Conditions: Metastatic Head and Neck Squamous Cell Carcinoma Recurrent Head and Neck Squamous Cell Carcinoma Unresectable Head and Neck Squamous Cell Carcinoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 14
Healthy volunteers: no

Brief summary:
This phase II trial studies how well tavokinogene telseplasmid with electroporation (tavo-EP), pembrolizumab, and epacadostat work in treating patients with squamous cell carcinoma of the head and neck that cannot be removed by surgery. Tavokinogene telseplasmid with electroporation is a gene therapy that may delay of tumor growth and which may have less toxicity than other methods of gene delivery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving tavokinogene telseplasmid with electroporation, pembrolizumab, and epacadostat may work better in treating squamous cell carcinoma of the head and neck.

Detailed description:
PRIMARY OBJECTIVES:

I. Dose Escalation Safety Lead-Ins: Assess the safety of tavo-EP and pembrolizumab in combination with epacadostat (CTCAE version 4).

II. Dose Expansion: Determine whether the combination therapy in each arm increases the best overall response rate (BORR) compared with historical data for pembrolizumab monotherapy

SECONDARY OBJECTIVES:

I. Dose Expansion: Determine the durability of clinical benefits in participants treated with combination therapy in each arm, as assessed by time to progression, median progression-free survival (PFS), median overall survival (OS).

EXPLORATORY OBJECTIVES:

I. Determine the effects of combination therapy on treated and untreated lesions by examining paired biopsy specimens for changes in inflammatory gene expression, relative proportion of effector versus regulatory T cells, evaluation of inflammatory cytokines, T-cell activation, clonality, and other hallmarks of immune activation.

II. Explore systemic markers of immune activation by examining circulating T-cell populations for changes in the frequency and effector function of short-lived effector cells and memory T cells.

III. Explore changes in functional immune responses using Elispot and other assays.

IV. To explore biomarkers that inform scientific understanding of this therapeutic treatment through analysis of specimens retained for Future Biomedical Research.

OUTLINE:

This is a multi-center, open label, 2-stage, double-arm, clinical trial in which participants in Stage 1 will receive either tavo-EP with pembrolizumab, and epacadostat (Arm A), tavo-EP and pembrolizumab (Arm B), or CORVax, tavo-EP and pembrolizumab (Arm C). Arms B and C will only open to enrollment if the treatment is determined to be effective in Arm A.

Participants will be followed at 3-month intervals for toxicity and radiographic imaging (1) until start of a new anti-cancer treatment, (2) until 30 days after documented disease progression, (3) until death, or (4) until 36 months from the initiation of treatment on study, whichever comes first. Each subject will be followed for overall survival until death, withdrawal of consent, or at the time of study closure, whichever occurs first.

Arms:
arm 1: Tavo-EP will be injected intratumorally on Days 1, 5 and 8 every 6 weeks to up to 7 accessible lesions without exceeding 20 mL per day. Injected lesions will then be electroporated using the ImmunoPulse electroporation device. Pembrolizumab will be administered by a 30 minute IV infusion at a dose of 200 mg every 3 weeks. Epacadostat will be administered at the dose level determined in the dose escalation safety lead-in. arm 2: Tavo-EP will be injected intratumorally on Days 1, 5 and 8 every 6 weeks to up to 7 accessible lesions without exceeding 20 mL per day. Injected lesions will then be electroporated using the ImmunoPulse electroporation device. Pembrolizumab will be administered by a 30 minute IV infusion at a dose of 200 mg every 3 weeks. arm 3: Tavo-EP will be injected intratumorally on Days 1, 5 and 8 every 6 weeks to up to 7 accessible lesions without exceeding 20 mL per day. Injected lesions will then be electroporated using the ImmunoPulse electroporation device. Pembrolizumab will be administered by a 30-minute IV infusion at a dose of 200 mg every 3 weeks. CORVax will be administered at a total dose of 0.2 mg of (S) protein plasmid in 120 microliter (uL) per lesion intratumorally into a maximum of 4 lesions of at least 0.3 mm in diameter for a total plasmid dose of 0.8 mg on treatment days 1 and 29 of cycle 1 followed by electroporation of the plasmid solution in infiltrated regions. On days when both tavo and CORVax is administered to the same lesions, tavo and CORVax will each be injected into the lesion followed by electroporation.

Interventions: intervention 1: ImmunoPulse intervention 2: Epacadostat intervention 3: Pembrolizumab intervention 4: CORVax intervention 5: Tavokinogene telseplasmid
Intervention descriptions: intervention 1: Intratumoral intervention 2: Given PO intervention 3: Given IV intervention 4: Intratumoral intervention 5: Intratumoral

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.
The Trifecta Study: Optimizing Antitumor Immunity Using Tavokinogene Telseplasmid 
with Electroporation, Pembrolizumab, and Epacadostat in Squamous Cell Carcinoma of 
the Head and Neck
Protocol Number:  CC #172021
Study Drugs: tavokinogene telseplasmid, electroporation, pembrolizumab, epacadostat
Version Number: 8
Version Date:  08/12/2019
IND Number:  18210
Statistician
Charles Davis 
Revision History
 Version 1.0
10/22/2017
 Version 2.0
12/30/2017
 Version 3.0
Version 4.0
04/27/2018
09/06/2018
 Version 5.0
Version 6.0
01/17/2019
04/22/2019
Version 7.0
06/25/2019
Version 8.0
08/12/2019
Sponsor/Principal Investigator
Chase Heaton, MD
University of California, San Francisco
Head and Neck Oncologic Surgery
San Francisco, CA 94158
NCT#: 03823131


Protocol Signature Page
Protocol No.: 172021
Version Date: 08-12-2019
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee
(PRC),Committee on Human Research (CHR), and Data Safety Monitoring
Committee(DSMC).
2.
I will conduct the study in accordance with applicable CHR requirements, Federal
regulations, and state and local laws to maintain the protection of the rights and welfare of
study participants.
3.
I certify that I, and the study staff, have received the requisite training to conduct this
research protocol.
4.
I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the
www.clinicaltrials.gov website.
5.
I agree to maintain adequate and accurate records in accordance with CHR policies,
Federal, state and local laws and regulations.
UCSF Principal Investigator / Study Chair
Printed Name
Signature
Date
Participating Site(s)
Telephone:   
E-mail:
Telephone:   
E-mail:
Principal Investigator
Site
Printed Name
Signature
Date


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Protocol Signature Page – Participating Sites
Protocol No.:      
Participating Site(s)
Principal Investigator Name: 
Institution Name:
Address:  
Telephone:  
E-mail:
Principal Investigator Name: 
Institution Name:
Address:  
Telephone:  
E-mail:
I have read this protocol and agree to conduct the protocol in accordance with Good Clinical 
Practices (ICH-GCP), the applicable ethical principles, the Statement of Investigator (Form FDA 
1572), Institutional Review Board regulations, and all national, state and local laws and/or 
requirements of the pertinent regulatory requirements. 
Principal Investigator
Site
Printed Name
Institution Name
Signature
Date


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Abstract
Title
The Trifecta Study: Optimizing Antitumor Immunity Using Tavokinogene 
Telseplasmid with Electroporation, Pembrolizumab, and Epacadostat in 
Squamous Cell Carcinoma of the Head and Neck
Patient 
population
Patients with recurrent or metastatic squamous cell carcinoma of the head 
and neck with tumors that are accessible for injection and electroporation
Rationale for 
Study
Squamous cell carcinoma of the head and neck (SCCHN) is a major cause 
of death globally with 380,000 deaths annually1. Anti-PD1 antibodies induce 
durable remissions in only 12-20% of patients with unresectable 
SCCHN2,3.  The presence of tumor infiltrating ‘partially exhausted’ PD-1+ 
tumor-specific CD8+ T cells and antigen/MHC I complexes on the tumor cell 
surface appear to be prerequisites for a response with anti-PD1 agents. Down 
regulation of antigen presentation is a common immune-evasion strategy in 
tumors, particularly in SCCHN, where impairment of normal pathways of MHC 
I antigen processing and presentation is observed in up to 50% of tumors. 
HNSCC patients who lack tumor-infiltrating lymphocytes (TILs) and the 
associated IFNγ-gene signature are extremely unlikely to respond to anti-PD-
14. Interleukin-12 (IL-12) promotes a pro-inflammatory tumor environment,
enhancing antigen presentation, Th1 polarization, the frequency of TIL and
ultimately productive systemic anti-tumor immune responses.
When IL-12 is administered systemically, it can be toxic5, but intratumoral 
electroporation of tavokinogene telseplasmid (tavo-EP) leads to sustained 
IL-12 exposure in the tumor microenvironment, priming immune responses 
and leading to regression of both treated and untreated lesions in the 
absence of systemic therapy.  In Phase 1 and 2 clinical trials in melanoma 
and in a pilot study in SCCHN, tavo-EP was shown to be well-tolerated, with 
one treatment related SAE in monotherapy (1 pt / 96) and one in 
combination (1pt /23) – both cellulitis6,7.tavo-EP monotherapy resulted in 
characteristics associated with an inflamed tumor, including increased 
presence of TILs and expression of IFNγ-associated pro-inflammatory 
genes. In a follow-up study, tavo-EP was combined with the PD-1 antibody 
pembrolizumab in melanoma patients predicted not to respond to 
pembrolizumab alone based on a flow cytometry assay where a low 
frequency of partially-exhausted CD8+ T cells in the tumor 
microenvironment yields a remarkably precise negative predictive value9. 
The BORR to combination therapy in this population was 43%, far higher 
than anticipated based on both the flow cytometry and an PD-L1 IHC 
predictive assays9,9, and durable responses were seen in patients with prior 
progression on PD-1 antibodies alone10.  Paired biopsy specimens in 
responders demonstrated both an increase in TILs and in the ratio of 
effector T cells to regulatory cells.  In contrast, non-responders often


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Rationale(cont
inued)
demonstrated an increase in TILs both in treated and untreated lesions, but 
the balance between effector CD8+ T cells is skewed towards suppressive 
lymphocytes (PD-L1+CD163+ monocytes and FoxP3+ Tregs).  In the SCCHN 
pilot study, lesions in non-responders were often richly infiltrated with TILs 
suggesting a significant role of regulatory cells in hindering antitumor 
immunity.
Epacadostat is an oral IDO1 inhibitor that increases proliferation and 
activation of effector cells including NK cells, DCs, and T lymphocytes while 
depleting Tregs.  Clinical data thus far has demonstrated that the 
combinations of epacadostat and PD-1 Abs and the combination of tavo-EP 
and PD-1 Abs have been well tolerated.  Our data thus far also suggest that 
effective anticancer immune responses require 3 steps: 1) immune priming 
and tumor infiltration with T cells; 2) activation of partially exhausted TILs; and 
3) selective modulation of T cell populations to maximize the CD8+ TE : Treg 
ratio.  Based on this framework, we hypothesize that the combination of tavo-
EP (step 1) with pembrolizumab (step 2) and epacadostat (step 3) will 
substantially increase the BORR to pembrolizumab and tavo-EP alone, in 
patients with squamous cell carcinoma of the head and neck and that this 
combination will be well tolerated in this population.
Primary 
Objective
Dose Escalation Safety Lead-In:

Assess the safety of tavo-EP and pembrolizumab in combination with 
epacadostat (CTCAE version 4)
Dose Expansion:

Determine whether the combination of tavo-EP, pembrolizumab, and 
epacadostat increases the best overall response rate (BORR) in SCCHN 
compared with historical data for pembrolizumab monotherapy
Secondary 
Objectives
Dose Expansion:
Determine the durability of clinical benefits in patients treated with tavo-
EP, pembrolizumab, and epacadostat as assessed by time to 
progression, median PFS, median OS


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Exploratory 
Objectives

Determine whether the combination of tavo-EP, pembrolizumab, and 
epacadostat increases the objective response rate in SCCHN compared 
with emerging data for pembrolizumab in combination with epacadostat

Determine the effects of combination therapy on treated and untreated 
lesions by examining paired biopsy specimens for relative changes in 
the expression of innate and adaptive immune-specific genes, the 
density of CD8+effector versus CD4+regulatory TIL, evaluation of 
systemic inflammatory cytokines, T-cell clonality, and other hallmarks of 
immune activation.

Interrogate different subsets of PBMC to explore changes in phenotypic 
markers associated with productive systemic anti-tumor immune 
responses such as frequencies of short-lived effector cells and memory 
T cells, activated NK cells and APCs.

Explore treatment-related changes in functional immune responses 
using ELISpot, intracellular cytokine release and other assays.

To explore biomarkers that inform scientific understanding of this 
therapeutic treatment through analysis of specimens retained for future 
biomedical research.


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Study Design
This is a multi-center, open label, 2-stage, double-arm, clinical trial in which 
patients in Stage 1 will receive either tavo-EP with pembrolizumab, and 
epacadostat (Arm A) or tavo-EP and pembrolizumab (Arm B).  Depending on 
the response from Stage 1, Stage 2 will continue to investigate the arms.
Dose Escalation Safety Lead-In:
tavo-EP:pUMVC3-hIL-12-NGVL33 (tavo-EP) will be injected intratumorally 
on Days 1, 5 and 8 every 6 weeks to up to 7 accessible lesions without 
exceeding 20 mL per day. Injected lesions will then be electroporated using 
the ImmunoPulse electroporation device.
Pembrolizumab: Pembrolizumab will be administered by a 30 minute IV 
infusion at a dose of 200 mg every 3 weeks.
Epacadostat:  Epacadostat will be administered at a dose of 300mg PO bid, 
and if well-tolerated, patients will be dose escalated to 600 mg PO bid.
Best overall response rate (BORR) by RECIST v1.1 will be compared to 
historical data for pembrolizumab monotherapy in SCCHN and to emerging 
data regarding the combination of pembrolizumab and epacadostat.
Stage 1:
Once the dose for epacadostat has been established in the dose escalation 
safety lead-in, Stage 1 will begin with the enrollment to both Arms A and B.  
Arm A:
tavo-EP:pUMVC3-hIL-12-NGVL33 (tavo-EP) will be injected intratumorally 
on Days 1, 5 and 8 every 6 weeks to up to 7 accessible lesions without 
exceeding 20 mL per day. Injected lesions will then be electroporated using 
the ImmunoPulse electroporation device.
Pembrolizumab: Pembrolizumab will be administered by a 30 minute IV 
infusion at a dose of 200 mg every 3 weeks.
Epacadostat:  Epacadostat will be administered at the dose level determined 
in the dose escalation safety lead-in.
Arm B: 
tavo-EP:pUMVC3-hIL-12-NGVL33 (tavo-EP) will be injected intratumorally 
on Days 1, 5 and 8 every 6 weeks to up to 7 accessible lesions without 
exceeding 20 mL per day. Injected lesions will then be electroporated using 
the ImmunoPulse electroporation device.
Pembrolizumab: Pembrolizumab will be administered by a 30 minute IV 
infusion at a dose of 200 mg every 3 weeks.


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Stage 2:
At the conclusion of Stage 1, if there are at least ≥ 3 responses in 15 
patients, in either Arms A or B, up to an additional 26 patients (13 patients in 
Arm A and 13 patients in Arm B) will be enrolled in the respective treatment 
arms.
Number of 
patients
The overall study (including dose escalation safety lead-in and dose 
escalation) plans to enroll up to 68 evaluable patients.
Dose Escalation Safety Lead-In: We expect to enroll 12 patients overall in the 
safety lead-in (minimum of 9)
Dose Expansion Phase, Stage 1:  We expect to enroll 30 patients in both arms 
(15 patients in Arm A and 15 patients in Arm B). We will allow patients who 
were enrolled in the dose escalation safety lead-in to enroll in Arm A of Stage 
1, depending on the final dose.
Dose Expansion Phase, Stage 2: Depending on the results of the clinical data 
in Stage 1, Stage 2 will enroll up to an additional 26 patients. 


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Inclusion 
Criteria
Patient Characteristics
1.
Age ≥ 18 years old;
2.
ECOG performance status 0-2;
3.
Life expectancy of at least 4 months;
Disease Characteristics
4.
Patients must have histological or cytological diagnosis of carcinoma 
of the head and neck that is not amenable to surgical resection or 
locoregional radiation therapy with curative intent;
5.
At least one accessible lesion (AL) for intratumoral injection. An AL is 
defined as meeting the following criteria; (1) at least 0.3 cm x 0.3 cm 
in longest perpendicular diameters (2) in a suitable location for 
application of electroporation. Tumors invading the carotid artery or at 
other sites that the investigator believes to be at high risk of life-
threatening hemorrhage should not be injected and these lesions may 
not be used to meet the inclusion criterion for injectable lesions
6.
Measureable disease as defined by RECIST v1.1; at least one lesion 
where the longest perpendicular diameter is at least 1.0 cm by clinical 
measurement; or at least 1.0 cm by radiographic imaging for non-
nodal lesions; at least 1.5 cm in short axis by radiographic imaging for 
malignant lymph nodes; If the biopsied lesions were previously 
irradiated, they must demonstrate either radiographic or pathological 
evidence of recurrent or residual disease. It is not necessary that this 
lesion is also an AL.
7.
If patient has known brain metastases, they must have stable 
neurologic status following local therapy (surgery or radiation) for at 
least 4 weeks without the use of steroids or on stable or decreasing 
dose of ≤10 mg daily prednisone (or equivalent), and must be without 
neurologic dysfunction that would confound the evaluation of 
neurologic and other AEs (patients with a history of carcinomatous 
meningitis are not eligible);
Treatment History
8.
Patients may have had prior chemotherapy or immunotherapy or 
radiation therapy. Any drug related adverse events identified during 
prior therapy must be well controlled (typically resolution to ≤ grade 1, 
OR resolved upon investigator review prior to initiation of this therapy;
9.
No systemic antineoplastic therapy may be received by the patient 
between the time of the biopsy and the first administration of study 
treatment;
Consent for Biopsies
10. Patient must agree to any protocol mandated biopsies of tumor 
(deemed accessible, safe and appropriate for biopsy by the 


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investigator’s assessment) and they must allow acquired tissue to be 
used for biomarker and immunological analysis.
Fertility
11. For women of childbearing potential, negative serum or urine 
pregnancy 
test 
within 
14 
days 
to 
the 
first 
epacadostat, 
pembrolizumab, or tavo-EP administration, and use of birth control 
from 30 days prior to the first epacadostat, pembrolizumab, or tavo-
EP administration and 120 days following last day epacadostat, 
pembrolizumab, or tavo-EP administration
12. Male patients must be surgically sterile, or must agree to use 
contraception during the study and at least 120 days following the 
last day of epacadostat, pembrolizumab, or tavo-EP administration.


