1.4 Response Criteria 
11.1.4.1 
Evaluation of Target Lesions 
Complete Response {CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <JO 
mm. 
Pa1tiaJ Response (PR): At least a 30% decrease in the s111n of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline stun if that is the smallest on study). In addition to the relative increase of 
20%, the stun must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered progressions). 
Stable Disease (SD): Neither sufficient slninkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
11.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response {CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<JO mm 
short axis). 
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Note: If tumor markers are initially above the upper nonnal limit, they must 
normalize for a patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not nonnally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase. 
Although a clear progression of "non-target" lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confumed at a later time by the review panel ( or Principal 
Investigator). 
11.1.4.3 
Evaluation of New Lesions 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some 'new' bone lesions may be sin1ply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will cla1ify if it truly represents new disease and if PD is confumed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
11.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the statt of the treatment 
until disease progression/recunence (taking as reference for progressive disease the 
smallest measw-ements recorded since the treatment sta1ted). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
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For Participants with Measurable Disease (i.e., Target Disease) 
Target 
Non-Target 
New 
Overall 
Best Overall Response when 
Lesions 
Lesions 
Lesions 
Res1>onse 
Confirmation ls Reaulred* 
CR 
CR 
No 
CR 
>4 wks Confumatiou**
CR 
Non-CR/Non-
No 
PR 
PD 
CR 
Not evaluated 
No 
PR 
:::4 wks Confumation** 
PR 
Non-CR/Non-
No 
PR 
PD/not 
evaluated 
SD 
Non-CR/Non-
No 
SD 
Documented at lea.st once Æ4 
PD/not 
evaluated 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
Any 
PD*** 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
Any 
Yes 
PD 
*
See RECIST 1.1 manuscript for fmther details on what is evidence of a new lesion.
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Pa1ticipants with a global dete1ioration of health status requiiing discontinuation of 
treatment without objective evidence of disease progression at that tiine should be 
reported as "symptomatic deterioration. " Eve1y effort should be made to document the 
objective pro!l°ression even after discontiimation of treatment. 
For Participants with Non-i\lleasurable Disease (i.e., Non-Target Disease) 
Non-T an1et Lesions 
New Lesions 
Ovet·all Resnonse 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Une<1uivocal PD 
Yes or No 
PD 
Any 
* 
Yes 
PD 
'Non-CR/non-PD' is prefened over 'stable disease' for non-target disease sii1ce SD is 
ii1creasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this catego1y when no lesions can be measured is not advised 
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11.1.5 Duration of Response
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Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recunent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment sta1ted, or 
death due to any cause. Participants without events repo1ted are censored at the last 
disease evaluation). 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any ca.use. Participants without events 
reported are censored at the last disease evaluation. 
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
11.1.6 Prow:ession-Free Smvival 
Overall Survival: Overall Survival (OS) is defmed as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Pai1icipants alive without disease progression are censored at date of last disease 
evaluation. 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression or censored at date of last disease 
evaluation for those without progression reported. 
11.2 
Other Response Parameters 
Immm1e related Response Criteria 
New end point definitions for trials of inllllunologic agents have been proposed based on novel 
pattems of clinical activity in malignant melanoma98,99 and are desc1ibed in detail in Appendi,x 
B. These alternative definitions allow time for irmnunologically mediated effectors to develop
that may result in late tumor responses even after initial progression by RECIST. Also, in some
patients, tunJors necrosis and inflammation may increase tumor size radiographically prior to
response. Changing the definitions of OR ai1d PD may alter (increase) the number of patients
achieving responses and the dmation of PFS.
On a subject by subject basis, we would consider allowing study treatment to continue during 
initial progression up to the 12-16 weeks assessment to allow time for responses to be obse1ved, 
if the patient is clinically stable, there is no deterioration in PS, and there is no need for 
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immediate additional treatment. V/hile maintaining standard definitions of progression and 
response, we would allow new lesions and some progression beyond 20% increases in tumor 
measurements during the initial treatment pe1iod to allow time for responses to develop (these 
delayed tumor responses may be seen in l 0-20% of melanoma patients who initially progress 
dtning the initial treatment cycles and evalt1ation). We do not have experience with response 
patterns with combination therapy nor in diseases other than melanoma. Please use standard 
response definitions as the primaiy end point in these studies. 
Note that the proposed irRC may be incorporated as seconda1y end points to compare to standard 
crite1ia and evaluate alternative patterns of response in va1ious disease setting and treatment 
regin1ens. A copy of the proposed crite1ia is presented in Appendix B. 
Patients who demonstrate mixed responses, stable disease, or objective responses by standard 
RECIST following initial progression may be identified separately as "delayed SD, PR, or CR". 