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Exclusion 
Criteria
Medical History
Autoimmune 
1.
Active autoimmune disease that has required systemic treatment in 
past 2 years.  Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency) is not considered a form of systemic treatment;
Cardiac 
2.
Congestive heart failure (New York Heart Association Class III to IV); 
3.
History or presence of an abnormal electrocardiogram (ECG) that, in 
the investigator's opinion, is clinically meaningful.  Screening QTc 
interval > 480 milliseconds is excluded.  In the event that a single QTc 
is > 480 milliseconds, the subject may enroll if the average QTc for 
the 3 ECGs is < 480 milliseconds.  For subjects with an intraventricular 
conduction delay (QRS interval > 120 milliseconds), the JTc interval 
may be used in place of the QTc with sponsor approval.  The JTc must 
be < 340 milliseconds if JTc is used in place of the QTc.  Subjects with 
left bundle branch block are excluded.
4.
Uncontrolled or clinically significant conduction abnormalities (e.g., 
ventricular tachycardia on anti-arrhythmic are excluded), 1st degree 
AV block or asymptomatic LAFB/RBBB are eligible;
5.
Uncontrolled, symptomatic ischemia within 6 months of first dose of 
study treatment or known myocardial infarction in the previous six 
months;
6.
Patients with electronic pacemakers or defibrillators;
Pulmonary
7.
Evidence of interstitial lung disease or any history of autoimmune 
pneumonitis including symptomatic and/or pneumonitis requiring 
treatment;
Oncologic
8.
Any other current or previous malignancy within the past 2 years that, 
in the opinion of the Principal Investigator will interfere with study-
specific endpoints;
Infectious
9.
Evidence of significant active infection (e.g., pneumonia, cellulitis, 
wound abscess, etc.) requiring systemic therapy at time of study 
enrolment;
10. Patients with HBV surface antigen positive (HBSAg) must have AST 
and total bilirubin < 1.5 x ULN AND negative HBV RNA PCR OR on 
antivirals for HBV AND at least 8 weeks of prior anti-PD1 antibody 
therapy AND no history ofAST or total bilirubin levels > 1.5 x ULN due 
to PD-1 antibody therapy.
11. Hepatitis C (HCV RNA [qualitative] is detected). 
Gastrointestinal


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12. Presence of a gastrointestinal condition that may affect drug 
absorption.  Administration of epacadostat through a feeding tube is 
permitted.
Medications / Medication Reactions
13. Patients receiving systemic steroid therapy for a chronic 
inflammatory condition. Topical steroids, nasal and inhaled steroids 
are permitted. Prednisone or equivalent ≤ 10 mg/day is permitted as 
hormone replacement; higher dosage prednisone should be stopped 
at least 14 days prior to C1D1;


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Exclusion 
Criteria
Medications / Medication Reactions
14. Subjects receiving Monoamine Oxidase Inhibitors (MAOIs) or drug 
which has significant MAOI activity (meperidine, linezolid, methylene 
blue) within the 21 days before screening.  
15. Any history of Serotonin Syndrome (SS) after receiving serotonergic 
drugs.
16. Use of any UGT1A9 inhibitor from screening through follow-up period, 
including the following: diclofenacc, imipramine, ketoconazole, 
mefenamic acid, and probenecid.  
17. Known allergy or reaction to any component of any study drug 
formulation.
18. Receipt of live attenuated vaccine within 30 days before the first dose 
of study treatment.  Examples of live vaccines include, but are not 
limited to, the following:  measles, mumps, rubella, chicken pox, 
yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid 
vaccine.  Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza 
vaccines (eg, FluMist®) are live attenuated vaccines and are not 
allowed. 
19. Subjects receiving Monoamine Oxidase Inhibitors (MAOIs) or drug 
which has significant MAOI activity (meperidine, linezolid, methylene 
blue) within the 21 days before screening.  
Laboratories
20. Screening Laboratory Abnormalities
a.
Absolute neutrophil count (ANC) < 1.0 × 109/L.
b.
Platelets < 75 × 109/L.
c.
Hemoglobin < 9 g/dL or < 5.6 mmol/L (transfusion is 
acceptable to meet this criterion).
d.
Serum creatinine ≥ 1.5 × institutional upper limit of normal 
(ULN) OR measured or calculated creatinine clearance 
(glomerular filtration rate can also be used in place of 
creatinine or CrCl) < 50 mL/min for subjects with creatinine 
levels > 1.5 × institutional ULN.
e.
AST or ALT > 2.5 × institutional ULN.
f.
Alkaline phosphatase > 2.5 x ULN.  Note:  Subjects with 1) 
bone metastases and GGT < 2.5 x ULN may enroll if the 
alkaline phosphatase is < 5 × ULN.
g.
Total bilirubin above 1.5 x the institutional ULN AND 
conjugated bilirubin ≥ 2.0 × ULN.
h.
International normalized ratio (INR) or prothrombin time (PT) 
> 1.5 × ULN.
i.
Activated partial thromboplastin time (aPTT) > 1.5 × 
ULN.


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Efficacy 
Endpoints
Primary efficacy endpoint:
Best overall response rate (BORR); defined as the percentage of patients 
who attain a confirmed CR or PR over the trial with the triplet treatment with 
a 4-week confirmatory scan per RECIST v1.1.
Secondary efficacy endpoints:
Progression free survival (PFS) is defined as the number of days from the 
date of enrollment to the date of progression or death regardless of cause. 
Patients who do not have a documented progression or death will be 
censored on the date of last assessment.  Overall survival (OS) is defined 
as the number of days from the date of enrollment to the date of death 
regardless of cause, patients without a death date will be censored on the  
date last known alive.
Exploratory / 
Translational 
Endpoints
Translational analyses are intended to be hypothesis generating.  
Translational endpoints will be met if there have been significant changes in: 

Inflammatory genes expression by Nanostring before and after 
initiation of treatment on study

The relative proportion of effector versus regulatory T-cells in pre-
treatment and post-treatment tumor specimens

Pre-treatment versus post-treatment in cytokine expression, T-cell 
repertoire, clonality

Pre-treatment versus post-treatment populations of immune cell 
populations in the peripheral blood including short-lived effector cells 
(SLECs) and memory T-cells 

Pre-treatment versus post-treatment functional immune responses 
using Elispot analysis

Experimental and statistical methods for these assessments are 
described in Appendix 4.
Safety 
Endpoints
Safety assessments include AEs (either reported by the patient or observed 
by the Investigator), concomitant medication use, performance status, vital 
signs, physical examination, and laboratory assessments. AEs will be 
graded and reported using CTCAE version 4 and reported descriptively.
Safety 
Assessment
Clinical evaluations including laboratory and clinical safety assessments will 
be performed at 3-week intervals for patients who are actively receiving 
treatment on study.  For patients in the follow-up portions of the study who 
are not actively receiving therapy, evaluations will be performed at 12-week 
intervals.  Safety will be assessed during the study by documentation of 
adverse events (AEs), clinical laboratory tests, physical examination, vital 
sign measurements, and Eastern Cooperative Oncology Group (ECOG) 
performance status. 


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Dose 
Escalation 
Safety Lead-In
and Mid-Study 
Interim Safety 
Analysis
Dose Escalation Safety Lead-In
1.     If, at any time, 1 or more of the first 3 safety-evaluable patients 
experience grade 3 or higher treatment-associated adverse events 
within the first 30 days of initiation of treatment, then no further 
patients will be enrolled at the current dose level.
2.     After 6 patients have been enrolled on study, enrollment will be 
halted for 30 days for completion of the dose escalation lead-in 
safety analysis.  If 0-1 patients experience grade 3 or higher 
treatment-associated adverse events within the first 30 days of 
initiation of treatment, then additional patients may be enrolled at 
the next dose level. 
3.     If enrollment is halted at any time during the lead-in period due to 
treatment-associated adverse events, the UCSF DSMB will review 
all available safety data with the Principal Investigator.  Based on 
this review, study discontinuation or reduction of the epacadostat 
dose may be recommended.  No further patients will be enrolled on 
study without the approval of the DSMB.  If the DSMB allows 
additional patients to enroll, the lead-in period will be repeated at 
the new dose level with a maximum of 6 additional patients enrolled 
prior to follow-up safety analysis.  At the discretion of the DSMB, 
patients who are currently on study may continue treatment at the 
reduced dose level.
4.     Patients who discontinue treatment on study within 30 days of 
initiation of therapy for reasons other than treatment-associated 
toxicity will be deemed inevaluable for safety and replaced for 
safety analysis.
Mid-Study Interim Safety Analysis (Stage 1)
Enrollment will also be halted for 30 days for interim safety analyses after a 
total of 30 safety-evaluable patients have initiated treatment on study in both 
Arms A and B  Patients who discontinue treatment on study within 30 days of 
initiation of therapy for reasons other than treatment-associated toxicity will 
be deemed inevaluable for safety and replaced for safety analysis.  The study 
will be discontinued under the following circumstance:
 
1.     On-study occurrence of 3 or more Grade 4 (life threatening) serious 
adverse events (SAEs) or deaths, which are deemed at least 
possibly related to the study agent.
2.     Based on the review of data the DSMB has serious concerns about 
the safety of patients on the study.  In addition to stopping the study, 
the DSMB may recommend that the epacadostat dose for all 
patients be de-escalated for all current and future patients or 
cessation of further patient accrual.


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Phase II – tavo-EP, pembrolizumab, epacadostat
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Duration of 
Therapy
Dose Escalation Safety Lead-In Phase: 6 patients will receive triplet therapy 
for 30 days at Dose level 0. After 30 days of therapy, if those patients do not 
experience a DLT, an additional 6 patients will be enrolled at the next Dose 
level, Level 1 which will increase epacadostat to 600 mg for 30 days, tavo-
EP and pembrolizumab will not be dose escalated. If no patients experience 
a DLT at 600 mg, that will be the dose level of epacadostat used in Stage 1, 
for both Arms A and B.
Dose Expansion Phase, Stage 1, Arm A: Patients will receive triplet therapy 
for 12 months or until the development of an unacceptable treatment 
associated toxicity or confirmed progression. After 12 months of therapy, 
patients will enter the follow-up phase for the next 24 months.  Patients with 
disease progression during the follow-up phase will have access to 12 
additional months of triplet therapy.  Patients who are eligible for treatment 
on study but who have experienced regression of all previously accessible 
lesions may continue on pembrolizumab and epacadostat without tavo-EP.
Dose Expansion Phase, Stage 1, Arm B: Patients will receive combination 
therapy for 12 months or until the development of an unacceptable 
treatment associated toxicity or confirmed progression.  After 12 months of 
therapy, patients will enter the follow-up phase for the next 24 months.  
Dose Expansion Phase, Stage 2: Depending on the results of the clinical data 
in Stage 1, Stage 2 will enroll up to an additional 26 patients accordingly:
If there are at least ≥ 3 responses in 15 patients, in either Arms A or B, up to 
an additional 26 patients (13 patients in Arm A and 13 patients in Arm B) will 
be enrolled in the respective treatment arms.
Duration of 
Follow up
Patients will be followed at 3 month intervals for toxicity and radiographic 
imaging 1) until start of a new anti-cancer treatment, (2) until 30 days after 
documented disease progression, (3) until death, or (4) until 36 months from 
the initiation of treatment on study, whichever comes first. Each subject will 
be followed for overall survival until death, withdrawal of consent, or the end 
of the study, whichever occurs first.
Duration Of 
Study
Study accrual will be sufficient to assess the primary endpoint within 24 
months from the time the study opens to accrual.


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Sample Size 
Justification 
and Efficacy 
Assessment
Sample Size Justification:
Dose Expansion Phase, Stage 1:  We expect to enroll 30 patients in both 
arms (15 patients in Arm A and 15 patients in Arm B). We will allow patients 
who were enrolled in the dose escalation safety lead-in to enroll in Arm A of 
Stage 1, depending on the final dose.
Dose Expansion Phase, Stage 2: Depending on the results of the clinical 
data in Stage 1, Stage 2 will enroll up to an additional 26 patients accordingly:
If there are at least ≥ 3 responses in 15 patients, in either Arms A or B, 
up to an additional 26 patients (13 patients in Arm A and 13 patients 
in Arm B) will be enrolled in the respective treatment arms.
The above Simon 2-stage sample sizes were based on the following 
assumptions: 
the 
objective 
response 
rate 
for 
pembrolizumab 
is 
approximately 15%3 and we suggest that a 20% absolute improvement in 
this response rate would be clinically meaningful.  We propose to test the 
hypothesis that the objective response rate for the combination of tavo-EP 
with pembrolizumab and epacadostat is 35% versus the null hypothesis that 
it is similar to the response rate for pembrolizumab monotherapy, 15%. The 
statistical power calculations are based on the Simon Two-Stage Optimal 
Design11 with a Type I error rate of 0.05 and power of 80%.
Efficacy Assessment:
The objective response rate for pembrolizumab is approximately 15%3 and 
we suggest that a 20% absolute improvement in this response rate would be 
clinically meaningful.  We propose to test the hypothesis that the objective 
response rate for the combination of tavo-EP with pembrolizumab and 
epacadostat is 35% versus the null hypothesis that it is similar to the response 
rate for pembrolizumab monotherapy, 15%. The following statistical power 
calculations are based on the Simon Two-Stage Optimal Design11 with a Type 
I error rate of 0.05 and power of 80%.


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Statistical 
consideration
The standard summary statistics for continuous variables are sample size (n), 
mean, standard deviation (SD), median, minimum and maximum. The 
standard summary statistics for categorical variables are frequencies and 
percentages. 
BORR will calculated as a percentage relative to all patients who received the 
study therapy, and 95% confidence interval is calculated by the Clopper-
Pearson (exact binomial) method. 
Time to event variables will be summarized using the Kaplan-Meier method. 
Where confidence limits are appropriate, the confidence level will be 95% 
(two-sided), as determined by the Brookmeyer and Crowley method, unless 
otherwise stated.
Individual data (including relevant derived variables) will be presented 
by parameter in listings. Results of statistical analyses, descriptive 
summary statistics and supportive listings will also be presented.
Statistical analyses (and experimental methods) for the exploratory, 
translational objective are described in Appendix 4.


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List of Abbreviations
AE
adverse event
AL
accessible lesion
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CR
complete response
CRC
Clinical Research Coordinator
CRF
case report form
CT
computerized tomography
CTCEA
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
CTMS
Clinical Trial Management System
DFS
disease-free survival
DLT
dose limiting toxicity
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECOG
EP
Eastern Cooperative Oncology Group
Electroporation
FCBP
female of childbearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBeAg
Hepatitis B “e” antigen
HBV
hepatitis B virus
HCT
hematocrit
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HGB
hemoglobin
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization
IND
IL
investigational new drug application
interleukin
IP
investigational product
IRB
Institutional Review Board
IRRC
immune related-Response Criteria


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List of Abbreviations
IT
intratumoral
IV
intravenous
LDH
lactate dehydrogenase
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI
National Cancer Institute
ORR
Objective response rate
PD
disease progression
tavo-EP
tavokinogene telseplasmid with electroporation
PK
pharmacokinetics
PR
partial response
PRC
Protocol Review Committee (UCSF)
RBC
SAE
red blood cell (count)
serious adverse event
SD
stable disease
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
TIL
TKI
TE AE
TR AE
tumor infiltrating lymphocytes
targeted kinase inhibitors
treatment emergent adverse event
treatment related adverse event
ULN
upper limit of normal
WBC
white blood cell (count)


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Phase II – tavo-EP, pembrolizumab, epacadostat
Page 21 of 96
Table of Contents
Protocol Signature Page ...............................................................................................................2
Protocol Signature Page – Participating Sites...............................................................................3
Abstract
.............................................................................................................................4
List of Abbreviations ....................................................................................................................18
Table of Contents ........................................................................................................................20
1
Introduction.........................................................................................................................23
1.1
Background ........................................................................................................23
1.1.1
Squamous cell carcinoma of the head and neck (SCCHN)............................23
1.1.2
FDA approved immunotherapy in SCCHN .....................................................23
1.2
Investigational Agents ........................................................................................23
1.2.1
tavo-EP...........................................................................................................23
1.2.2
Epacadostat....................................................................................................27
1.3
Rationale for the Proposed Study ......................................................................29
2
Objectives of the Study ......................................................................................................29
2.1
Primary ...............................................................................................................29
2.2
Secondary ..........................................................................................................29
2.3
Exploratory Objectives .......................................................................................30
2.4
Endpoints ...........................................................................................................30
2.4.1
Primary Endpoint ............................................................................................30
2.4.2
Secondary Endpoints .....................................................................................30
2.4.3
Exploratory and Translational Endpoints........................................................30
3
Study Design......................................................................................................................31
3.1
Characteristics....................................................................................................31
3.2
Number of Subjects............................................................................................31
3.3
Eligibility Criteria.................................................................................................31
3.3.1
Inclusion Criteria.............................................................................................31
3.3.2
Exclusion Criteria............................................................................................32
3.4
Schedule of Procedures and Observations........................................................37
4
Treatment...........................................................................................................................37
4.1
Dose Escalation Schedule .................................................................................37
4.2
Dose Expansion Schedule .................................................................................38
4.3
Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD)..................38
4.3.1
Dose Limiting Toxicity.....................................................................................39
4.3.2
Dose Modifications and Management of Toxicity ...........................................39
4.3.3
Treatment Modification – All Agents...............................................................40
Guidelines for Subjects Exhibiting Serotonin Syndrome.............................................49
4.3.4
Seriousness....................................................................................................49
4.3.5
Autonomic signs .............................................................................................49
4.3.6
Neurological signs ..........................................................................................49
4.3.7
Mental status ..................................................................................................49
4.3.8
Other...............................................................................................................49
4.3.9
Mild .................................................................................................................49
4.3.10
Moderate .......................................................................................................49
4.3.11
Severe ...........................................................................................................50
Dose Modification versus Dose Interruption ...............................................................50
4.4
Duration of Treatment ........................................................................................50
4.4.1
Treatment After Disease Progression ............................................................50


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4.5
Post-Treatment Follow-up..................................................................................50
4.6
Clinical and Pharmacy Considerations...............................................................51
4.6.1
tavo-EP...........................................................................................................51
4.6.2
Epacadostat....................................................................................................53
4.6.3
Pembrolizumab...............................................................................................53
5
Safety
...........................................................................................................................53
5.1
Safety Assessments...........................................................................................53
5.2
Safety Stopping Rules........................................................................................54
6
Efficacy Assessments ........................................................................................................55
6.1
Efficacy Assessments ........................................................................................55
6.1.1
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.......................55
7
Statistical Plan....................................................................................................................59
7.1
Sample Size Justification ...................................................................................59
7.2
Analysis Populations ..........................................................................................59
7.3
Primary Efficacy Analysis...................................................................................59
7.4
Secondary / Exploratory Efficacy Analysis.........................................................60
7.5
Exploratory Analysis...........................................................................................60
7.6
Safety Analysis...................................................................................................60
8
Restricted Medications.......................................................................................................60
Restricted Medications/Treatment........................................................................................60
Prohibited Medications/Treatment........................................................................................61
9
Discontinuation of Therapy ................................................................................................62
9.1
Birth Control, Pregnancy and Paternity..............................................................62
9.2
Use in Pregnancy...............................................................................................63
9.3
Use in Nursing Women ......................................................................................63
10
Correlative Studies.............................................................................................................63
10.1
Future Biomedical Research..............................................................................64
11
Reporting and Documentation of Results ..........................................................................64
11.1
Evaluation of Efficacy (or Activity)......................................................................64
11.1.1
Antitumor Effect – Solid Tumors....................................................................64
11.2
Evaluation of Safety ...........................................................................................67
11.3
Evaluating Adverse Events ................................................................................67
11.3.1
Definitions of Adverse Events........................................................................71
11.4
Recording of an Adverse Event..........................................................................72
11.5
Follow-up of Adverse Events..............................................................................73
11.6
Adverse Events Monitoring ................................................................................73
11.7
Expedited Reporting...........................................................................................74
11.8
Clinical Criteria for Early Trial Termination.........................................................75
12
Study Management ............................................................................................................76
12.1
Pre-study Documentation...................................................................................76
12.2
Institutional Review Board Approval...................................................................76
12.3
Informed Consent...............................................................................................76
12.4
Changes in the Protocol.....................................................................................77
12.5
Handling and Documentation of Clinical Supplies..............................................77
12.6
Case Report Forms (CRFs) ...............................................................................77
12.7
Oversight and Monitoring Plan...........................................................................78
12.8
Multicenter communication.................................................................................78
12.9
Record Keeping and Record Retention..............................................................78
12.10
Coordinating Center Documentation of Distribution...........................................79
12.11
Regulatory Documentation.................................................................................79


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13
Protection of Human Subjects............................................................................................80
13.1
Protection from Unnecessary Harm ...................................................................80
13.2
Protection of Privacy ..........................................................................................80
References
81
Appendices
84
Appendix 1
 Performance Status Criteria..............................................................................84
Appendix 2 Data and Safety Monitoring Plan for a Multicenter Institutional Study (For Lead-In 
Phase)................................................................................................................85
Appendix 3 Data and Safety Monitoring Plan for a Multicenter Study (Phase II or III study) ......89
Appendix 4 Translational Medicine Methods and Statistical Analysis.........................................93


V er si o n d at e: 0 8- 1 2- 2 0 1 9
Pr ot o c ol C C #: 1 7 2 0 2 1
P h a s e II – t a v o- E P, p e m br oli z u m a b, e p a c a d o st at
P a g e 2 4 of 9 6
1
I ntr o d u cti o n
1. 1  
B a c k gr o u n d
1. 1. 1
S q u a m o u s c ell c ar ci n o m a of t h e h e a d a n d n e c k ( S C C H N)
W hil e l o c ali z e d a n d l o c or e gi o n al S C C of t h e h e a d a n d n e c k ( H N S C C) c a n b e c ur e d wit h s ur g er y, 
r a di ati o n, or c h e m or a di ati o n, a s u b st a nti al n u m b er of p ati e nt s will d e v el o p r e c urr e nt or di st a nt 
m et a st ati c di s e a s e aft er d efi niti v e l o c or e gi o n al t h er a p y.  T h e s e r e c urr e n c e s ar e a s s o ci at e d wit h 
a p o or o v er all pr o g n o si s 1 2 , a n d t h e m e di a n o v er all s ur vi v al i n p ati e nt s wit h m et a st ati c S C C of t h e 
h e a d a n d n e c k i s u n d er a y e ar e v e n wit h i nt e n si v e c o m bi n ati o n c h e m ot h er a p y 1 3 . T h e a d diti o n of 
m o n o cl o n al a nti b o di e s t ar g eti n g t h e e pi d er m al gr o wt h f a ct or r e c e pt or ( E G F R) t o c h e m ot h er a p y 
i m pr o v e s t h e s e o ut c o m e s s o m e w h at, b ut t h e s e m ulti- a g e nt c o m bi n ati o n s oft e n i n d u c e si g nifi c a nt 
tr e at m e nt- a s s o ci at e d t o xi cit y t h at n e g ati v el y i m p a ct s q u alit y of lif e. A s a r e s ult of t h e li mit e d 
effi c a c y of st a n d ar d of c ar e tr e at m e nt o pti o n s, 1 1, 5 0 0 p ati e nt s di e e v er y y e ar fr o m s q u a m o u s c ell 
c ar ci n o m a of t h e or al c a vit y a n d t h e or o p h ar y n x i n t h e U nit e d St at e s al o n e 1 4 .
1. 1. 2
F D A a p pr o v e d i m m u n ot h er a p y i n S C C H N
1. 1. 2. 1 A nti- P D 1 A nti b o di e s
T h e a nti P D- 1 a nti b o di e s p e m br oli z u m a b a n d ni v ol u m a b h a v e b e e n a p pr o v e d b y t h e F D A f or t h e 
tr e at m e nt of c h e m ot h er a p y r efr a ct or y r e c urr e nt / m et a st ati c S C C H N.  Alt h o u g h t h e s e a g e nt s c a n 
i n d u c e d ur a bl e, o bj e cti v e t u m or r e s p o n s e s i n b ot h H P V p o siti v e a n d H P V n e g ati v e t u m or s, 
r e s p o n s e r at e s ar e l o w, r a n gi n g fr o m 1 2- 1 8 %2, 3 .  A nti- P D- 1 a nti b o di e s h a v e b e e n w ell t ol er at e d 
wit h o nl y 1 i n 8 S C C H N p ati e nt s e x p eri e n ci n g gr a d e 3 or hi g h er a d v er s e e v e nt s.  P D- 1 a n d P D-
L 1 tr e at m e nt f ail ur e s i n a d v a n c e d s oli d t u m or s h a v e b e e n a s s o ci at e d wit h i n a d e q u at e i ntr at u m or al 
i nfl a m m at or y i m m u n e r e s p o n s e s1 5  
a n d 
a n 
e x c e s s 
of r e g ul at or y 
c ell s i n t h e t u m or 
mi cr o e n vir o n m e nt
1 0 .
1. 2 
I n v e sti g ati o n al A g e nt s
1. 2. 1
t a v o- E P
t a v o- E P: B a c k gr o u n d
T a v o ki n o g e n e t el s e pl a s mi d wit h el e ctr o p or ati o n (t a v o- E P) i s a g e n e t h er a p y a p pr o a c h t o i n d u ci n g 
st a bl e i ntr at u m or al e x pr e s si o n of t h e pr o-i nfl a m m at or y c yt o ki n e I L- 1 2.  I nt erl e u ki n- 1 2 (I L- 1 2) i s 
a n a n e n d o g e n o u s, 7 0 kil o d alt o n pr ot ei n c o n si sti n g of t w o s u b u nit s li n k e d b y a di s ulfi d e b o n d 1 6 . It 
i s a p ot e nt pl e otr o pi c c yt o ki n e, c a p a bl e of dri vi n g c ell- m e di at e d i m m u nit y t hr o u g h m ulti pl e p ar all el 
m e c h a ni s m s, i n cl u di n g a cti v ati o n of N K c ell s a n d c yt ot o xi c T l y m p h o c yt e s ( C T L s) a s w ell a s 
i n hi biti o n of r e g ul at or y T c ell s a n d m y el oi d- d eri v e d s u p pr e s s or c ell s ( M D S C s)1 6 – 1 8 . Al s o, a s a 
p ot e nt i n d u c er of i nt erf er o n- g a m m a (I F N- , I L- 1 2 c a n dri v e u pr e g ul ati o n of a nti g e n pr o c e s si n g 
a n d pr e s e nt ati o n m a c hi n er y ( A P M) wit hi n t u m or s.
t a v o- E P: Pr e- Cli ni c al D at a
F or a t h or o u g h di s c u s si o n of t h e p h ar m a c ol o g y a n d pr e cli ni c al b a c k gr o u n d of t a v o ki n o g e n e 
t el s e pl a s mi d, r ef er t o t h e t a v o I n v e sti g at or' s Br o c h ur e, S e cti o n 4. 0
Cli ni c al tri al s of t a v o- E P m o n ot h er a p y
t a v o- E P: S af et y
O v er all, 9 6 p ati e nt s ( 5 p ati e nt s wit h s q u a m o u s c ell c ar ci n o m a of t h e h e a d a n d n e c k) h a v e b e e n 
tr e at e d wit h m o n ot h er a p y t a v o- E P.  I n g e n er al, tr e at m e nt h a s b e e n w ell t ol er at e d a n d tr a n si e nt, 


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Page 25 of 96
grade 3 procedural pain has been the only observed grade 3 or higher adverse event.  A summary 
of all grade treatment associated AEs seen in over 5% of patients and all grade 3 or higher AEs 
(N = 96) is given in Table 1-1.One SAE potentially related to monotherapy was cellulitis in one 
patient (1/96) that resolved with antibiotics. Additionally, one patient with head and neck cancer 
died from a tumoral bleeding episode involving a lesion that was distant from any treatment site.  
The patient’s death was unrelated to treatment on study in the opinion of the treating investigator.
Table 1-1All grade treatment associated AEs seen in over 5% of patients and all grade 3 
or higher AEs (N = 96)
Category
Adverse Reaction
Gr 1-2
Gr 3-4
Grade 5
All Grades
Procedural Pain
47.9%
5.2%
-
53.1%
Inflammation
12.5%
-
-
12.5%
Discoloration
11.5%
-
-
11.5%
Reactions at Treatment Site
Bruising
5.2%
-
-
5.2%
Pruritus
5.2%
-
-
5.2%
Skin
Cellulitis
5.2%
2.6%
-
5.2%
Constitutional
Fatigue
5.2%
-
-
5.2%
Any Related AE
61.5%
5.2%
-
66.7%
tavo-EP: Safety Data in SCCHN
In a pilot / feasibility study, four patients with SCCHN were administered at least 1 cycle of 
intratumoral TAVO EP, with one participant receiving 9 cycles of treatment.  Of the 4 participants 
enrolled in the study, 1 participant completed the study, 2 had progressive disease and 1 died 
from disease.
Treatment with intratumoral TAVO EP had an acceptable safety profile and was well tolerated 
(Table 1-2). There was 1 death during the study, which was reported as a serious adverse event 
(SAE), however, this event was not related to intratumoral TAVO EP, but as a result of disease 
progression. For this patient, treatment was restricted to a superficial subcutaneous lesion on the 
left anterior neck. The patient received a total volume of 0.55 mL of plasmid IL-12 at a 
concentration of 0.5 mg/mL. Approximately 33 days after cycle one day one and approximately 
18 days since his most recent treatment (cycle 1 day 15), the patient presented to the emergency 
department with uncontrolled bleeding from a tumor that was on the contralateral side of his neck 
(right medial neck). This lesion had grown in size during the course of study and the episode was 
attributed to disease progression.
There were 3 participants who experienced study drug-related TEAEs, including procedural pain, 
bruising, or bleeding. There were no TEAEs leading to study drug withdrawal. 


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Table 1-2Treatment-emergent adverse events (AEs) regardless of attribution.
tavo-EP: Efficacy in Melanoma
Intratumoral injection of tavo-EP is currently under investigation in metastatic melanoma. A Phase 
I trial in melanoma was conducted involving seven dosing cohorts with a total of 24 patients. 
Patients received one cycle consisting of three days of treatment. Maximum total plasmid injected 
per visit ranged from 0.2-6 mg, at concentrations ranging from 0.1-1.6 mg/mL. A dose proportional 
increase in IL-12 protein expression compared to pretreatment in biopsied tumors was seen in all 
patients with no significant IL-12 spillage into circulation. Most (76%) electroporated lesions 
demonstrated greater than 20% necrosis at the time of follow-up biopsy or excision performed 
between 3 and 31 days after the last injection. Four of 19 patients who had distant disease had 
evidence of distant responses including 3 complete responses in patients with progressive 
metastatic disease. Of these patients, 2 patients had not had any subsequent systemic therapy 
while 1 patient had received dacarbazine following tavo-EP therapy. All three complete responses 
occurred in the setting of patients with disseminated progressive cutaneous lesions. No dose 
related or treatment related toxicity was seen except for transient pain and discomfort at the 
injection site22. 
In a3 part, phase II multicenter study of intratumoral tavo-EP (0.5 mg/mL)  in subjects with in-
transit or cutaneous melanoma, the primary objectives of the first two study parts (Main and 
Addendum) were to assess the overall response rate (CR + PR) by either investigator modified 
skin Response Evaluation Criteria in Solid Tumors (msRECIST) or derived msRECIST. The trial 
has enrolled 51 subjects (Main =30, Addendum = 21). Efficacy data with tavo-EP as monotherapy 
with different dosing regimens showed a best overall response rate (BORR) of 25% to 34% as 


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well as 38.5 to 50.0% observed regression of distal untreated lesions. Moreover, subjects who 
received intratumoral tavo-EP and later went on to receive an anti-PD-1 antibody demonstrated 
a high PD-1-associated response rate (64% complete response [CR] + partial response [PR]). 
Interestingly, subjects who received an anti PD-1 antibody with no intervening therapy post 
intratumoral tavo-EP had a BORR of 75% (CR+PR).  
Clinical data for tavo-EP in combination with pembrolizumab
Safety
Intratumoral tavo-EP was administered in combination with pembrolizumab in 22 advanced 
melanoma patients as part of a phase 2 clinical trial.  The only grade 3 or higher adverse events 
observed were treatment site reactions and, in 1 patients, a transient grade 3 AST elevation.  All 
adverse events seen in > 10% of patients treated with tavo-EP in combination with pembrolizumab 
and all grade 3+ AEs (N = 22) are given in Table 1-3.
Table 1-3All AEs seen in > 10% of patients treated with tavo-EP in combination with 
pembrolizumab and all grade 3+ AEs (N = 22)
tavo-EP: Efficacy in Melanoma in combination with aPD-1
The ongoing combination therapy study (tavo-EP with pembrolizumab; CC 15852/OMS I102) in 
subjects with low TILs showed a BORR of 50% (11/22); a CR of 41% (9/22); a disease control 
rate (DCR; CR + PR + stable disease [SD]) of 59% (13/22); progression free survival (PFS) of 
57% at 15 months; and duration of response (DOR) of 100% (11/11) (Algazi, Tsai et al. 2016; 
Algazi, Tsai et al. 2016 AACR; Algazi 2017). These results are highly promising, since the eligible 
population are predicted to not responder to anti-PD-1 therapy alone.