Overall Risk/Benefit Assessment 
The mlique illll1ltllle-based mechanism of action is reflected in the clinical patterns of anti-cancer 
activity in some patients. Immtme checkpoint blockade affects flllllor cells illdirectly, and 
measurable clinical effects emerge after the inummological effects. Tumor infiltration with 
lymphocytes and tlle associated illflammation (docwnented by biopsy in some subjects) is likely 
the cornerstone of the effect of ilrumme checkpoint inhibition and can manifest in va1ious 
patterns of clinical activity leading to tumor control. In some cases, response may be preceded by 
an apparent iI1crease ill iI1itial ttunor voltlllle and/or tlle appearance of new lesions, which may be 
nlistaken for tumor progression on radiological evaluations. Therefore, in subjects who are not 
experiencing rapid clinical deterioration, confumation of progression is recommended, at tile 
investigator's discretion, to better tmderstand the prognosis as well as to avoid unnecessarily 
illitiatillg potentially toxic alternative therapies in subjects who might be benefitting from 
treatment. Immune-related (ir) response crite1ia were developed based on these obse1vations to 
systematically catego1ize novel patterns of clinical activity and are cmTently being prospectively 
evaluated iii clinical smdies. 
In meta.static diseases, stabilization is more common tllan response, and in some illstances is 
associated with slow, steady decline in tumor bm·den over many months, sometimes improving 
to pa1iial and/or complete responses. Thus, the inlllltme-based mechanism of action of 
Ipilimumab results ill durable disease control, sometimes witl1 novel patterns of response, which 
connibute to its iniprovement in OS. 
The inumme-based mechanism of action is also reflected in the safety profile. The most coilUuon 
drng-related AEs are illll1ltllle-mediated, consistent with the mechanism of action of the drng and 
generally medically manageable with topical and/or systemic immtmosuppressants. As 
previously discussed, the inlllltme-mediated adverse reactions p1imarily involve the GI tract, 
skin, liver, endocrine glands, and nervous system. 
The early diagnosis of immune-mediated adverse reactions is ilnpo1tant to initiate tl1erapy and 
minimize complications. Immune-mediated adverse reactions are generally manageable using 
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symptomatic or immunosuppressive therapy as recommended through detailed diagnosis and 
management guidelines, as described fully in the cuffent IB. TI1e management guidelines for 
general immune-mediated adverse reactions and Ipilinrnmab-related GI toxicities, hepatotoxicity, 
endocrinopathy, and neuropathy are provided in the appendices of the Cll!Tent IB. 
12. DATA REPORTING/ REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and inslluctions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
12.1 
Data Reporting 
12.1.1 Method 
The Office of Data Quality (ODQ) will collect, manage, and perfo1m quality checks on 
the data for this study. 
12.1.2 Responsibility for Data Submission 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data fonns to the Office of Data Quality (ODQ) in accordance with DF/HCC policies. 
12.2 
Data Safety Monito1ing 
The DF/HCC Data and Safety Monito1ing Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pha1maci.sts and biosta.ti.sticians with direct experience in cancer clinical research. 
Infonnation that raises any questions about participant safety will be addressed with the Overall 
PI and study team. 
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. Info1mation to be provided to the committee may include: up­
to-date pa1ticipant accmal; cruTent dose level information; DLT information; all grade 2 or 
higher tmexpected adverse events that have been repo1ted; summary of all deaths occun-i.ng 
within 30 days of inte1vention for Phase I or II protocols; for gene therapy protocols, smlllllary of 
all deaths while being treated and dtning active follow-up; any response info1mation; audit 
results, and a stmnnary provided by the study team. Other i.rrfo1mation ( e.g. scans, laborato1y 
values) will be provided upon request. 
13. STATISTICAL CONSIDERATIONS
13.1 
Study Design/Endpoints 
The pri.rnaiy goal of this Phase I tiial is to assess safety of the vaccine (neoa11tigen peptides and 
poly-ICLC) and locally-delivered Ipilimmnab and determine the recommended maximum 
tolerated dose (MTD). 
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Primary Endpoint: Rate ofDLT(s) 
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Adverse events classified as dose-limiting toxicities (DLT) and the assessment time for DLTs are 
sununaiized in Section 5.5. Five patients will be treated for the initial safety evaluation (Cohort 
I). We have chosen dose escalation cohorts of 5 patients, rather than a more traditional 3+3 
design, because the detennination of whether to treat at a different dose in this trial is made over 
a longer pe1iod of time due to the time required for vaccine preparation and the extended period 
for safety evaluation. These larger cohort sizes help us avoid having to pause and then resta1t 
enrollment to a dosing cohort several months later. 
If none or only I patient in Coho1t I Dose Level I experiences a dose limiting toxicity (DLT) 
during the first 7 weeks of treatment of Coho1t I, 5 patients will be treated as Cohort 2 dose 
Level 2. If two or more patients in Coho1t 1 expe1ience a DLT dming the first 7 weeks of 
treatment, then 5 patients will be treated as Coho1t 2 Dose Level -1. 
If none or only I patient experiences a DLT on Coho1t 2 Dose Level 2, then Dose Level 2 will be 
the maximtnn tolerated dose (MTD) and an additional l O patients will be treated at that dose 
level (Cohort 3 Dose Level 2) to increase the likelihood of detecting serious toxicities, to 
complete biologic co!l'elative endpoints and to gain preli1ninaiy experience with clinical 11.nnor 
activity. If two or more patients in Cohort 2 Dose Level 2 experience dose limiting toxicity 
(DL T), then Dose Level I will be the MTD and an additional JO patients will be treated in an 
expansion coho1t (Coho1t # Dose Level I) at this dose. 