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1.2.2 Epacadostat
IDO Background
Inhibition of Indoleamine 2,3-Dioxygenase 1 as a Target for Cancer
Recent interest has focused on the role of IDO1 as a mechanism of induction of tolerance to 
malignancy24. Indoleamine 2,3-dioxygenase 1 is a heme-containing, monomeric oxidoreductase 
that catalyzes the degradation of the essential amino acid tryptophan to N-formyl-kynurenine.  
Kynurenine can be subsequently metabolized through a series of enzymatic steps to nicotinamide 
adenine dinucleotide.  Indoleamine 2,3-dioxygenase 1 is the first rate-limiting enzyme in one of 
the breakdown pathways of tryptophan.  In another pathway, tryptophan hydroxylase catalysis of 
tryptophan leads to the formation of serotonin and melatonin.
The expression and activity profiles of IDO1 are distinct from those of tryptophan dioxygenase, 
an enzyme predominantly expressed in liver that catalyzes the same enzymatic reaction as IDO1 
and maintains proper tryptophan balance in response to dietary uptake.  In contrast to tryptophan 
dioxygenase, IDO1 is expressed in a variety of tissues, with particularly high levels found in areas 
of contact with potential sources of immune challenge (eg, gut, respiratory tract, placenta, spleen), 
consistent with a role for regulating tryptophan metabolism in a local microenvironment25.  Within 
the immune system, IDO1 activity is specifically induced in cells such as DCs and macrophages 
at localized sites of inflammation26.
Indoleamine 2,3-dioxygenase 1–driven oxidation of tryptophan results in a strong inhibitory effect 
on the development of T-cell–mediated responses by blocking T-cell activation and inducing T-
cell apoptosis27.  Both the reduction in local tryptophan levels and the production of tryptophan 
catabolites that are inhibitory to cell proliferation contribute to the immunosuppressive effects28.  
Indoleamine 2,3-dioxygenase 1 activity also promotes the differentiation of naive T cells to cells 
with a regulatory phenotype (Treg)29.  Because increased Treg activity has been shown to 
promote tumor growth and Treg depletion has been shown to allow an otherwise ineffectual 
antitumor immune response to occur30, IDO1 expansion of Treg may provide an additional 
mechanism whereby IDO1 could promote an immunosuppressive environment.
The biological relevance of IDO1 inhibition to immune tolerance was first demonstrated when it 
was shown that treating mice with a small molecule inhibitor of the IDO1 pathway, 1 methyl 
tryptophan, could break the tolerogenic state that protects the allogeneic conceptus from the 
maternal immune system31.  A critical role for IDO1 in immunomodulation has been confirmed in 
numerous animal models, including models of allograft tolerance, inflammation, and cancer25.  
While IDO1 inhibition can exacerbate disease in models of autoimmune disorders25, IDO1 null 
mice show no evidence of susceptibility to developing spontaneous autoimmunity or alterations 
in immune system development27, suggesting that IDO1 inhibition, in a therapeutic setting, may 
produce minimal side effects in subjects without pre-existing autoimmune conditions.
Within the context of cancer, there are several lines of evidence to suggest that IDO1 is a key 
regulator of the immunosuppressive mechanisms responsible for tumor escape from immune 
surveillance.  Several groups have demonstrated that blockade of IDO1 activity can directly 
influence the ability of tumor-bearing animals to reject tumors32,33.  In addition, studies with 1-
methyl-tryptophan demonstrate that IDO1 inhibition dramatically increases the efficacy of various 
chemotherapeutic agents (eg, platinum compounds, taxane derivatives, cyclophosphamide) 
without increased toxicity33.  Although the specific mechanisms responsible for this potentiation 
remain to be fully elucidated, the effects were not observed in T-cell–deficient animals, suggesting 


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that the results may be the consequence of the disablement of immunosuppressive mechanisms 
that exist within the tumor microenvironment.
Based on studies examining serum levels of tryptophan and kynurenine, IDO1 appears to be 
chronically activated in patients with cancer, and IDO1 activation correlates with more extensive 
disease34,35.  Indoleamine 2,3-dioxygenase 1 has subsequently been found to be overexpressed 
by a wide variety of human tumor cell types, as well as by the DCs that localize to the tumor-
draining lymph nodes25,32.  Increased expression of IDO1 in tumor cells has been shown to be an 
independent prognostic variable for reduced overall survival (OS) in subjects with melanoma, 
ovarian, colorectal, and pancreatic cancers36–40.
Together, these results suggest that the IDO1 pathway is a key regulatory element responsible 
for the induction and maintenance of tumor immune tolerance.  Small molecule inhibitors of IDO1 
may provide an innovative and tractable method to treat malignancies either alone or in 
combination with chemotherapeutics and/or immunotherapy-based strategies.
EPACADOSTAT: BACKGROUND
Mechanism of Action
Epacadostat represents a novel, potent, and selective inhibitor of the enzyme indoleamine 
2,3-dioxygenase 1 (IDO1) in both human tumor cells and human dendritic cells (DCs).  
Pharmaceutical and Preclinical Background
For a thorough discussion of the pharmacology and preclinical background of epacadostat, refer 
to the epacadostat Investigator's Brochure, Sections 3.0 and 4.0
Epacadostat: Clinical safety data
Combination Therapy
As of the data cut off (28 MAR 2016), 60 subjects have been enrolled in INCB 24360-202 
(epacadostat 
25 
mg, 
50 mg, 
100 
mg, 
and 
300 
mg 
BID 
in 
combination 
with 
pembrolizumab).  Based on the preliminary unaudited safety data (unaudited), no Grade 4 
treatment related AEs were reported. Three subjects (5%) discontinued for a treatment-related 
AE: Grade 3 arthralgia, Grade 3 AST elevation, and Grade 2 nervous system disorder. No 
treatment-related deaths occurred.  Treatment-emergent AEs were reported in 44 subjects 
(73.0%). The most frequently reported AEs were rash (27%) followed by fatigue (23%). Rash 
includes the preferred terms rash, rash generalized, rash maculopapular, rash pruritic, and rash 
follicular. As of the data cutoff (28 MAR 2016), 18 subjects in the Phase 1 portion of the INCB 
24360-202 study and 119 subjects in the Phase 2 portion of the study have received combination 
treatment with pembrolizumab and the 100 mg BID dose of epacadostat, the recommended dose 
for the Phase 3 study. The data for Phase 2 presents a subset of 99 subjects who had at least 1 
month of safety data. The most frequently reported (≥ 15%) AEs of any grade for the combined 
Phase 1 and Phase 2 subjects treated with epacadostat 100 mg BID were fatigue (35.0%), 
constipation (24.8%), diarrhea (20.5%), nausea (20.5%), vomiting (18.8%), pyrexia (16.2%), and 
dyspnea (15.4%). Fatigue (13.7%) and rash (11.1%; including the preferred terms rash, rash 
maculopapular, rash generalized, and rash macular) were the only treatment-related AEs 
reported in > 10% of subjects. Treatment-related AEs of rash were only reported in Phase 2. 
Treatment-related AEs ≥ Grade 3 occurring in more than 1 subject who received epacadostat 100 
mg BID in Phase 1 or Phase 2 included rash (5 subjects, 4.3%) and dehydration, lipase increased, 
AST increased, and nausea (2 subjects [1.7%] each). 


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For a thorough discussion of the pharmacology and preclinical background of epacadostat, refer 
to the epacadostat Investigator's Brochure, Sections 6.0 and 7.0
Clinical efficacy data for epacadostat in combination with pembrolizumab in HNSCC
Efficacy
Epacadostat was tested in combination with the PD-1 antibody pembrolizumab in 38 patients with 
SCCHN as part of a phase 1 / 2 clinical trial.  Objective responses were seen in 11 of 36 evaluable 
patients (30.5%) and disease stabilization was observed in 10 additional patients for an overall 
disease control rate of 58.3%17.
Rationale for the Proposed Study
Anti-PD1 antibodies induce durable remissions in only 12-20% of patients with unresectable 
SCCHN2,3.  HNSCC patients, who lack tumor-infiltrating lymphocytes (TILs) and the associated 
IFN-γ-gene signature are extremely unlikely to respond to anti-PD-14. Interleukin-12 (IL-12) 
promotes a pro-inflammatory tumor environment, enhanced antigen presentation, Th1 
polarization, an increased frequency of TIL and ultimately productive systemic anti-tumor immune 
responses.  When IL-12 is administered systemically, it can be toxic5, but intratumoral 
electroporation of plasmid IL-12 (tavokinogene telseplasmidor tavo-EP) leads to sustained IL-12 
exposure in the tumor microenvironment, priming immune responses and leading to regression 
of both treated and untreated lesions in the absence of systemic therapy.  tavo-EP demonstrates 
substantial clinical synergy with the PD-1 antibody, pembrolizumab, and even non-responders 
often demonstrated an increase in TILs both in treated and untreated lesions.  However, the 
balance between effector CD8+ T cells is skewed towards suppressive leukocytes (PD-
L1+CD163+ monocytes and FoxP3+ Tregs) in non-responders.  Epacadostat is an oral IDO1 
inhibitor that increases proliferation and activation of effector cells including NK cells, DCs, and T 
lymphocytes while depleting Tregs.  Our data thus far also suggest that effective anticancer 
immune responses require 3 steps: 1) immune priming and tumor infiltration with T cells; 2) 
activation of partially exhausted TILs; and 3) selective modulation of T cell populations to 
maximize the CD8+ TE : Treg ratio.  Based on the results of the clinical and translational data in 
Stage 1, Stage 2 will be developed in consultation with the Principal Investigator and leadership 
from both OncoSec and Incyte. Which will be submitted to the local and federal regulatory bodies 
for review and approval prior to being implemented.
2
Objectives of the Study
2.1
Primary
Dose Escalation Safety Lead-In: 

Assess the safety of tavo-EP and pembrolizumab in combination with epacadostat (CTCAE 
version 4)
Dose Expansion: 

Determine whether the combination of tavo-EP, pembrolizumab, and epacadostat increases 
the best overall response rate (BORR) in SCCHN compared with historical data for 
pembrolizumab monotherapy


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2.2
Secondary
Dose Expansion: 

Determine the durability of clinical benefits in patients treated with tavo-EP, pembrolizumab, 
and epacadostat as assessed by time to progression, median PFS, median OS
2.3
Exploratory Objectives

Determine whether the combination of tavo-EP, pembrolizumab, and epacadostat 
increases the objective response rate in SCCHN compared with emerging data for 
pembrolizumab in combination with epacadostat

Determine the effects of combination therapy on treated and untreated lesions by 
examining paired biopsy specimens for changes in inflammatory gene expression, relative 
proportion of effector versus regulatory T cells, evaluation of inflammatory cytokines, T-
cell activation, clonality, and other hallmarks of immune activation.

Explore systemic markers of immune activation by examining circulating T-cell populations 
for changes in the frequency and effector function of short-lived effector cells and memory 
T cells.

Explore changes in functional immune responses using Elispot and other assays.

To explore biomarkers that inform scientific understanding of this therapeutic treatment 
through analysis of specimens retained for Future Biomedical Research.
2.4
Endpoints
Primary Endpoint
Dose Escalation Safety Lead-In: 

Adverse events by CTCAE version 4.0. Safety assessments include AEs (either reported 
by the patient or observed by the Investigator), concomitant medication use, 
performance status, vital signs, physical examination, and laboratory assessments. AEs 
will be graded and reported using CTCAE version 4 and reported descriptively.
Dose Expansion: 

Best overall response rate (BORR) by RECIST version 1.1 compared to single agent 
pembrolizumab. BORR is defined as the percentage of patients who attain a confirmed 
CR or PR over the trial with the combination treatment with a 4-week confirmatory scan 
per RECIST v1.1.
2.4.2
Secondary Endpoints

Median overall survival and progression free survival. Progression free survival (PFS) is 
defined as the number of days from the date of enrollment to the date of progression or 
death regardless of cause. . Patients who do not have a documented progression or death 
will be censored on the date of last assessment.  Overall survival (OS) is defined as the 
number of days from the date of enrollment to the date of death regardless of cause, 
patients without a death date will be censored on the date last known alive.  


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2.4.3
Exploratory and Translational Endpoints
Best overall response rate compared to emerging data for pembrolizumab in combination with 
epacadostat once historical comparison data for the doublet become available. 
Translational analyses are intended to be hypothesis generating.  Translational endpoints will be 
met if there have been significant changes in: 

Inflammatory genes expression by Nanostring before and after initiation of treatment on 
study

The relative proportion of effector versus regulatory T-cells in pre-treatment and post-
treatment tumor specimens

Pre-treatment versus post-treatment in cytokine expression, T-cell repertoire, clonality

Pre-treatment versus post-treatment populations of immune cell populations in the 
peripheral blood including short-lived effector cells (SLECs) and memory T-cells 

Pre-treatment versus post-treatment functional immune responses using Elispot analysis
The experimental methods and statistical analysis plans for these endpoints are described in 
Appendix 4TranslationalMedicine Methods and Statistical AnalysisAppendix 4.
3
Study Design
3.1
Characteristics
This is a multi-center, open label, 2-stage, double-arm, clinical trial in which patients in Stage 1 
will receive either tavo-EP with pembrolizumab, and epacadostat (Arm A) or tavo-EP and 
pembrolizumab (Arm B).  Based on the results of the clinical data in Stage 1, Stage 2 enroll up 
to an additional 26 patients.
3.2
Number of Subjects
This trial is planned for up 68 evaluable patients.
3.3
Eligibility Criteria
Patients must have baseline evaluations performed prior to the first dose of epacadostat, 
pembrolizumab, or tavo-EP and must meet all inclusion and exclusion criteria.  In addition, the 
patient must be thoroughly informed about all aspects of the study, including the study visit 
schedule and required evaluations and all regulatory requirements for informed consent.  The 
written informed consent must be obtained from the patient prior to enrollment.  The following 
criteria apply to all patients enrolled onto the study unless otherwise specified.
3.3.1
Inclusion Criteria
Patient Characteristics
1.
Age ≥ 18 years old;
2.
ECOG performance status 0-2;
3.
Life expectancy of at least 4 months;


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Disease Characteristics
4.
Patients must have histological or cytological diagnosis of carcinoma of the head and neck 
that is not amenable to surgical resection or locoregional radiation therapy with curative 
intent;
5.
At least one accessible lesion (AL) for intratumoral injection. An AL is defined as meeting 
the following criteria; (1) at least 0.3 cm x 0.3 cm in longest perpendicular diameters (2) 
in a suitable location for application of electroporation. Tumors invading the carotid 
artery or at other sites that the investigator believes to be at high risk of life-threatening 
hemorrhage should not be injected and these lesions may not be used to meet the 
inclusion criterion for injectable lesions
6.
Measureable disease as defined by RECIST v1.1; at least one lesion where the longest 
perpendicular diameter is at least 1.0 cm by clinical measurement; or at least 1.0 cm by 
radiographic imaging for non-nodal lesions; at least 1.5 cm in short axis by radiographic 
imaging for malignant lymph nodes; If the biopsied lesions were previously irradiated, 
they must demonstrate either radiographic or pathological evidence of recurrent or 
residual disease. It is not necessary that this lesion is also an AL.
7.
If patient has known brain metastases, they must have stable neurologic status following 
local therapy (surgery or radiation) for at least 4 weeks without the use of steroids or on 
stable or decreasing dose of ≤10 mg daily prednisone (or equivalent), and must be 
without neurologic dysfunction that would confound the evaluation of neurologic and 
other AEs (patients with a history of carcinomatous meningitis are not eligible);
Treatment History
8.
Patients may have had prior chemotherapy or immunotherapy or radiation therapy. Any 
drug related adverse events identified during prior therapy must be well controlled 
(typically resolution to ≤ grade 1, OR resolved upon investigator review prior to initiation 
of this therapy; 
9.
No systemic antineoplastic therapy may be received by the patient between the time of 
the biopsy and the first administration of study treatment;
Consent for Biopsies
10. Patient must agree to any protocol mandated biopsies of tumor (deemed accessible and 
safe for biopsy by the investigator’s assessment) and they must allow acquired tissue to 
be used for biomarker analysis. 
Fertility
11. For women of childbearing potential, negative serum or urine pregnancy test within 14 
days to the first epacadostat, pembrolizumab, or tavo-EP administration, and use of birth 
control from 30 days prior to the first epacadostat, pembrolizumab, or tavo-EP 
administration and 120 days following last day of epacadostat, pembrolizumab, or tavo-
EP administration; 
12. Male patients must be surgically sterile, or must agree to use contraception during the 
study and at least 120 days following the last day of epacadostat, pembrolizumab, or tavo-
EP administration.