If none or only I patient experiences a DLT on Cohort 2 Dose Level -1, then Dose Level-I will 
be the maximum tolerated dose (MTD) and an additional l O patients will be treated in an 
expansion coho1t ( Coho1t 3 Dose Level -I) at that dose level. If two or more patients in Coho1t 2 
Dose Level -1 experience dose limiting toxicity (DLT), then the study will be stopped. 
The table below shows the probability of moving to the dose expansion phase (0 or I patients 
with DLT out of 5 patients at the MID) for va1ious possible values of the true, but unknown, 
toxicity rate. 
True rate ofDLT (%) 
ProbabUltv of Dose Exl)ansion (%) 
10 
92 
20 
74 
30 
53 
40 
34 
50 
19 
60 
9 
If the tme probability of DLT is 10% or less, then the probability of proceeding to dose 
expansion is at least 92%. The probability of dose expansion is Jess than 50% if the trne rate of 
dose-limiting toxicities is 32% or greater. 
l\lllnlmum vaccination requirement to pass DLT observation period: A mininunn of 2 
vaccinations and absence of DLTs are required for a patient to complete the 7-week DLT 
obse1vation period successfully. 
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Expansion Cohort: V/hen the recommended dose has been dete1mined, an expansion coho1t of 
IO patients will be ti-eared to assess the performance of the vaccine and to gain additional 
infonuation about toxicities. B ecause of the long lead time between patient registration and fust 
vaccination, patients in the expansion cohort may be registered to the Ilia! while safety in the 
initial cohort(s) is being assessed. Patients in the expansion cohort will not be treated until the 
safety evaluation of the initial cohorts is complete. 
Stopping rule for Expansion Cohort: If four or more patients in the expansion cohort 
experience dose limiting toxicity (DL 1) dw-ing the first 7 weeks of 11·eatment, then the dose 
expansion coho11 will be detemlined to have unacceptable toxicity and the study will be stopped 
prior to completion of em·olhuent of the expansion coho1i. The table below summarizes the 
probability of obse,ving 4 or more DLTs within the IO patients of the expansion cohort for 
va1ying underlying rates of toxicity. 
Tme, but unknown, toxicitv rate 
5% 
10% 
20% 
30% 
36% 
40% 
Probability 
of obse1ving 
4 or more 
0.001 
0.013 
0.121 
0.350 
0.513 
0.618 
patients with 
DLT 
If the trne probability of DLT in the expansion cohort is higher than 35%, then the probability is 
at least 50% of obse,ving 4 or more patients with DLT within the IO patients of the expansion 
coho1t. 
Total Sample Size: The final sample size for th.is trial will depend upon the number of dose­
escalation cohorts; however, the number of patients treated will be between 4 and 20. The 
minimwn nwnber of patients to be treated is based on obse,ving DLTs after the first dose of 
Neoantigen Vaccine in the first two patients of Coho1t 1 and similarly in Cohort 2. The 
maximwn would occur if two dose-escalation coho1ts were tI·eated, with an additional IO patients 
at theMTD. 
Timelines: We expect to enroll one patient per month. We expect FPFV to occm by September 
2020. LPFV is expected for July 2022 and overall dw·ation of the study will be 4 years. 
Analysis of Secon<lary Endpoints 
Secondary endpoint in this clinical tiial will: (a) assess the induction ofIFN--y T-cell response or 
tetramer staining to the assay peptides, and (b) to estimate rates of disease progression or 
recwTence (RECIST 1.1) depending on whether the patient is resected or has measmable 
disease.Analyses of the secondary endpoint will be based on 15 patients ti·eated at the MTD. 
The induction of IFN-y T-cell response will be based on ELISPOT assessments taken prior to 
vaccine administration and at week 16. The proportion of patients who achieve more than 55 
SFU/106 PBMC or 3 times their baseline level will be presented with a 90% exact binomial 
91 
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DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
confidence inte1val. Based on a coho1t of size 15, the confidence inte1val will be no wider than 
0.46. 
The proportions of patients with disease progression or recunence, according to melanoma stage, 
will be presented with 90% exact binomial confidence inte1vals. 
Analysis of Correlative Endpoints 
Longitudinal analyses of PBMC immune response kinetics to the peptide pool and to individual 
epitopes will be presented graphically and descriptively at each time point. Changes in the 
magnitude of the response relative to pre-treatment at several different time points after 
vaccination will be swnmarized descriptively. Changes in response benveen pre-treatment and 
16 weeks post-vaccination, which is the tin1e of the prima1y innnunologic endpoint, will be 
assessed using the Wilcoxon signed-rank test. 
Immune studies of T cell subpopulations (CD4 . , CD8-t, central/effector memo1y cells, Thl/fb2 
cells, T-regs, etc.), myeloid-derived suppressor cells (MDSC), CTL response, and T cell 
activation status will be sullllllarized using desc1iptive statistics. 
14. PUBLICATION PLAJ',
This study is intended for publication, even if tenninated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript. The Sponsor!Principal Investigator will 
work with all authors to submit a manuscript desc11bi.ng study results witllin 24 months after the 
last data become available, which may take up to several months after the last pa1ticipant visit. 
This is a NIH-funded research. De-identified genomic information obtained from pa1ticipa11ts on 
this study will be shared with NIH's dbGaP. 
92 
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REFEREI',CES 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
I.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for
clinicians 2014;64:9-29.
2.