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3.3.2
Exclusion Criteria
Medical History
Autoimmune 
1.
Active autoimmune disease that has required systemic treatment in past 2 years.  
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment;
Cardiac 
2.
Congestive heart failure (New York Heart Association Class III to IV); 
3.
History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's 
opinion, is clinically meaningful.  Screening QTc interval > 480 milliseconds is excluded.  
In the event that a single QTc is > 480 milliseconds, the subject may enroll if the average 
QTc for the 3 ECGs is < 480 milliseconds.  For subjects with an intraventricular conduction 
delay (QRS interval > 120 milliseconds), the JTc interval may be used in place of the QTc 
with sponsor approval.  The JTc must be < 340 milliseconds if JTc is used in place of the 
QTc.  Subjects with left bundle branch block are excluded. 
4.
Uncontrolled or clinically significant conduction abnormalities (e.g., ventricular tachycardia 
on anti-arrhythmic are excluded), 1st degree AV block or asymptomatic LAFB/RBBB are 
eligible;
5.
Uncontrolled, symptomatic ischemia within 6 months of first dose of study treatment or 
known myocardial infarction in the previous six months;
6.
Patients with electronic pacemakers or defibrillators;
Pulmonary
7.
Evidence of interstitial lung disease or active, noninfectious pneumonitis including 
symptomatic and/or pneumonitis requiring treatment;
Oncologic
8.
Any other current or previous malignancy within the past 2 years that, in the opinion of the 
Principal Investigator will interfere with study-specific endpoints;
Infectious
9.
Evidence of significant active infection (e.g., pneumonia, cellulitis, wound abscess, etc.) 
requiring systemic therapy at time of study enrolment;
10. Hepatitis B – Most NPC patients have been infected with hepatitis B (Cancer Epidemol 
Biomarkers Prev. 2015. 24:1766-73, N = 711) and, therefore, the inclusion of healthy 
patients with a history of hepatitis B is a central part of this study.  In addition, PD-1 
antibodies have been proven to be safe in patients with active hepatitis and hepatocellular 
carcinoma (e. g. KEYNOTE 224).  However, patients with HBV surface antigen positive 
(HBSAg) must have AST and total bilirubin < 1.5 x ULN AND:
11. Negative HBV RNA PCR OR;
12. On antivirals for HBV AND at least 8 weeks of prior anti-PD1 antibody therapy AND no 
history of AST or total bilirubin levels > 1.5 x ULN due to PD-1 antibody therapy
13. Hepatitis C (HCV RNA [qualitative] is detected). 


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Gastrointestinal
14. Presence of a gastrointestinal condition that may affect drug absorption.  Administration 
of epacadostat through a feeding tube is permitted.
Medications / Medication Reactions
15. Patients receiving systemic steroid therapy for a chronic inflammatory condition. Topical 
steroids, nasal and inhaled steroids are permitted. Prednisone or equivalent ≤ 10 mg/day 
is permitted as hormone replacement; higher dosage prednisone should be stopped at 
least 14 days prior to C1D1;
16. Receipt of live attenuated vaccine within 30 days before the first dose of study treatment.  
Examples of live vaccines include, but are not limited to, the following:  measles, mumps, 
rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid 
vaccine.  Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed. 
17. Subjects receiving Monoamine Oxidase Inhibitors (MAOIs) or drug which has significant 
MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before screening.  
18. Any history of Serotonin Syndrome (SS) after receiving serotonergic drugs.
19. Use of any UGT1A9 inhibitor from screening through follow-up period, including the 
following:  diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid.  
20. Known allergy or reaction to any component of epacadostat, pembrolizumab, or tavo-EP 
formulation.
Laboratories
21. Screening Laboratory Abnormalities
a.
Absolute neutrophil count (ANC) < 1.0 × 109/L.
b.
Platelets < 75 × 109/L.
c.
Hemoglobin < 9 g/dL or < 5.6 mmol/L (transfusion is acceptable to meet this 
criterion).
d.
Serum creatinine ≥ 1.5 × institutional upper limit of normal (ULN) OR measured 
or calculated creatinine clearance (glomerular filtration rate can also be used in 
place of creatinine or CrCl) < 50 mL/min for subjects with creatinine levels 
> 1.5 × institutional ULN.
e.
AST or ALT > 2.5 × institutional ULN.
f.
Alkaline phosphatase > 2.5 x ULN.  Note:  Subjects with 1) bone metastases and 
GGT < 2.5 x ULN may enroll if the alkaline phosphatase is < 5 × ULN.
g.
Total bilirubin above 1.5 x the institutional ULN AND conjugated bilirubin ≥ 2.0 × 
ULN.
h.
International normalized ratio (INR) or prothrombin time (PT) > 1.5 × ULN.
i.
Activated partial thromboplastin time (aPTT) > 1.5 × ULN.


Table 3-1: Study Calendar
Period/Procedure
Screening
Cycle 1 (42 days)
Cycle 2+ (42 days)
Safety Follow-Up
Study Day/Visit Day
-28 to 0
1
5
8
22
1
5
8
22
30 days from Last Dose 
Informed Consent
Informed consent
X
Clinical Procedures
Medical history1
X
Medication review
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
Vital signs2
X
X
X
X
X
X
X
X
X
X
Performance status3
X
X
X
X
X
X
AE assessment4
X
X
X
X
X
Treatment: Dose Escalation 
Safety Lead-In and Stage 1 
and Stage 2, Arm A
tavo-EP
X
X
X
X
X
X
Pembrolizumab
X
X
X
X
epacadostat
Continuous oral or per G-tube dosing
Treatment: Stage 1 and Stage, Arm B
tavo-EP
X
X
X
X
X
X
Pembrolizumab
X
X
X
X
Biospecimen Collections
Screening Labs5
X
Safety Labs6
X
X
X
X
X
ECG7
X
(X)
Archival Specimen Collection
X
Fresh biopsy8
X
X
X
Research Blood (mandatory)9
X
X
X
Research Blood (optional)9
X
X
Tumor Assessments
Tumor measurements10
X
(X)


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1 Medical history includes any conditions resolved within 6 months of enrollment as well as surgeries and therapies related to the treatment of melanoma and any residual 
toxicity.
2 Includes blood pressure (systolic and diastolic), respiratory rate, heart rate and temperature. Height only required at screening. Weight only required at screening and day 
1 of each cycle. 
3 ECoG
4 CTCAE version 4
5 Screening labs include CBC with platelets and differential, LFTs (AST, ALT, total bilirubin, alkaline phosphatase), PT, PTT, electrolytes, BUN, creatinine, glucose, ionized 
calcium, lipase, amylase, HBsAg, HCV RNA quantitative
6 Safety labs include CBC with platelets and differential, LFTs (AST, ALT, total bilirubin, alkaline phosphatase), electrolytes, BUN, creatinine, glucose, ionized calcium, 
lipase, amylase
7 ECGs will be performed at screening and on day 1 of each odd numbered cycle excluding cycle 1.
8 Fresh biopsy collection will be done at screening, Cycle 2 Day 1, and at progression/end of treatment. Additional biopsies may be performed if clinically indicated. 
9 Research blood requirements are described in Section 10.  Mandatory blood collection will occur on Cycle 2, Day 1; Optional sample collection will occur on Day 22 for 
Cycles 2 and beyond and then on Day 1 for Cycles 3 and beyond.  Additional research blood acquisition, storage, and distribution information in provided in Section 10.  
Every effort shall be made to collect mandatory post-treatment (follow-up) research blood samples, but failure to collect this sample due to patient refusal or logistical 
constraints shall not constitute a protocol deviation or violation.
10 MRI, contrast-enhanced CT, or PET/CT imaging of the face, neck, chest, abdomen, and pelvis are required at screening and on day 1 of each odd-numbered cycle 
excluding cycle 1.  Both clinical and radiographic measurements may be used.  All superficial, clinically apparent lesions that cannot be adequately assessed 
radiographically (e. g. subcutaneous lesions) must be numbered and photographed with a metric ruler visible in each photograph.  For photographed lesions with borders 
that are not clearly visible, investigators should trace the lesions’ outline, making a solid line with a felt-tipped pen. Visible lesions should never be circled with a solid line 
but dashed or dotted lines may be used to distinguish these markings from the borders of otherwise invisible lesions.  Tumor assessments will be made using RECIST 
version 1.1.  IL-12 plasmid dosing may be based on the most recent tumor measurements and measurements need not be repeated immediately prior to each tavo-EP 
treatment.
11 Epacadostat dose may be changed if indicated based on dose escalation safety run-in described below in Table 4-1.


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3.4
Schedule of Procedures and Observations
The study-specific assessments are detailed in this section and outlined in Table 3-1: Study 
Calendar.  Screening assessments must be performed within 28 days prior to the first dose 
of investigational product unless otherwise noted.  Any results falling outside of the reference 
ranges may be repeated at the discretion of the investigator. All on-study visit procedures are 
allowed a window of ± 3 days unless otherwise noted.  Treatment or visit delays for public 
holidays or weather conditions do not constitute a protocol violation.
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy 
will be filed in the medical record.  The original will be kept on file with the study records.  
Informed consent for specimens for Future Biomedical Research may also be obtained during 
screening and must be obtained prior to collection of all Future Biomedical Research 
specimens.
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is 
password protected and meets HIPAA requirements.
4
Treatment
Treatment will be administered on an outpatient basis.
4.1
Dose Escalation Schedule
The recommended starting dose of single agent epacadostat is 300 mg twice daily. The 
current study is designed to determine the MTD of epacadostat in combination with 
pembrolizumab and tavo-EP.
Table 4-1: Dose Escalation for epacadostat 
Dose 
N
Epacadostat(mg)
(po BID) in 28 day cycles
-1
3
200 mg
0
3
300 mg
1
3
600 mg
Rationale for dose levels -1 to 1: The primary endpoint of the dose escalation safety run-in 
is to determine if epacadostat at 600 mg is a safe and tolerable dose in the combination of 
tavo-EP and pembrolizumab in patients with recurrent or metastatic squamous cell carcinoma 
of the head and neck with tumors.
The starting dose will be dose level 0. Dose level -1 may be selected if higher dosing cohorts 
are not tolerated.
Higher dose of epacadostat will be considered if no DLTs are seen at dose level 0. e.g. 300 
mg bid.


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4.2
Dose Expansion Schedule
Table 4-2: Dose Expansion Arms in both Stage 1 and 2
Treatment 
Arms
N
Epacadostat
pembrolizumab
tavo-EP
Arm A
tavo-EP, 
pembrolizumab 
ad epacadostat
28*
MTD - as 
determine by 
dose escalation
Arm B
tavo-EP and 
pembrolizumab
28
200 mg via IV.  
Days 1 and 22 of 
each cycle for 6 
weeks (42 days)
¼ tumor volume at 
concentration of 
0.5 mg/mL1 given 
intratumoral on 
Days 1, 5, 8 of 
each cycle for 6 
weeks (42 days)
*Patients in the dose escalation safety lead-in will have an opportunity to participate in Stage 
1, Arm A per Investigator’s discretion.
Rationale for cohort expansion: In the dose expansion cohorts, we will determine the 
tolerability of this combination, the recommended phase II dose (RP2D) and preliminary 
efficacy in 56 evaluable patients with recurrent or metastatic squamous cell carcinoma of the 
head and neck with tumors. Hence the cohort expansion warrants the confirmation of 
tolerability of this combination, was deemed safe will be pursued for further patients.
4.3
Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD)
If DLT is encountered during the first cycle, the following rules (see table below) will be 
applied. If no DLT is encountered at a given dose level, escalation will be continued to the 
next higher dose level. If no DLT is found at the highest cohort, this cohort will be considered 
the recommended Stage 1 dose for epacadostat.
Table 4-3: Dose Escalation Decision Rules - DLT and MTD
Number of Patients with DLT at a Given 
Dose Level
Escalation Decision Rule
0 out of 3
Escalate dose to next higher dose level
1 out of 3
Enter at least 3 more patients at this dose level
If 0 of these 3 additional patients experience DLT 
(1 of 6), proceed to the next dose level
If 1 or more of the 3 additional patients suffer 
DLT (2 of 6), then dose escalation is stopped 
and this dose is declared the maximal 
administered dose (highest dose administered)
Determination of the MTD will continue at the 
next lowest dose cohort, at which an additional 
3 patients will be added, for a total of 6 (unless 
that cohort already has 6 patients)


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≥ 2 out of 3
Dose escalation will be stopped
This dose level is declared the maximum 
administered dose
The next lower cohort will be expanded to 6 
patients
If < 1 experience DLT, this dose is the maximal 
tolerated dose (MTD)
≤ 1 out of 6 at highest dose level below the 
maximum administered dose
This is generally the recommended Phase 2 
dose
At least 6 patients must be entered at the 
recommended Phase 2 dose
4.3.1
Dose Limiting Toxicity
Adverse Events and other symptoms will be graded according to the NCI Common 
Terminology 
Criteria 
for 
Adverse 
Events 
Version 
4.03 
(NCI, 
CTC 
web 
site 
http://ctep.info.nih.gov).
A DLT will be defined as any one of the following adverse events occurring during Cycle 1 
when association to therapy that is part of this study is related or possibly related:
1.
Hematologic dose-limiting toxicity 

Grade 4 neutropenia lasting for ≥7 days in duration. 

Febrile neutropenia of any grade

Grade 4 thrombocytopenia (≤25.0 x 109/L) lasting for ≥7 days in duration.

Grade 3 thrombocytopenia complicated by clinically significant bleeding and/or 
requiring platelet or blood transfusion 
2.
Non-hematologic dose-limiting toxicity
This will be defined as any Grade ≥3 non-hematologic toxicity, which is clinically meaningful 
and related with the specific EXCEPTION of:

Any grade alopecia 

Grade 3 total hyperbilirubinemia if <35% is direct component

Grade 3 transient ALT/AST elevation 

Grade 3 rash, nausea, vomiting or diarrhea for ≤ 3 days or is not properly managed 
with optimal supportive care

Grade 3 lab abnormalities must be clinically significant, meaningful and dose related. 
4.3.2
Dose Modifications and Management of Toxicity
Dose modifications are permitted in Cycle 1 only in the event of a DLT.
Dose modifications of epacadostat will be made per the dose escalation table.


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1.
If dose reduction of epacadostat is necessary: 
o
The dose should be reduced stepwise based on the dose escalation table. The 
patient should be monitored for approximately 10 to 14 days at each dose level.
Treatment or visit delays for public holidays or weather conditions do not constitute a protocol 
violation. After cycle 2, patients who have benefit are allowed to request treatment 
interruptions for personal reasons up to three weeks. Longer treatment interruptions must be 
approved by the PI and the drug sponsor.
The following dose modification rules will be used with respect to potential toxicity. Toxicity 
will be assessed according to the NCI Common Terminology Criteria for Adverse Events 
Version 4.03 (CTCAE v4.03).
4.3.3
Treatment Modification – All Agents
Adverse events associated with treatment on study may be immune-related or not immune-
related.  Immune-related AEs (irAEs) may be predicted based on the nature of the 
compounds, their mechanism of action, and reported experience with immunotherapies that 
have a similar mechanism of action.  Special attention should be paid to AEs that may be 
suggestive of potential irAEs.  An irAE can occur shortly after the first dose or several months 
after the last dose of treatment.  If an irAE is suspected, efforts should be made based on the 
investigator’s clinical judgment to rule out neoplastic, infectious, metabolic, toxins, or other 
etiologic causes prior to labeling an AE as an irAE.  
In some circumstances, it may be necessary to temporarily interrupt pembrolizumab, tavo-EP 
or epacadostat as a result of AEs that may have an unclear relationship to any individual study 
drug.  If an interruption for an adverse event is necessary and the causative agent cannot be 
identified, all agents should be interrupted.  Immune-related adverse events may also be 
attributable to epacadostat alone, pembrolizumab alone, tavo-EP, alone or the combination 
of two or three of these agents.  If the event is clearly related to one of the agents, follow the 
instructions specific for that agent.  If the event is related to more than one agent, follow the 
action taken instructions for each causative agent.
General supportive care recommendations to manage irAEs are detailed in Table 4-4.  
Additional treatment modification recommendations may be found in subsequent sections, in 
the pembrolizumab package insert, and in the investigator’s brochures for epacadostat and 
tavo-EP.
Table 4-4: General Guidelines for Immune-Related Adverse Events
irAE 
Toxicity 
Grade
Withhold/Discontinue 
Agent(s)
Action Taken With 
Respect to Agent(s)
Supportive Care
Grade 1
No action.
Not applicable.
Provide symptomatic 
treatment.


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Grade 2
May withhold agent per 
investigator's 
discretion.
Not applicable.  
Investigators 
discretion.
Consider systemic 
corticosteroids in addition 
to appropriate 
symptomatic treatment.
Grade 3
Withhold or discontinue 
agent(s).
Discontinue if unable to 
reduce corticosteroid 
dose to < 10 mg/day of 
prednisone or 
equivalent within 6 
weeks of toxicity.
Return to treatment if 
improves to Grade 1 or 
resolves within 6 
weeks.  If AE resolves 
within 4 weeks, subject 
may restart at the 
same dose and 
schedule for 
epacadostat.
For an AE that does 
not resolve within 4 
weeks, agent(s) should 
be reduced 1 dose 
level.  If AE does not 
resolve within 6 weeks, 
study treatment with 
agent(s) should be 
discontinued or 
discussed with 
principal investigator.
Systemic corticosteroids 
are indicated in addition to 
appropriate symptomatic 
treatment.  May use 1-
2 mg/kg prednisone or 
equivalent per day.
Steroid taper should be 
considered once 
symptoms improve to ≤ 
Grade 1 and tapered over 
at least 4 weeks in most 
cases.
Grade 4
Discontinue agent(s).
Not applicable.  Any 
exceptions require 
principal investigator 
approval.
Systemic corticosteroids 
are indicated in addition to 
appropriate symptomatic 
treatment.  May use 1-
2 mg/kg prednisone or 
equivalent per day.
Steroid taper should be 
considered once 
symptoms improve to ≤ 
Grade 1 and tapered over 
at least 4 weeks in most 
cases.
Any interruptions of > 2 weeks or for LFT abnormalities must be discussed with the principal 
investigator before resuming treatment.  Treatment with epacadostat, pembrolizumab, and 
tavo-EP should be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 (including laboratory abnormalities), and severe or life-
threatening AEs.