Chapman PB, Hauschild A, Robert C, et al. Improved smvival with vemurafenib in
melanoma with BRAF V600E mutation. The New England journal of medicine 2011;364:2507-
16.
3.
Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in
metastatic melanoma. The New England jomual of medicine 2010;363 :809-19.
4. 
Sosman JA, Kim KB, Schuchter L, et al. SruvivaJ in BRAF V600-mutant advanced
melanoma treated with vemurafenib. The New England jomnal of medicine 2012;366:707-14.
5.
Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK Inhibition in
Melanoma with BRAF V600 Mutations. The New England journal of medicine 2012.
6.
Flaherty KT, Robe1t C, Hersey P, et al. Improved Smvival with ũ.ffiK Inhibition in
BRAF-Mutated Melanoma. The New England journal of medicine 2012.
7.
Hodi FS, O'Day SJ, McDermott DF, et al. Improved s1uvival with ipili.mumab in
patients with metastatic melanoma. The New England journal of medicine 2010;363 :711-23.
8. 
Robert C, Thomas L, Bondarenko I, et al. Ipilinmmab plus dacarbazine for previously
untreated metastatic melanoma. The New England journal of medicine 2011;364:2517-26.
9.
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-LI antibody
in patients with advanced cancer. The New England journal of medicine 2012;366:2455-65.
10.
Topalian SL, Hodi FS, Braluner JR, et al. Safety, activity, and immune cotTelates of
anti-PD-I antibody in cancer. The New England jomnal of medicine 2012;366:2443-54.
11.
Lundegaard C, Ltmd 0, Nielsen M. Prediction of epitopes using neural network based
methods. J Immunol Methods 2011;374:26-34.
12.
Sidney J, Southwood S, OseroffC, de! Guercio MF, Sette A, Grey HM. Measurement
of MHC/peptide interactions by gel filtration. CtttTent protocols in immunology/ edited by John
E Coligan [et al] 200l;Chapter 18:Unit 18 3.
13.
Fritsch EF, Rajasagi M, Ott PA, Brnsic V, Hacohen N, Wu CJ. HLA-binding
properties of n1mor neoepitopes in humans. Cancer i.nununology research 2014;2:522-9.
14.
Schreiber RD, Old LJ, Smyth MJ. Cancer inununoediting: integrating illlllmnit)1s
roles in cancer suppression and promotion. Science 201 I ;331: 1565-70.
15.
Welters MJ, Kenter GG, Piersma SJ, et al. Induction ofllm1or-specific CD4+ and
CD8+ T-cell immunity in ce1vical cancer patients by a hruuan papillomavirns type 16 E6 and E7
long peptides vaccine. Clinical cancer research : an official joumal of the Ame1ican Association
for Cancer Research 2008;14: 178-87.
16.
Kenter GG, Welters MJ, Valentijn AR, et al. Phase I inllllunotherapeutic uial with
long peptides spanning the E6 and E7 sequences of high-risk hmuan papillomavirns 16 in end­
stage cervical cancer patients shows low toxicity and robust immunogenicity. Clinical cancer
research : an official joumal of the American Association for Cancer Research 2008; 14: 169-77.
17.
Caskey M, Lefebvre F, Filali-Mouhim A, et al. Synthetic double-stranded RNA
induces innate immune responses similar to a live viral vaccine in humans. The Jomual of
expe1imental medicine 2011;208:2357-66.
18.
Sabbatini P, Tsuji T, FetTan L, et al. Phase I trial of overlapping long peptides from a
tumor self-antigen and poly-lCLC shows rapid induction of integrated i.nmmne response in
ovarian cancer patients. Clin Cancer Res 2012;18:6497-508.
93 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 

DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
19.
Wood LD, Parsons DW, Jones S, et al. The genomic landscapes of human breast and
colorectal cancers. Science 2007;318:1108-13.
20.
Hacohen N FE, Catter TA, Lander ES, and Wu CJ. Getting Personal with
Neoantigen-Based Therapeutic Cancer Vaccines Cancer Immunol Res 2013;Published
OnlineFirst April 7, 2013; doi:10.1158/2326-6066.CIR-13-0022
21.
Mandelboim O, Vadai E, Fridkin M, et al. Regression of established murine
carcinoma metastases following vaccination with tumour-associated antigen peptides. Nat Med
1995;1:1179-83.
22.
Zwaveling S, FetTeira Mota SC, Nouta J, et al. Established human papillomavirns
type 16-expressing ttunors are effectively eradicated following vaccination with long peptides. J
Immunol 2002;169:350-8.
23.
Castle JC, Kreiter S, Diekmann J, et al Exploiting the mutanome for tumor
vaccination. Cancer Res 2012;72:1081-91.
24.
Dubey P, Hendrickson RC, Meredith SC, et al. The inunm1odominant antigen of an
ultraviolet-induced regressor tumor is generated by a somatic point mutation in the DEAD box
helicase p68. The Journal of experin1ental medicine 1997;185:695-705.
25.
Sensi M, Anichini A. Unique ttunor antigens: evidence for immune control of
genome integrity and immimogenic targets for T cell-mediated patient-specific inununotherapy.
Clinical cancer research : an official jomnal of the American Association for Cancer Research
2006;12:5023-32.
26.