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Discontinuation Rules and Procedures for Specific Immune-Related Adverse Events 
Associated with Epacadostat and Pembrolizumab
Supportive care measures for the management of adverse events with potential immunologic 
etiology that are, in the judgment of the investigator, at least possibly associated with 
pembrolizumab and/or epacadostat are outlined in Table 4-5 below and Table 4-6 for 
pembrolizumab infusion-related reactions.  For AEs listed in Table 4-5 and Table 4-6, follow 
the guidelines in Table 4-5, and Table 4-6.  For AEs not listed in Table 4-5 or Table 4-6, follow 
the guidelines in Table 4-4.  For each disorder listed in Table 4-5, and Table 4-6 attempts 
should be made based in the investigator’s clinical judgment to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. 
Table 4-5: Dose Modification Guidance for Epacadostat and Pembrolizumab
Adverse Event
CTCAE 
v4.03 
Grade
Action Taken
2
Hold pembrolizumab and epacadostat until patient is 
clinically stable. Treat with corticosteroids.  If toxicity 
worsens, then treat as Grade 3 or Grade 4. Pembrolizumab 
and epacadostat can be resumed once event stabilizes and 
after completion of steroid taper.
Patient can be retreated with study drug/study regimen on 
the following conditions:
1.
The event stabilizes and is controlled.
2.
The patient is clinically stable as per investigator or 
treating physician’s clinical judgement.
3.
Doses of prednisone are ≤10 mg/day or equivalent.
Adrenal 
Insufficiency
3 or 4
Hold pembrolizumab and epacadostat until patient is 
clinically stable. Treat with corticosteroids.  Pembrolizumab 
and epacadostat can be resumed once event stabilizes and 
after completion of steroid taper.
Patient can be retreated with study drug/study regimen on 
the following conditions:
1.
The event stabilizes and is controlled.
2.
The patient is clinically stable as per investigator or 
treating physician’s clinical judgement.
3.
Doses of prednisone are ≤10 mg/day or equivalent.


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Adverse Event
CTCAE 
v4.03 
Grade
Action Taken
1
Subjects should be carefully monitored for signs and 
symptoms of enterocolitis (such as diarrhea, abdominal 
pain, blood, or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).
Continue treatment with epacadostat and pembrolizumab, 
and initiate supportive care measures, which include 
drinking liberal quantities of clear fluids.  If sufficient oral 
fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion.  An antidiarrheal can be started.
2
Interrupt epacadostat and pembrolizumab, and initiate 
supportive care measures, which include drinking liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV 
infusion.  An antidiarrheal should be started.
When diarrhea resolves to baseline, restart epacadostat and 
pembrolizumab at the same dose.
Diarrhea/colitis
3
Interrupt epacadostat and pembrolizumab.  When diarrhea 
resolves to baseline, resume pembrolizumab and restart 
epacadostat at a reduced dose.  
Monitor subjects for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, mucus or blood in stool, 
with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus).  In symptomatic subjects, rule 
out infectious etiologies and consider endoscopic evaluation 
for persistent or severe symptoms. 
For recurrent or persistent Grade 3 diarrhea, consider 
further dose reduction of epacadostat, or discontinuation of 
pembrolizumab and epacadostat.
4
Discontinue epacadostat and pembrolizumab
Pneumonitis
2
Interrupt epacadostat and pembrolizumab and initiate 
systemic corticosteroids.  Taper as necessary.  May return 
to study treatment if condition improves to ≤ Grade 1.  
Permanently discontinue if toxicity does not resolve within 
12 weeks of last dose or if subject shows inability to reduce 
corticosteroid to ≤ 10 mg prednisone or equivalent per day 
within 12 weeks.


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Adverse Event
CTCAE 
v4.03 
Grade
Action Taken
3 or 4
Permanently discontinue epacadostat and pembrolizumab.  
Immediately treat with intravenous corticosteroids.  
Administer additional anti-inflammatory measures, as 
needed.
Add prophylactic antibiotics for opportunistic infections in the 
case of prolonged steroid administration.
Type I diabetes 
mellitus (TIDM; 
if new onset, 
including 
diabetic 
ketoacidosis 
[DKA]) or 
≥ Grade 3 
hyperglycemia, 
if associated 
with ketosis 
(ketonuria) or 
metabolic 
acidosis (DKA)
Newly 
onset 
TIDM 
or 
Grade 
3 or 4
Insulin replacement therapy is recommended for Type I 
diabetes mellitus and for Grade 3-4 hyperglycemia 
associated with metabolic acidosis or ketonuria. 
Evaluate subjects with serum glucose and a metabolic 
panel, urine ketones, glycosylated hemoglobin, and C-
peptide.
Once serum glucose is stabilized, pembrolizumab, tavo-EP 
and epacadostat should restart at the same dose if the 
episode is thought to be unrelated to treatment.  If the 
episode is related, resume treatment with a one level dose 
reduction of epacadostat.
2
Hold pembrolizumab and epacadostat.  Treat with oral 
corticosteroids.  When symptoms improve to ≤ Grade 1, 
steroid taper should be started and continued over no less 
than 4 weeks.  Replacement of appropriate hormones may 
be required as the steroid dose is tapered.
Hypophysitis
3 or 4
Discontinue epacadostat and pembrolizumab.  Treat with an 
initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no 
less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered.
Hyperthyroidism 
or 
hypothyroidism
2
Thyroid disorders can occur at any time during treatment.  
Monitor subjects for changes in thyroid function (at the start 
of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and 
symptoms of thyroid disorders.
In hyperthyroidism, nonselective beta-blockers (eg, 
propranolol) are suggested as initial therapy.
In hypothyroidism, thyroid hormone replacement therapy, 
with levothyroxine or liothyronine, is indicated per standard 
of care.


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Adverse Event
CTCAE 
v4.03 
Grade
Action Taken
3 or 4
In hypothyroidism, thyroid hormone replacement therapy, 
with levothyroxine or liothyronine, is indicated per standard 
of care.
In hyperthyroidism, treat with an initial dose of IV 
corticosteroid followed by oral corticosteroids.  When 
symptoms improve to ≤ Grade 1, steroid taper should be 
started and continued over no less than 4 weeks.  
Replacement of appropriate hormones may be required as 
the steroid dose is tapered.  Once hyperthyroidism has 
resolved and steroids tapered, subject may resume 
epacadostat, pembrolizumab and tavo-EP or permanently 
discontinue at the discretion of the investigator.
2
Hold pembrolizumab and epacadostat.  Monitor liver 
function tests more frequently until returned to baseline 
values (consider weekly or twice weekly if steroids are not 
initiated).  Treat with IV or oral corticosteroids.
Hepatic
3 or 4
Permanently discontinue pembrolizumab and epacadostat if 
related to these agents.  Treat with intravenous 
corticosteroids.  When liver chemistry tests improve to ≤ 
Grade 1, a steroid taper should be started and continued 
over no less than 4 weeks. If unrelated to pembrolizumab, 
treatment with pembrolizumab and epacadostat may be 
resumed once steroids have been discontinued.
Myocarditis
2
Hold pembrolizumab and epacadostat until resolution to 
Grade 0. Monitor symptoms daily, hospitalize.  Promptly 
start IV methylprednisolone 2 to 4 mg/kg/day or equivalent 
after Cardiology consultation has determined whether and 
when to complete diagnostic procedures including a cardiac 
biopsy.  Once the patient is improving, gradually taper 
steroids over ≥28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections 
[Category 2B recommendation]). If toxicity rapidly improves 
to Grade 0, then the decision to reinitiate study drug/study 
regimen will be based upon treating physician’s clinical 
judgment and after completion of steroid taper. If toxicity 
does not rapidly improve, permanently discontinue 
pembrolizumab and epacadostat.


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Adverse Event
CTCAE 
v4.03 
Grade
Action Taken
3 or 4
Permanently discontinue pembrolizumab and epacadostat if 
related to these agents.  Monitor symptoms daily, 
hospitalize.  Promptly start IV methylprednisolone 2 to 4 
mg/kg/day or equivalent after Cardiology consultation has 
determined whether and when to complete diagnostic 
procedures including a cardiac biopsy.  Once the patient is 
improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals, or anti-PJP 
treatment (refer to current NCCN guidelines for treatment of 
cancer-related infections [Category 2B recommendation]).
2
Treat with oral corticosteroids.
Renal failure or 
nephritis
3 or 4
Permanently discontinue pembrolizumab and epacadostat if 
related to these agents.  Treat with systemic corticosteroids.  
When severity of the event improves to ≤ Grade 1, steroid 
taper should be started and continued over no less than 4 
weeks.  If unrelated to pembrolizumab, treatment with 
pembrolizumab and epacadostat may be resumed once 
steroids have been discontinued.
Any toxicity, if 
clinically 
significant and 
not manageable 
by supportive 
care
2 or 3
Interrupt epacadostat and pembrolizumab if toxicity is 
attributed to epacadostat and pembrolizumab.  When 
toxicity resolves to ≤ Grade 1, resume pembrolizumab and 
epacadostat.
For recurrent or persistent Grade 2 or 3 toxicity that is 
clinically significant and not manageable with supportive 
care, consider further dose reduction of epacadostat or 
epacadostat and pembrolizumab discontinuation.
Other AEs
4
In general, epacadostat and pembrolizumab should be 
discontinued.  Treatment with epacadostat and 
pembrolizumab may only be restarted after consideration of 
the benefit versus the risk and the approval of the principal 
investigator.
Procedures for Other Immune-Mediated Adverse Reactions, Including Ocular 
Manifestations
Epacadostat and pembrolizumab should be permanently discontinued for severe (Grade 4) 
irAEs.  Systemic corticosteroids treatment should be initiated at a dose of 1 to 2 mg/kg per 
day of prednisone or equivalent for severe irAEs.
Corticosteroid eye drops should be administered to subjects who develop uveitis, iritis, or 
episcleritis.  Epacadostat and pembrolizumab should be permanently discontinued for 
immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy.


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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Error! Reference source not found.
Table 4-6: Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of 
vital signs as medically 
indicated until the 
participant is deemed 
medically stable in the 
opinion of the 
investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs.
Stop Infusion.
Additional appropriate 
medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital 
signs as medically indicated 
until the participant is 
deemed medically stable in 
the opinion of the 
investigator.
If symptoms resolve within 1 
hour of stopping drug 
infusion, the infusion may 
be restarted at 50% of the 
original infusion rate (e.g. 
from 100 mL/hr. to 50 
Participant may be pre-
medicated 1.5h (± 30 
minutes) prior to infusion of 
_____ with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg po (or equivalent dose 
of analgesic).


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mL/hr.).  Otherwise dosing 
will be held until symptoms 
resolve and the participant 
should be pre-medicated for 
the next scheduled dose.
Participants who develop 
Grade 2 toxicity despite 
adequate premedication 
should be permanently 
discontinued from further 
study drug treatment
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate 
medical therapy may 
include but is not limited to:

Epinephrine**

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids

Increase monitoring 
of vital signs as 
medically indicated 
until the participant 
is deemed medically 
stable in the opinion 
of the investigator.

Hospitalization may 
be indicated.

**In cases of 
anaphylaxis, 
epinephrine should 
be used 
immediately.
Participant is permanently 
discontinued from further 
study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician 
readily available during the period of drug administration. For further information, 
please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
at http://ctep.cancer.gov


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Guidelines for Subjects Exhibiting Serotonin Syndrome
There is a rare chance that epacadostat could cause an increase in serotonin levels in the 
brain that might trigger Serotonin Syndrome when administered in combination with other 
serotonergic agents.  This syndrome has been most closely associated with use of MAOIs, 
meperidine, linezolid, or methylene blue; all of these agents are prohibited during the study.  
Serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors 
(SNRIs) are permitted in the study.  Serotonin syndrome usually manifests with autonomic 
changes, mental status changes, and neurological findings. Mild, moderate, and severe signs 
and symptoms of SS are summarized in table below and should be evaluated in the context 
of possible comorbid conditions as well. The following procedures will be implemented if 
participants exhibit the signs/symptoms of SS described in the following table:

Immediately interrupt epacadostat or matching placebo administration.  Administration 
of pembrolizumab may continue.

Immediately interrupt any SSRI or SNRI administration.
Provide appropriate medical management of the participant until all signs/symptoms are 
resolved (e.g., IV fluids and/or sympathomimetic amines for hypotension, benzodiazepines 
for agitation, administration of 5-hydroxytryptamine antagonists such as cyproheptadine).
If participant chooses to remain in the study, restart treatment with epacadostat or matching 
placebo after the SSRI or SNRI has been discontinued, no sooner than 5 half-lives have 
elapsed for the specific SSRI or SNRI in question, and after resolution of signs/symptoms of 
SS.  The SSRI or SNRI dosing MAY NOT be restarted.
If participant chooses to withdraw from the study, or must restart treatment with SSRI or SNRI, 
the participant should be scheduled for a follow-up visit.  Treatment with SSRI or SNRI may 
be initiated 2 weeks after resolution of signs and symptoms of SS.
Additionally, sites should contact the Incyte Clinical Director if Serotonin Syndrome is 
suspected.
Table 4-7: Sign and Symptoms of Serotonin Syndrome
4.3.4
Seriousness
4.3.5
Autonomic 
signs
4.3.6
Neurological 
signs
4.3.7
Mental 
status
4.3.8
Other
4.3.9
Mild
Afebrile or low-
grade fever
Intermittent tremor
Restlessness
Tachycardia
Akathisia
Anxiety
Mydriasis
Myoclonus
Diaphoresis or 
shivering
Mild hyperreflexia
4.3.10
Moderate
Increased 
Tachycardia
Hyperreflexia
Easily startled
Rhabdomyolysis
Fever (up to 41 0C)
Inducible clonus
Increased 
confusion
Metabolic 
acidosis


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Diarrhea with 
hyperactive bowel 
sounds
Ocular clonus (slow 
continuous lateral eye 
movements)
Agitation and 
hypervigilance
Renal Failure
Diaphoresis with 
normal skin color
Myoclonus
Disseminated 
intravascular 
coagulopathy 
(secondary 
to 
hyperthermia)
4.3.11
Severe
Temperature often 
more than 41 0C 
(Secondary 
to 
increased tone)
Increased muscle tone 
(lower limb > upper)
Delirium
As above
Spontaneous clonus
Coma
Substantial myoclonus 
or hyperreflexia
1 Boyer EW, Shannon M. The serotonin syndrome. New Engl J Med 2005;352: 1112-1120.
Dose Modification versus Dose Interruption
Epacadostat, pembrolizumab and tavo-EP may be held for up to 6 weeks as clinically 
indicated or required due to treatment associated AEs but dose reductions are not permitted.
Dosing interruptions of all agents may be permitted in the case of medical/surgical events or 
logistical reasons not related to study therapy (eg, elective surgery, unrelated medical events, 
subject vacation, and/or holidays).  Subjects should be placed back on study therapy within 6 
weeks of the scheduled interruption.  The reason for interruption should be documented in the 
subject's study record.
4.4
Duration of Treatment
During the treatment phase, patients will receive combination therapy for 12 months or until 
the development of unacceptable treatment associated toxicity or confirmed progression. 
After the initial 12 months of therapy, patients who remain on treatment will enter the follow-
up phase for the next 24 months.  Patients with disease progression during the follow-up 
phase will have access to 12 additional months of triplet therapy.  Patients who are eligible 
for treatment on study but who have experienced regression of all previously accessible 
lesions may continue on pembrolizumab and epacadostat without tavo-EP.
4.4.1 Treatment After Disease Progression
Patients with disease progression by RECIST version 1.1 who are benefiting from treatment 
in the opinion of the principal investigator may continue on treatment for up to 12 months from 
the initiation (or re-initiation) of treatment on study.
4.5
Post-Treatment Follow-up
Patients will be followed for toxicity and radiographic imaging will be performed at 3 month 
intervals 1) until start of a new anti-cancer treatment, (2) until 30 days after documented 


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disease progression, (3) until death, or (4) until 36 months from the initiation of treatment on 
study, whichever comes first. Each subject will be followed for overall survival until death, 
withdrawal of consent, or the end of the study, whichever occurs first.
4.6
Clinical and Pharmacy Considerations
4.6.1 tavo-EP
4.6.1.1 Drug Availability, Handling, and Storage
Availability
Plasmid interleukin-12 (tavo-EP) is formulated in phosphate buffered saline (PBS) for direct 
intratumoral injection following by in vivo EP. GMP-grade tavo-EP is manufactured by VGXI 
USA and available batches will be supplied as 2.0 mL vials at a concentration of 0.5 mg/mL 
and fill volume of 1.7 mL.
Storage and handling
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Unopened vials of tavo-EP must be stored at -20°C ±5°C. Once thawed, the plasmid solution 
will be drawn into a tuberculin syringe with a 25-gauge 5/8-inch needle. Only authorized 
investigators listed on the form FDA 1572 will administer the plasmid injection.  Once thawed, 
the tavo-EP solution should be stored at 4ºC and used within 8 hours as supported by in-use 
stability testing. Refer to the tavo Pharmacy manual for details.
Accountability
The Investigational Pharmacist will manage drug accountability records.
Drug Ordering
A 3rd party vendor CRO, will be supplying the tavo-EP to the investigational site.
Packaging and Labeling of epacadostat, pembrolizumab, and tavo-EP
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided.