Matsushita H, Vesely MD, Koboldt DC, et al. Cancer exome analysis reveals a T-
cell-dependent mechanism of cancer immunoediting. Natt1re 2012;482:400-4.
27.
Wolfe! T, Hauer M, Sclmeider J, et al. A pl6INK4a-insensitive CDK4 mutant
targeted by cytolytic T lymphocytes in a hmnan melanoma. Science 1995;269: 1281-4.
28.
Coulie PG, Lehmallll F, Lethe B, et al. A mutated intron sequence codes for an
antigenic peptide recognized by cytolytic T lymphocytes on a hmnan melanoma. Proceedings of
the National Academy of Sciences of the United States of America 1995;92:7976-80.
29.
Le1merz V, Fatho M, Gentilini C, et al. The response of autologous T cells to a human
melanoma is dominated by mutated neoantigens. Proceedings of the National Academy of
Sciences of the United States of America 2005;102:16013-8.
30.
van Rooij N, van Buuren MM, Philips D, et al. Ttunor exome analysis reveals
neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma.. Jotunal of clinical
oncology: official jomnaJ of the American Society of Clinical Oncology 2013;3 l :e439-42.
31.
Tran E, Turcotte S, Gros A, et al. Cancer inummotherapy based on mutation-specific
CD4+ T cells in a patient with epithelial cancer. Science 2014;344:641-5.
32.
Baurain JF, Colau D, van Baren N, et al. High frequency of autologous anti-
melanoma CTL directed against an antigen generated by a point mutation in a new helicase gene.
J Inunm101 2000;164:6057-66.
33.
Chia1i R, Foury F, De Plaen E, Baurain JF, Thonnard J, Coulie PG. Two antigens
recognized by autologous cytolytic T lymphocytes on a melanoma result from a single point
mutation in an essential housekeeping gene. Cancer Res 1999;59:5785-92.
34.
Huang J, El-Gamil M, Dudley ME, Li YF, Rosenberg SA, Robbins PF. T cells
associated with tumor regression recognize frameshifted products of the CDKN2A tmnor
suppressor gene locus and a. mutated HLA class I gene product. J Immunol 2004; 172:6057-64.
94 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 

DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
35.
Karanikas V, Colau D, Baurain JF, et al. High frequency of cytolytic T lymphocytes
directed against a rumor-specific mutated antigen detectable with HLA tetramers in the blood of
a hmg carcinoma patient with long smvival. Cancer Res 2001;61:3718-24.
36.
Zorn E, Hercend T. A natural cytotoxic T cell response in a spontaneously regressing
human melanoma targets a neoantigen resulting from a somatic point mutation. European joumal 
of immunology 1999;29:592-601. 
37.
Brown SD, Warren RL, Gibb EA, et al. Neo-antigens predicted by tumor genome
meta-analysis coITelate with increased patient stuvival. Genome research 2014;24:743-50.
38.
Baskar S, Kobrin CB, Kwak LW. Autologous lymphoma vaccines induce human T
cell responses against multiple, unique epitopes. J Clin Invest 2004;113:1498-510.
39.
Schuster SJ, Neelapu SS, Gause BL, et al. Vaccination with patient-specific ttunor-
derived antigen in first remission improves disease-free stuvival in follicular lymphoma. Journal
of clinical oncology : official jomnal of the American Society of Clinical Oncology
2011;29:2787-94.
40.
Kenter GG, Welters MJ, Valentijn AR, et al. Vaccination against HPV-16
oncoproteins for vulvar intraepithelial neoplasia. The New England journal of medicine
2009;361: 1838-47.
41.
Sampson JH, Aldape KD, Archer GE, et al. Greater chemotherapy-induced
lymphopenia enhances ttuuor-specific uruum1e responses that eliminate EGFRvIII-expressu1g
nun or cells in patients with glioblastoma. Neuro-oncology 2011; 13 :324-33.
42.
Sampson JH, Heimberger AB, Archer GE, et al. lirununologic escape after prolonged
progression-free smvival with epidennal growth factor receptor va1iant ill peptide vaccination in
patients with newly diagnosed glioblastoma. Journal of clinical oncology : official journal of the
American Society of Clinical Oncology 2010;28:4722-9.
43.
Caneno BM, Magiini V, Becker-Hapak M, et al. Cancer urummotherapy. A dendritic
cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science
2015;348:803-8.
44.
Mo1ton DL, Hsueh EC, Essner R, et al. Prolonged smvival of patients receiving
active i.mmunotherapy with Canvaxin therapeutic polyvalent vaccine after complete resection of
melanoma metastatic to regional lymph nodes. Annals of surgery 2002;236:438-48; discussion
48-9.
45.
Soiffer R, Hodi FS, Haluska F, et al. Vaccination with urndiated, autologous
melanoma cells engineered to secrete granulocyte-macrophage colony-stuuulating factor by
adenovii'al-mediated gene transfer augments antin1mor urununity in patients with metastatic
melanoma. Journal of clinical oncology : official journal of the American Society of Clinical
Oncology 2003;21 :3343-50.
46.
Vaishampayan U, Abrams J, Danah D, Jones V, Mitchell MS. Active unmunotherapy
of metastatic melanoma with allogeneic melanoma lysates and interferon alpha. Clinical cancer
research : an official joumal of the American Association for Cancer Research 2002;8:3696-701.
47.
Testori A, Richards J, Whitman E, et al. Phase III comparison ofvitespen, an
autologous nunor-de1ived heat shock protein gp96 peptide complex vaccine, with physician's
choice of treatment for stage IV melanoma: the C-100-21 Stt1dy Group. Journal of clinical
oncology : official jomnal of the American Society of Clinical Oncology 2008;26:955-62.
48.
Kawai T, Akii'a S. TLR signalu1g. Seminars in urununology 2007;19:24-32.
49.
Adams S. Toll-like receptor agonists u1 cancer therapy. 1Iruum1otherapy 2009; I :949-
64.
95 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 

DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
50.
Bogunovic D, Manches 0, Godefroy E, et al. TLR4 engagement dw·ing TLR3-
induced proinflammato1y signaling in dendritic cells promotes IL-I 0-mediated suppression of
antin1mor immunity. Cancer Res 2011;71:5467-76.
51.
Stahl-Hennig C, Eisenblatter M, Jasny E, et al. Synthetic double-stranded RNAs are
adjuvants for the induction of T helper l and humoral immune responses to lnrman
papillomavirns in rhesus macaques. PLoS pathogens 2009;5:el000373.
52.
Boscardin SB, HafaJla JC, Masilamani RF, et al. Antigen targeting to dendritic cells
elicits Jong-lived T cell help for antibody responses. The Joumal of expe1imenta.l medicine
2006;203:599-606.
53.
Soares H, Waechter H, Glaichenhaus N, et al. A subset of dend1itic cells induces
CD4+ T cells to produce IFN-gamma by an IL-12-independent but CD70-dependent mechanism
in vivo. Tue Journal of experimental medicine 2007;204: I 095-106.
54.
Trumpfheller C, Caskey M, Nchinda G, et al. The microbial mimic poly IC induces
durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine.
Proc Na.ti Acad Sci US A 2008;105:2574-9.
55.
Trumpfheller C, Finke JS, Lopez CB, et al. Intensified and protective CD4+ T cell
immunity in mice with anti-dendritic cell HIV gag fusion antibody vaccine. The Jo1u11al of
experimental medicine 2006;203:607-17.
56.
Salem ML, Kadima AN, Cole DJ, Gillanders \VE. Defining the antigen-specific T­
cell response to vaccination and poly(l:C)filR3 signaling: evidence of enhanced prima1y and
memo1y CDS T-cell responses and antitumor inummity. J Immunother 2005;28:220-8.
57.
Tough DF, Borrow P, Sprent J. Induction of bystander T cell proliferation by vimses
and type I interferon in vivo. Science 1996;272: 1947-50.
58.
Zhu X, Nishimura F, Sasaki K, et al. Toll like receptor-3 ligand poly-ICLC promotes
the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in mmine
CNS tumor models. Journal of translational medicine 2007;5:I0.
59.
Gaucher D, Thenien R, Ketta.fN, et al. Yellow fever vaccine induces integrated
multilineage and polyfonctional immune responses. The Journal of experin1ental medicine
2008;205:3119-3 l.
60.
Okada H, Kalinski P, Ueda R, et al. Induction of CD8+ I-cell responses against novel
glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type I
pola1ized dend1itic cells and polyinosinic-polycytidylic acid stabilized by lysine and
carboxymethylcellulose in patients with recurrent malignant glioma. Journal of clinical oncology
: official joumal of the American Society of Clinical Oncology 2011;29:330-6.
61.
Robinson RA, De Vita VT, Levy HB, Baron S, Hubbard SP, Levine AS. A phase 1-11
trial of multiple-dose polyi-iboinosic-polyribocytidylic acid in patieonts with leukemia or solid
tumors. Jownal of the National Cancer Institute 1976;57:599-602.
62.
Aucouturier J, Dupuis L, Deville S, Ascarateil S, Gaime V. Montanide ISA 720 and
51: a new generation of water in oil emulsions as adjuvants for human vaccines. Expe1t review
of vaccines 2002; I: 111-8.
63.
Rachel Lubong Sabado ACP, Sa.cha Gnjatic, Farah Hasan, Meredith Spada.ccia, Bike
Su Oner, Hanqing Dong, Rose Marie Holman, Isabelita Vengco, Caroline Muren, Crystal
Escano, Ethel Yepes, Claire Stein, Achim A Jungbluth, Linda S. Pan, Ralph Rudolph Venhaus,
Andres M. Salazar, Patiick Alexander Ott, Nina Bhardwaj. Poly-ICLC as an adjuvant for NY­
ESO-1 protein vaccination with or without Montanide ISA-51 VG in patients with melanoma.
96 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 

DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Journal of clinical oncology : official journal of the Ame1ican Society of Clinical Oncology 
2016;33:suppl; abstr el4034. 
64.
1B BMSR. BMS-734016 (MDX-010) Comparative Tissue-Binding Study with
Mouse, Rat, Rabbit, Monkey and Human Tissues (Study DS05067), Report2005.
65.
1B BMSR. Study SBi 0919-128: A 2-week toxicity study of human anti-CTLA4
administered by intravenous injection to cynomologous monkeys.2000.
66.