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Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from OncoSec, Incyte or designees, the amount dispensed to and returned by the subjects 
and the amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal 
are kept.
4.6.1.2 Administration
Prior to plasmid injection, using sterile precautions, 1% lidocaine may be injected around the 
lesion to obtain local anesthesia. In addition, the patient may be given analgesics or anxiolytics 
as necessary prior to or during treatment. tavo-EP:pUMVC3-hIL-12-NGVL33 (tavo-EP) will be 
injected intratumorally to accessible lesions without exceeding 20 mL per day. After injecting 
the plasmid solution into the accessible tumor, an Immunopulse® applicator containing 6 
stainless steel electrodes will be inserted into the tumor such that the electrode span the 
plasmid injection site. The applicator will be connected to the power supply and six pulses at 
a field strength (E+) of 1300 V/cm and pulse width of 100 μs at 1-second intervals will be 
administered to each previously injected tumor. 
4.6.1.3 Treatment Parameters 
Intratumoral tavo-may be administered at each odd cycle as long as the subject has at least 
one accessible lesion (AL) for treatment. An AL is defined as meeting the following criteria; 
(1) at least 0.3 cm x 0.3 cm in longest perpendicular diameters, (2) in a suitable location for 
application of electroporation.  This includes visible or palpable sites in the oral cavity or 
oropharynx, palpable lymph nodes, and cutaneous lesions. Prior to initiation of a new 
treatment cycle of tavo-EP EP, the investigator will determine ALs for treatment during that 
cycle based on the most recent schedule tumor measurements. The same ALs must be 
treated on each day of the cycle (i.e. Days 1, 55, 8). Previously treated, previously identified 
lesions present at baseline that were left untreated and new lesions which appear during the 
course of the study that meet the definition of an AL may be treated as long as the maximum 
plasmid injection volume per patient per day does not exceed 20 mL. Tumors invading the 
carotid artery or at other sites that the investigator believes to be at high risk of life-threatening 
hemorrhage should not be injected.
4.6.1.4 Dose Holds
If no ALs are present at subsequent cycles, the subject may skip that cycle of tavo-EP and 
continue on the study calendar (Table 3-1).  Treatment should also be held if the patient 
develops any sustained grade 3 or higher adverse event other than rash that is at least 
possibly attributed to tavo-EP in the opinion of the treating investigator.  Tavo-EP may be 
resumed once the AE resolves to grade 1 or lower.  Treatment should also be held for any 
intolerable rash or if holding treatment is in the best interests of the patient in the opinion of 
the treating investigator.


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4.6.2
Epacadostat
4.6.2.1 Supply, Packaging, and Labeling
Epacadostat is available as 25, 100 and 300 mg tablets packaged in high-density polyethylene 
bottles.
4.6.2.2 Storage 
Clinical supplies must be stored as described in the IB.
4.6.2.3 Administration
Epacadostat will be administered orally BID every 12 hours without regard to food at the dose 
identified in this study.  If a dose is missed by more than 4 hours, then that dose should be 
skipped, and the next dose should be taken at the next scheduled time point.  All BID doses 
will be taken in the morning and evening, approximately 12 hours apart.
Subjects will begin treatment with epacadostat on cycle 1, day 1 of the study and will continue 
administration through the end of treatment.  There is no priority to the order of administration 
of epacadostat, pembrolizumab, and tavo-EP when administered in combination; however, 
the dose of epacadostat should be taken as close to the regularly scheduled 12-hour dosing 
interval as possible.  
4.6.3 Pembrolizumab
4.6.3.1 Supply, Packaging and Labeling
See manufacturer’s guidelines as described in the package insert.
4.6.3.2 Storage
See manufacturer’s guidelines as described in the package insert.
4.6.3.3 Administration 
See manufacturer’s guidelines as described in the package insert.
5
Safety
5.1
Safety Assessments
Clinical evaluations including laboratory and clinical safety assessments will be performed at 
3-week intervals for patients who are actively receiving treatment on study.  For patients in 
the follow-up portions of the study who are not actively receiving therapy, evaluations will be 
performed at 12-week intervals.  Safety assessments are outlined in the Study Calendar 
(Table 3-1). Safety assessments include AEs (either reported by the patient or observed by 
the Investigator), concomitant medication use, performance status, vital signs, physical 
examination, and laboratory assessments. AEs will be graded and reported using CTCAE 
version 4 and reported descriptively.


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5.2
Safety Stopping Rules
Clinical evaluations including laboratory and clinical safety assessments will be performed at 
3-week intervals for patients who are actively receiving treatment on study.  For patients in 
the follow-up portions of the study who are not actively receiving therapy, evaluations will be 
performed at 12-week intervals.  Safety will be assessed during the study by documentation 
of adverse events (AEs), clinical laboratory tests, physical examination, vital sign 
measurements, and Eastern Cooperative Oncology Group (ECOG) performance status.
Lead-In Period and De-Escalation
1.     If, at any time, 2 or more of the first 6 safety-evaluable patients experience grade 3 
or higher treatment-associated adverse events within the first 30 days of initiation 
of treatment, then no further patients will be enrolled at the current dose level.
2.     After 6 patients have been enrolled on study, enrollment will be halted for 30 days 
for completion of lead-in safety analysis.  If 0-1 patients experience grade 3 or 
higher treatment-associated adverse events within the first 30 days of initiation of 
treatment, then additional patients may be enrolled at the current dose level. 
3.     If enrollment is halted at any time during the lead-in period due to treatment-
associated adverse events, the UCSF DSMB will review all available safety data 
with the Principal Investigator.  Based on this review, study discontinuation or 
reduction of the epacadostat dose may be recommended.  No further patients will 
be enrolled on study without the approval of the DSMB.  If the DSMB allows 
additional patients to enroll, the lead-in period will be repeated at the new dose level 
with a maximum of 6 additional patients enrolled prior to follow-up safety 
analysis.  At the discretion of the DSMB, patients who are currently on study may 
continue treatment at the reduced dose level.
4.     Patients who discontinue treatment on study within 30 days of initiation of therapy 
for reasons other than treatment-associated toxicity will be deemed inevaluable for 
safety and replaced for safety analysis.
Mid-Study Interim Safety Analysis
Enrollment will also be halted for 30 days for interim safety analyses after a total of 30 safety-
evaluable patients have initiated treatment on study.  Patients who discontinue treatment on 
study within 30 days of initiation of therapy for reasons other than treatment-associated toxicity 
will be deemed inevaluable for safety and replaced for safety analysis.  The study will be 
discontinued under the following circumstance:
 
1.     On-study occurrence of 3 or more Grade 4 (life threatening) serious adverse events 
(SAEs) or deaths, which are deemed at least possibly related to the study agent.
2.     Based on the review of data the DSMB has serious concerns about the safety of 
patients on the study.  In addition to stopping the study, the DSMB may recommend 


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that the epacadostat dose for all patients be de-escalated for all current and future 
patients, or cessation of further patient accrual.
Safety review at participating sites
During the dose escalation safety lead-in phase of the study, weekly calls will be scheduled 
to review the safety data at all sites.  Once the lead-in phase is completed, calls with be 
scheduled monthly.  All sites with any active patients on study will be expected to have at 
least one representative on these calls.  One or more representatives of the UCSF DSMC will 
be invited to participate as well.
6
Efficacy Assessments
MRI, contrast-enhanced CT, or PET/CT imaging of the face, neck, chest, abdomen, and pelvis 
are required at screening and on day 1 of each odd-numbered cycle excluding cycle 1.  Both 
clinical and radiographic measurements may be used.  All superficial, clinically apparent 
lesions that cannot be adequately assessed radiographically (e. g. subcutaneous lesions) 
must be numbered and photographed with a metric ruler visible in each photograph.  For 
photographed lesions with borders that are not clearly visible, investigators should trace the 
lesions’ outline, making a solid line with a felt-tipped pen. Visible lesions should never be 
circled with a solid line but dashed or dotted lines may be used to distinguish these markings 
from the borders of otherwise invisible lesions.  Tumor assessments will be made using 
RECIST version 1.1.  IL-12 plasmid dosing may be based on the most recent tumor 
measurements and measurements need not be repeated immediately prior to each tavo-EP 
treatment.
6.1
Efficacy Assessments
Response to treatment in this study will be evaluated using the international criteria 
proposed by the RECIST Committee (Therasse et al. 2000a), modified in 2009 (Eisenhauer 
et al. 2009) and clarified for disease-specific adaptation (Schwartz et al. 2016). The primary 
efficacy endpoint, BORR, will be evaluated using RECIST v1.1 (Section 6.1.1.1). 
6.1.1
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
Tumor response will be evaluated according to RECIST guidelines (Therasse et al. 2000b) 
using tumor imaging (see Section 6.1.1.1 for tumor imaging details).
Assessment by RECIST v1.1 will be done at 12-week intervals as specified in Table 3-1. 
Lesions will be numbered identically for each visit as target and non-target, new lesions (see 
definitions in Table 6-1). Tumor assessments during the Core study (over 24 weeks) will be 


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done by independent central radiologic review1 and integrated medical oncologist disease 
assessment based on RECIST v1.1 and investigator assessment of RECIST and iRECIST 
(will be throughout the study).
In support of RECIST v1.1, when more than one accessible and measurable tumor is present 
at baseline, all lesions (those with the longest diameter(s)/ organ that are measurable in the 
physicians’ discretion) up to 2 cutaneous lesions should be identified as measurable 
representative Target Lesions. A target lesion may be a treated or untreated lesion.
An ‘accessible lesion’ is defined as a cutaneous or subcutaneous lesion that can be reached 
from the surface with the electroporation needle array (with depth of up to 1.5 cm from the 
surface). Refer to section 5.1.1.3.
Each patient will be assigned a response category (Table 6-1
Table 6-1 Response Evaluation Criteria in Solid Tumors v1.1): complete response (CR), 
partial response (PR), stable disease (SD), progressive disease (PD).
Per RECIST 1.1, partial response (PR) or complete response (CR) should be confirmed by a 
repeat tumor imaging assessment not less than 4 weeks from the date the response was first 
documented. The tumor imaging for confirmation of response may be performed at the earliest 
4 weeks after the first indication of response, or at the next scheduled scan (i.e. 12 weeks 
later), whichever is clinically indicated.
1 In accordance to FDA “Clinical Trial Imaging Endpoint Process Standards Guidance for Industry” (Version 1 
March 2015); 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm268555.pdf


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Table 6-1 Response Evaluation Criteria in Solid Tumors v1.1
RECIST v1.1 Response 
Criteria
Target Lesions
Non-Target Lesions
Complete Response (CR)2
Disappearance of all target 
lesions, determined by two 
separate observations 
conducted not less than 4 
weeks apart. Any 
pathological lymph nodes 
(whether target or non-
target) must have reduction 
in short axis to <10 mm (the 
sum may not be “0” if there 
are target nodes). There 
can be no appearance of 
new lesions.
Disappearance of all non-
target lesions and 
normalization of tumor 
marker level. All lymph 
nodes must be non-
pathological in size (<10 
mm short axis).
Partial Response 
At least a 30% decrease in 
the sum of the longest 
diameter (LD) of target 
lesions, taking as reference 
the baseline sum LD. There 
can be no appearance of 
new lesions.
Non-target lesions must be 
non-PD.
Stable Disease (SD)
Neither sufficient shrinkage 
to qualify for PR nor 
sufficient increase to qualify 
for PD, taking as reference 
the smallest sum LD since 
the treatment started.
Persistence of one or more 
non-target lesion(s) and/or 
maintenance of tumor 
marker level above the 
normal limits.
2 Patients will meet the primary endpoint (BORR) if they attain a confirmed CR or PR over the 24 weeks with 
the combination treatment with a 4-week confirmatory scan per RECIST v1.1.


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Progressive Disease (PD)
At least a 20% increase in 
the sum of diameters of 
measured lesions taking as 
references the smallest sum 
of diameters recorded on 
study (including baseline) 
AND an absolute increase 
of ≥5 mm, or the 
appearance of one or more 
new lesions.
Appearance of one or more 
new lesions and/or 
unequivocal progression of 
existing non-target lesions.
6.1.1.1
Evaluation of Best Overall Response with RECIST v1.1
The best overall response (BOR) is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria (Table 6-2).
Table 6-2: Overall Response Definitions using RECIST v1.1
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also Requires 
CR 
CR 
No 
CR 
Normalization of tumor 
markers, tumor nodes <10 
mm 
CR 
Non-CR/ Non-
PD 
No 
PR 
CR
Not all 
evaluated
No
PR
PR 
Non-PD / No all 
evaluated
No 
PR 
SD 
Non-PD 
No 
SD 
Documented at least once 
≥4 weeks from baseline 
Not all 
evaluated
Non-PD
No
NE
PD 
Any 
Any 
PD 


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Any 
PD* 
Any 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression Source: (Seymour et al. 2017)
Other definitions

Progression free survival (PFS) – PFS is defined as the time, in months, from the first 
dosing date until the date of disease progression (i.e., the date of the tumor imaging) or 
death from any cause. RECIST v1.1 will be used to determine the dates of progression as 
this methodology is accepted by regulatory authorities. In addition, final determination of 
radiologic progression will be based on the central imaging vendor assessment of 
progression, rather than site study team assessment. Determination of radiologic 
progression as determined by central imaging vendor (verification of PD) will be 
communicated to the site study team. 
7
Statistical Plan
7.1
Sample Size Justification
Dose Expansion Phase, Stage 1:  We expect to enroll 30 patients in both arms (15 patients 
in Arm A and 15 patients in Arm B). We will allow patients who were enrolled in the dose 
escalation safety lead-in to enroll in Arm A of Stage 1, depending on the final dose.
Dose Expansion Phase, Stage 2: Depending on the results of the clinical data in Stage 1, 
Stage 2 will enroll up to an additional 26 patients accordingly:
If there are at least ≥ 3 responses in 15 patients, in either Arms A or B, up to an additional 
26 patients (13 patients in Arm A and 13 patients in Arm B) will be enrolled in the respective 
treatment arms.
The above Simon 2-stage sample sizes were based on the following assumptions: the 
objective response rate for pembrolizumab is approximately 15%3 and we suggest that a 
20% absolute improvement in this response rate would be clinically meaningful.  We 
propose to test the hypothesis that the objective response rate for the combination of tavo-
EP with pembrolizumab and epacadostat is 35% versus the null hypothesis that it is similar 
to the response rate for pembrolizumab monotherapy, 15%. The statistical power 
calculations are based on the Simon Two-Stage Optimal Design11 with a Type I error rate of 
0.05 and power of 80%.
Efficacy Assessment:
The objective response rate for pembrolizumab is approximately 15%3 and we suggest that 
a 20% absolute improvement in this response rate would be clinically meaningful.  We 
propose to test the hypothesis that the objective response rate for the combination of tavo-
EP with pembrolizumab and epacadostat is 35% versus the null hypothesis that it is similar 


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to the response rate for pembrolizumab monotherapy, 15%. The following statistical power 
calculations are based on the Simon Two-Stage Optimal Design11 with a Type I error rate of 
0.05 and power of 80%.
7.2
Analysis Populations
The analysis population is defined as All Treated Subjects, defined as all enrolled subjects 
who received at least one dose of study treatment.  Efficacy and safety analyses will be 
completed in the All Treated Subjects population.
7.3
Primary Efficacy Analysis
The primary efficacy analysis will be conducted on All Treated Subjects, by treatment arm and 
dose levels as appropriate, and overall.  The primary endpoint of BORR will be calculated and 
applied in the proceeding of Simon two-stage design, however, no formal statistical testing 
will be conducted between dose levels or between treatment arms as the sample size is not 
powered adequately for the testing, and comparisons will be made in a qualitative fashion.  
Patients’ best overall response will be summarized by the number and percentage of subjects 
who achieved a CR, PR, SD and PD.  BORR is calculated as the percentage of patients who 
achieved a CR or PR relative to the total size of the All Treated Subjects population.  The 95% 
confidence interval of BORR will be calculated by the Clopper-Pearson (exact binomial) 
method.
The primary endpoint of safety will be performed for all patients having received at least one 
dose of study drug.  The study will use the NCI CTCAE v4.0.
7.4
Secondary/ Exploratory Efficacy Analysis
All secondary and exploratory efficacy analyses will be conducted on All Treated Subjects, by 
treatment arm and dose levels as appropriate, and overall. 
The secondary endpoints of PFS and OS will be analyzed and plotted using the Kaplan-Meier 
method, estimates of the median will be provided and the 95% CI of median will be calculated 
by the Brookmeyer and Crowley method. 
Time to response is defined as the number of days from the date of enrollment to the date of 
the first documented response of CR or PR. Time to response will be summarized by 
descriptive statistics including mean, median, and standard deviation, minimum and 
maximum. 
Disease control rate (DCR) is defined as the percentage of patients who achieved a best 
overall response of CR, PR or SD.  Clinical benefit rate (CBR) is defined as the percentage 
of patients who achieved a best overall response of CR, PR and SD with a duration of at least 
6 months or longer. DCR and CBR will be analyzed using the method similar to BORR. 
Duration of response (DOR) will be calculated for patients who achieved a best overall 
response of CR or PR, and calculated as the number of days from the date when CR or PR 
is first met to the date of progression or death.  Patients who do not have a documented 
progression or death will be censored on the last date of tumor assessment.  The number and 
percentage of patients whose DOR is longer than certain milestone times (such as 6 months, 


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9 months and 12 months) will be quantified.  If the number of responders is sufficient, DOR 
may also be analyzed using the Kaplan-Meier method, with the median DOR and 95% CI 
calculated similar to PFS and OS analysis. 
7.5
Exploratory Analysis
The plan for the exploratory / translational endpoint is described in Appendix 4.  Correlative 
analyses between exploratory/translational endpoint and clinical endpoints may also be 
conducted if warranted. 
7.6
Safety Analysis
Safety analyses will be conducted on All Treated Subjects, by treatment arm and dose levels 
as appropriate, and overall. Safety analyses will be based on adverse events, clinical 
laboratory tests, physical examination, and vital sign measurements. All adverse event will be 
graded using CTCAE version 4 or later. Safety analyses will be summarized using descriptive 
statistics.  Continuous measurements will be summarized using n (number of subjects with 
the measured quantity), mean, and standard deviation, median, minimum and maximum.  
Categorical measurement will be summarized by frequencies and percentages.  
8
Restricted Medications
Restricted Medications/Treatment

Systemic steroids may be used at doses ≤ 10 mg/day prednisone or equivalents.