1B BMSR. Study SBi 0992-128: An iimuunogenic study following combii1ed
intravenous/intramuscular administration ofMAbl0Dl/HBsAg, respectively, to cynomologous
monkeys.200 I.
67.
1B BMSDR. Covance Study No. 7114-100: 14 day intravenous toxicity sn1dy with
mAB l 0Dl in cynomologous monkeys.2000.
68.
Document BMS. Sn1dy No. DS0604: BMS-663513 and BMS-734016 (MDX-010):
One-month ii1travenous combination toxicity in monkeys2007.
69.
1B BMSR. Study SBi 1416-128: A repeat dose toxicology and effficacy study MDX-
010 or MDX-010-HYB in combination with HBsAg and SKMel vaccines in cynomologous
monkeys2003.
70.
1B BMSDR. Repeated-dose (q3d x 3, 14-day) toxiciyt sn1dy of anti-CTLA4/10Dl
administered via illtravenous injection to cynomologous monkeys (Study 126-002). Repo1t
Redfield Laboratories2000.
71.
Document BMS. Sn1dy 01-3460: MDX-CTLA4: A 6-Month intravenous toxicology
study in cynomologous monkeys2002.
72.
1B BMSDR. Cross-reactivity sn1dy of fluoresceina.ted human monoclonal antibody
l0Dl with n01mal human tissues (Study IM578) Repo1t Pathology Associates International
2000.
73.
1B BMSDR. Cross-reactivity study offluoresceinated MDX-010 with limited nonnal
human tissues (Study ™933), Report Pathology Associates Intemational2003.
74.
1B BMSDR. Ipilinrnmab (BMS-734016): Intravenous study of pre- and postnatal
development in cynomologous monkeys with a 6-month postnatal evaluation.2011.
75.
Hodi FS, O'Day SJ, McDermott DF, et al. Improved s1uvival with ipilimumab in
patients with metastatic melanoma. N Engl J Med 2010;363:711-23.
76.
van den Eertwegh AJ, Versluis J, van den Berg HP, et al. Combined iimum1otherapy
with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer
cells and ipilimumab iii patients with metastatic castration-resistant prostate cancer: a phase 1
dose-escalation tiial. Lancet Oncol 2012;13:509-17.
77.
Madan RA, Mohebtash M, Arlen PM, et al. lpilimmnab and a poxviral vaccine
targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 
dose-escalation nial. Lancet Oncol 2012;13:501-8. 
78.
Le OT, Lutz E, Uram JN, et al. Evaluation of ipilimmuab in combination with
allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated
pancreatic cancer. J Immunother 2013;36:382-9.
79.
Samaik AA, Yu B, Yu D, et al. Extended dose ipili.mumab with a peptide vaccine:
immune conelates associated with clinical benefit in patients with resected high-1isk stage
Ille/IV melanoma. Clin Cancer Res 2011;17:896-906.
80.
SchadendorfD, Hodi FS, Robert C, et al. Pooled Analysis of Long-Tenn Smvival
Data From Phase II and Phase III Trials oflpilimmnab in Unresectable or Metastatic Melanoma.
97 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 

DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Journal of clinical oncology : official journal of the Ame1ican Society of Clinical Oncology 
2015;33: 1889-94. 
81.
Weber JS, Kudchadkar RR, Yu B, et al. Safety, efficacy, and bioma.rkers of
nivolumab with vaccine in ipilinunnab-refracto1y or -naive melanoma. Journal of clinical
oncology : officialjoumal of the Ameiican Society of Clinical Oncology 2013;31:4311-8.
82.
Robe1t C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma
without BRAF mutation. N Engl J Med 20l5;372:320-30.
83.
Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients
with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a
randomised, controlled, open-la.be!, phase 3 ttial. Lancet Oncol 2015;16:375-84.
84.
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced
melanoma. N Engl J Med 2013;369:122-33.
85.
Quezada SA, Peggs KS, Cmrnn MA, Allison JP. CTLA4 blockade and GM-CSF
combination inummotherapy alters the intratumor balance of effector and regulato1y T cells. J
Clin Invest 2006;116: 1935-45.
86.
Simpson TR, Li F, Montalvo-O1tiz W, et al. Fe-dependent depletion of tumor-
infiltrating regulatory T cells co-defmes the efficacy of anti-CTLA-4 therapy against melanoma.
J Exp Med 2013;210:1695-710.
87.
Son CH, Bae JH, Shin DY, et al. Ctla-4 blockade enhances antitumor inunm1ity of
intrattlllloral injection of immature dendiitic cells into im1diated tumor in a mouse colon cancer
model. J Inunm1otber 2014;3 7: 1-7.
88.
Hodi FS, Butler M, Obie DA, et al Immunologic and clinical effects of antibody
blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer
patients. Proc Natl Acad Sci USA 2008;105:3005-10.
89.
Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-
associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and
ovarian carcinoma patients. Proc Na.ti Acad Sci US A 2003;100:4712-7.
90.
Ka1yampudi L, Lamichhane P, Scheid AD, et al. Accumulation of Memo1y Precursor
CD8 T Cells in Regressing Tumors Following Combination Therapy with Vaccine and Anti-PD-
1 Antibody. Cancer Res 2014.
91.
Hacohen N, Fritsch EF, Ca1ter TA, Lander ES, Wu CJ. Getting personal with
neoantigen-based therapeutic cancer vaccines. Cancer lninumology Research (Cancer
Inununology at the Crossroads) 2013;1:ll-5.
92.
Heemskerk B, Kvistborg P, Schtmiacher lN. The cancer antigenome. EMBO J
2013;32: 194-203.
93.
Schmnacher TN, Schreiber RD. Neoantigens in car1cer inuum1otherapy. Science
2015;348:69-74.
94.
Tumeh PC, Ha1view CL, Yearley JH, et al. PD-1 blockade induces responses by
inhibiting adaptive immtme resistance. Nature 2014;515:568-71.
95.
Rizvi NA, Hellmam1 MD, Snyder A, et al. Mutational landscape determines
sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015.
96.
Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal neoantigen vaccine for
patients with melanoma. Narure 2017;547:217-21.
97.
Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in
Advanced Melanoma. N Engl J Med 2015;372:2521-32.
98 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 

DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
98.
Hoos A, Eggennont AM, Janetzki S, et al. Improved endpoints for cancer
iimnunotherapy trials. Jomnal of the National Cancer Institute 2010;102: 1388-97.
99.
Wolchok JD, Hoos A, O'Day S, et al Guidelines for the evaluation of immune
therapy activity in solid tumors: iimnune-related response c1iteria. Clinical cancer research : an
official journal of the Ame1ican Association for Cancer Research 2009; 15 :7 412-20.
JOO. 
Weber J, Mandala M, DelVecchio M, et al. Adjuvant Nivolumab versus lpiliinumab ii1 
Resected Stage III or IV Melanoma. N Engl J Med 2017; 377:1824-1835. 
101.
Ascie1to PA, Del Vecchio M, Mandala M, Gogas H, Arance AM, Daile S, Cowey
CL, et al. Adjuvant nivolmnab versus ipilimmnab in resected stage IIIB-C and stage IV
melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised,
controlled, phase 3 trial. Lancet Oncol. 2020 Nov;21(1 l):1465-1477.
99 
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APPENDIX A 
PERFORMA.t'1CE STATUS CRITERIA 
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ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
0 
1 
2 
3 
4 
5 
Descriptions 
Percent 
No1mal activity. Fully active, able 
100 
to cany on all pre-disease 
performance without restriction. 
90 
Symptoms, but ambulatory. 
Restiicted in physically strenuous 
80 
activity, but ambulato1y and able 
to cany out work of a light or 
sedentaiy nature (e.g., light 
70 
housework, office work). 
In bed <50% of the time. 
Ambulato1y 3lld capable of all 
60 
self-<:are, but tmable to cany out 
any work activities. Up and about 
50 
more than 50% ofwakinll: hours. 
In bed >50% of the time. Capable 
40 
of only limited self-care, confined 
to bed or chair more than 50% of 
30 
wakinll: hours. 
100% bedridden. Completely 
20 
disabled. Cannot cany on any self-
c31·e. Totally confmed to bed or 
10 
chair. 
Dead. 
0 
100 
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Description 
Nonna!, no complaints, no evidence 
of disease. 
Able to cany on 1101mal activity; 
minor siQlls or symptoms of disease. 
Nonna) activity with effo1t; some 
signs or symptoms of disease. 
Cares for self, unable to cany on 
normal activity or to do active work. 
Requires occasional assist3llce, but 
is able to care for most of bis/her 
needs. 
Requires considerable assist3llce and 
freouent medical c31·e. 
Disabled, requires special care and 
assist3llce. 
Severely disabled, hospitalization 
indicated. Death not imminent. 
Very sick, hospitalization indicated. 
Death not imminent. 
Moribund, fatal processes 
proirressine. rapidlv. 
Dead. 
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APPENDIXB 
Appendix Bl: 
ADVERSE EVENT MANAGEMENT 
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Appendix B2: 
102 
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Appendix B3: 
103 
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Appendix B4: 
104 
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Appendix BS: 
105 
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Appendix B6: 
106 
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Appendix B7: 
107 
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Appendix B8: 
108 
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APPENDIXC 
REGULATORY CONSIDERATIONS 
DP/HCC Protocol #:18-279 
Version 8.0 / November 20, 2023 
Dana-Farber/Haivard Cancer Center (DF/HCC) follows the Intemational Conference on 
Hannonisation Guidelines for Good Clinical Practice (ICH GCP) to the extent those guidelines 
reflect the regulations and guidance set forth by the Food and Drng Administration (FDA) 
regulations. Where the ICH GCP guidelines include recommendations or requirements that go 
beyond those set fo1th under the FDA regulations, DF/HCC may or may not choose to institute 
those additional recommendations or requirements. 
Tue study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Collllnittee (IRB/IEC) approval/favorable opinion prior to initiation of the study. 
All potential serious breaches must be reported to the study PI, study sponsor (Dr. Patrick Ott, 
Md PhD), and DF/HCC IRB. 
A se1ious breach is a breach of the conditions and p1inciples of GCP in connection with the study 
or the protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study. 
Personnel involved in conducting this study will be qualified by education, tranung, and 
experience to perfonn their respective tasks. l11is study will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct or 
fraud ( e.g., loss of medical licensure, deba1ment). 
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