Use of coumarin-based anticoagulants (eg, Coumadin) is discouraged.  Low-dose 
Coumadin® (1 mg) is acceptable; however, doses that increase the INR are 
discouraged and will require routine monitoring. 
Epacadostat  Dose
Stable Baseline INR
≤ 300mg BID
INR  ≤ 2.5
Close INR monitoring
INR  > 2.5
Close INR monitoring

Use of the anticonvulsant carbamazepine (a UGT1A9 inducer) is discouraged.  
Because there is a potential interaction that could result in lower epacadostat 
exposures, an alternative to carbamazepine should be used, if possible.
Prohibited Medications/Treatment
Subjects are prohibited from receiving the following therapies starting from screening through 
end of treatment phase of this study unless otherwise noted below:

Any investigational medication other than pembrolizumab, epacadostat, and tavo-
EP. 

Use of any anticancer medications, including chemotherapy or biologic therapy 
other than the study medications.


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
Any chronic immunological-suppressive treatment for any reason.  (Note:  Inhaled 
or topical steroids are allowed, and systemic steroids at doses ≤10 mg/day 
prednisone or equivalents are allowed and immune suppressants are allowed for 
short-term treatment for immune toxicities or as prophylaxis for contrast allergy for 
imaging procedures.)

Radiation therapy
Note:  In the presence of a mixed response (some lesions improving or stable and 
other lesions progressing), radiation therapy to a symptomatic solitary lesion or to 
the brain is allowed. 

Administration of a live attenuated vaccine within 30 days before the first dose of 
study treatment and while participating in the study.  Examples of live vaccines 
include, but are not limited to, the following:  measles, mumps, rubella, chicken 
pox, yellow fever, rabies, BCG, and typhoid vaccine.  Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed; however, 
intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are 
not allowed.

Use of any MAOI or drug associated with significant MAOI activity agents is 
prohibited from 21 days prior to Day 1 through 2 weeks after the final dose of 
epacadostat has been administered 

Use of any immunological-based treatment for any reason from screening through 
follow-up visit is prohibited.
Note:  Completed adjuvant therapy (eg, vaccines) with principal investigator 
approval, inhaled or topical steroids, and systemic steroids at doses ≤ 10 mg/day 
prednisone equivalents are allowed, as described in Restricted Medications.

Any 
UGT1A9 
inhibitor, 
including 
acitretin, 
amitriptyline, 
androsterone, 
cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, estradiol (17-
beta), flutamide, gefitinib, gemfibrozil, glycyrrhetinic acid glycyrrhizin, imatinib, 
imipramine, 
ketoconazole, 
linoleic 
acid 
supplements, 
mefenamic 
acid, 
mycophenolic acid, niflumic acid, nilotinib, phenobarbital, phenylbutazone, 
phenytoin, probenecid propofol, quinidine, ritonavir, sorafenib, sulfinpyrazone, 
valproic acid, and verapamil.  Note: Propofol is allowed for short term sedation for 
biopsies.
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The exclusion criteria describe other medications that are prohibited during this study.  There 
are no prohibited therapies during the post-treatment follow-up phase.
9
Discontinuation of Therapy
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests.  Reasons for withdrawing a patient include, but are not limited to, 
disease progression, the occurrence of an adverse event or a concurrent illness, a patient’s 


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request to end participation, a patient’s non-compliance or simply significant uncertainty on 
the part of the Investigator that continued participation is prudent.  There may also be 
administrative reasons to terminate participation, such as concern about a patient’s 
compliance with the prescribed treatment regimen.
9.1
Birth Control, Pregnancy and Paternity
Pembrolizumab and/or tavo-EP EP may have adverse effects on a fetus in utero.  
Furthermore, it is not known if pembrolizumab and/or tavo-EP EP has transient adverse 
effects on the composition of sperm.  Non-pregnant, non-breast-feeding women may be 
enrolled if they are willing to use 2 methods of birth control or are considered highly unlikely 
to conceive.  Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) 
postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 
1 year will be considered postmenopausal), or 3) not heterosexually active for the duration of 
the study.  The two birth control methods can be either two barrier methods or a barrier method 
plus a hormonal method to prevent pregnancy. Subjects should start using birth control from 
study Visit 1 throughout the study period up to 120 days after the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined above. Reporting of Pregnancy 
and Lactation to the DSMC is required.  If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the 
study.
9.2
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment, the subject will immediately 
be removed from the study.  The site will contact the subject at least monthly and document 
the subject’s status until the pregnancy has been completed or terminated.  The outcome of 
the pregnancy will be reported to the UCSF Data Safety Monitoring Committee (DSMC) 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the mother 
or newborn).  The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the DSMC.   If 
a male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the DSMC and followed as described 
above.  
Please note, the investigator will notify Incyte within 24 hours of investigator awareness.


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9.3
Use in Nursing Women
It is unknown whether the study agents are excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.
10 Correlative Studies
Tumor Biopsy: 
The clinical investigator and study pathologist have the responsibility for submitting 
representative diagnostic material for banking. Please refer to the OncoSec Laboratory 
manual for detailed instructions regarding these assessments. Patients will have a research 
biopsy taken from at least one tumor site prior to the initiation of treatment. An additional 
biopsy should be taken on cycle 2 day 1(+/- 3 days) at progression/end of treatment, and 
additional biopsies may be performed if clinically indicated. 
Biopsy Types
Punch, core, incisional, and excisional biopsy specimens are permitted and should be 
obtained using standard institutional practices. Tumor biopsy may be formalin fixed and 
paraffin-embedded or frozen at -80C. If core biopsies are used, 3-4 cores should be taken as 
feasible, but any attempt to acquire at least one specimen will meet protocol requirements.  
Fine needle aspiration biopsies are not acceptable.   Biopsy requirements may be waived by 
the PI if biopsies pose an excess risk to the patient.
Blood Immune Response Collection: 
Patients will have blood drawn for research as outlined in the Study Calendar. Blood for 
Immune response monitoring will be collected as follow: 40 ml of blood.  Specimen distribution 
and required tubes will be specified in the laboratory manual.
Correlative Analyses: 
Correlative analyses include but are not limited to:

Analysis of paired biopsy specimens for changes in inflammatory gene expression 
(Nanostring), relative proportion of effector versus regulatory T cells (mIHC), evaluation 
of elaboration of inflammatory cytokines, T-cell repertoires, clonality, and other hallmarks 
of immune activation.

Analysis of circulating T-cell populations for changes in the frequency and effector 
function of immune cells including short-lived effector cells and memory T cells.

Analysis of pre- and post-treatment cytokine expression, T-cell repertoire, clonality

Analysis of functional immune responses using Elispot and other assays.

Additional assessments that could assist in the understanding of the immune response 
to cancer at the discretion of the principal investigator
10.1
Future Biomedical Research
Future Biomedical Research on blood and leftover tumor biopsy specimens will be performed 
on collected samples during this clinical trial. This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 


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the measurement of other analytes. This research is for biomarker testing to address 
emergent questions not described elsewhere in the protocol (as part of the main biomarker 
correlative objectives). The objective is to explore and identify biomarkers that inform scientific 
understanding of this therapeutic treatment and tumor biology responses to combination 
therapy. Such studies will be conducted with appropriate statistical considerations and 
evaluation of results.
11 Reporting and Documentation of Results
11.1
Evaluation of Efficacy (or Activity)
11.1.1 Antitumor Effect – Solid Tumors
Response and progression in this study will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST v1.1 criteria.
11.1.1.1 Definitions
Evaluable for toxicity
All patients will be evaluable for toxicity from the time of their first treatment with 
epacadostat, pembrolizumab, or tavo-EP.
Evaluable for objective response
Only those patients 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 response.  These patients will have their response classified according to the definitions 
stated below.  (Note:  Patients who exhibit objective disease progression prior to the end of 
Cycle 1 will also be considered evaluable).
11.1.1.2 Disease Parameters
Measurable disease
Measurable disease is defined as lesions (or tumors) that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with a minimum size of 10mm by CT 
scan (irrespective of scanner type), 10mm caliper measurement by clinical exam (when 
superficial), and/or 20mm by chest X-ray (if clearly defined and surrounded by aerated lung).
All tumor measurements will be recorded in millimeters or decimal fractions of centimeters.  
Previously irradiated lesions are considered non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy.It is recommended that 
previously irradiated lesions that would otherwise be considered measurable be followed 
closely by investigators by comments, measurements and photographs if applicable for 
retrospective review.
Target lesions
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  Target lesions will be selected on the basis of their size (lesions 
with the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will 


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be calculated and reported as the baseline sum LD.  The baseline sum LD will be used as 
reference by which to characterize the objective tumor response.
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.  It is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”).  Bone lesions may be measureable if ≥ 1 cm on MRI.    Measurements of 
these lesions are not required, but the presence or absence of each will be noted throughout 
follow-up. It is recommended that bone lesions be followed closely by investigators with 
comments and measurements whenever possible for retrospective review.
Non-measurable disease
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan).  
Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques are all 
non-measurable.
11.1.1.3 Methods for Evaluation of Measurable Disease
All measurements will be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations will be performed as closely as possible to the beginning of treatment 
and never more than 28 days before the beginning of the treatment.
The same method of assessment and the same technique will be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment.
Conventional CT (or PET-CT)
These techniques should be performed with cuts of 10 mm or less in slice thickness 
contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction 
algorithm.  This applies to tumors of the chest, abdomen, and pelvis. If measurable disease 
is noted in other areas of the body, CT imaging of those areas should be performed as well. 
Whole-body PET-CT is the preferred imaging technique whenever possible.
11.1.1.4 Response Criteria
Evaluation of Target Lesions
Complete Response (CR)
Disappearance of all target lesions, determined by two separate observations conducted not 
less than 4 weeks apart.  Any pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm (the sum may not be “0” if there are target nodes).  
There can be no appearance of new lesions.
Partial Response (PR)
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as 
reference the baseline sum LD.  There can be no appearance of new lesions


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Progressive Disease (PD)
At least a 20% increase in the sum of the SLD of target lesions, taking as reference the 
smallest sum SLD recorded since the treatment started and minimum 5 mm increase over the 
nadir, or the appearance of one or more new lesions.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum LD since the treatment started.
Evaluation of Non-Target Lesions
Complete Response (CR)
Disappearance of all non-target lesions and normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (< 10 mm short axis).
Incomplete Response/Stable Disease (SD)
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.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria.
Table 10
Response Criteria
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Response for this Category 
Also Requires
CR
CR
No
CR
≥4 weeks confirmation
CR
Non-CR/
Non-PD
No
PR
PR
Non-PD
No
PR
≥4 weeks confirmation
SD
Non-PD
No
SD
documented at least once ≥4 
weeks from baseline
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression


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Evaluation of Safety
Analyses will be performed for all patients having received at least one dose of epacadostat, 
pembrolizumab, or tavo-EP. The study will use the CTCAE v4.0 for reporting of adverse 
events and modified criteria for adverse events, see Section 5. Safety will be assessed during 
the study by documentation of adverse events (AEs), clinical laboratory tests, physical 
examination, vital sign measurements, and Eastern Cooperative Oncology Group (ECOG) 
performance status.
For multicenter studies, the Principal Investigator at the UCSF Coordinating Center will hold 
the role of Study Chair.  The Study Chair is responsible for the overall conduct of the study 
and for monitoring its safety and progress at all participating sites.
11.3
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.


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Table 11-1: Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization 
indicated; disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of investigational product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not 
include an adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, 
even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective 
procedure] for a preexisting condition which has not worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious 
adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed previously (designated above by a †).


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Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken
Did the adverse event cause the Investigational product to be discontinued?
Relationship 
to test drug
Did the Investigational product cause the adverse event? The determination of the likelihood that the Investigational product caused the adverse event 
will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that 
supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be 
retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the 
likelihood of a relationship between the test drug and the adverse event based upon the available information. 
The following components are to be used to assess the relationship between the Investigational product and the AE; the greater the 
correlation with the components and their respective elements (in number and/or intensity), the more likely the Investigational product caused the 
adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Investigational product such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily 
specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Investigational product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or 
environmental factors
Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to 
Investigational 
product
(continued) 
Dechallenge
Was the Investigational product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Investigational product; or (3) the trial is a single-dose drug trial); or (4) Investigational product(s) is/are only 
used one time.)
Rechallenge
Was the subject re-exposed to the Investigational product in this study?


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If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose 
drug trial); or (3) Investigational product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE INVESTIGATIONAL PRODUCT, OR IF REEXPOSURE TO THE INVESTIGATIONAL PRODUCTPOSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE U.S. CLINICAL MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Investigational product or drug 
class pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of anInvestigational 
product relationship).
Yes, there is a reasonable 
possibility of Investigational 
product relationship.
There is evidence of exposure to the Investigational product.  The temporal sequence of the AE onset relative to the administration 
of the Investigational product is reasonable.  The AE is more likely explained by the Investigational product than by another cause.
No, there is not a reasonable 
possibility Investigational 
product relationship
Subject did not receive the Investigational product OR temporal sequence of the AE onset relative to administration of the 
Investigational product is not reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose 
without an associated AE.)


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11.3.1 Definitions of Adverse Events
11.3.1.1 Adverse Event
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related.  
More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, 
without any judgment about causality. An adverse event can arise from any use of the drug (e.g., 
off-label use, use in combination with another drug) and from any route of administration, 
formulation, or dose, including an overdose. 
11.3.1.2 Adverse reaction
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event.
11.3.1.3 Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship between 
the drug and the adverse event.  A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction.
11.3.1.4 Unexpected
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the 
investigator brochure or package insert(s), or is not listed at the specificity or severity that has 
been observed, or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the current 
application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation.
Adverse events that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the investigator 
brochure.  For example, a certain number of non-acute deaths in a cancer trial would be 
anticipated as an outcome of the underlying disease, but such deaths would generally not be 
listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation. Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class effect, 
the first case of angioedema observed with the drug under investigation should be considered 
unexpected for reporting purposes.


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11.3.1.5 Serious
An adverse event or suspected adverse reaction is considered serious if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 

Death

Life-threatening adverse event

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function

Congenital anomaly/birth defect
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
11.3.1.6 Life-threatening
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
11.4
Recording of an Adverse Event
All grade 3 and above adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of epacadostat, pembrolizumab, or tavo-EP.  Data about these 
events and their severity will be recorded using the NCI CTCAE v4.0.  
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below: 
Relationship 
Attribution 
Description 
Unrelated
The AE is clearly NOT related to the 
intervention 
Unrelated to investigational 
drug/intervention
Unlikely
The AE is doubtfully related to the 
intervention 
Possible
The AE may be related to the intervention 
Probable
The AE is likely related to the intervention 
Related to investigational 
drug/intervention
Definite
The AE is clearly related to the intervention 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions:


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Grade 0
No AE (or within normal limits)
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL)
Grade 3:
Severe 
or 
medically 
significant 
but 
not 
immediately 
life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL
Grade 4:
Life-threatening consequences; urgent intervention indicated
Grade 5:
Death related to AE
11.5
Follow-up of Adverse Events
All adverse events will be followed with appropriate medical management until resolved.  Patients 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator.
11.6
Adverse Events Monitoring
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of epacadostat, pembrolizumab, or tavo-EP, will be entered into OnCore®, as noted 
above.
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board, 
the Committee on Human Research (CHR); and, when the study is conducted under an 
Investigational New Drug Application (IND), to the Food and Drug Administration (FDA) if it meets 
the FDA reporting criteria.
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis.  The Site Committee will 
review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of epacadostat, 
pembrolizumab, or tavo-EP.
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
Site Committee meetings. The Site Committee will review and discuss the selected toxicity, the 
toxicity grade, and the attribution of relationship of the adverse event to the administration of 
epacadostat, pembrolizumab, or tavo-EP.
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and 
discussed at DSMC meetings, which take place every six weeks.
For a detailed description of the Data and Safety Monitoring Plan for a Multicenter Phase 2or 3 
Institutional Study at the Helen Diller Comprehensive Cancer Center please refer to Appendix 2 
Data and Safety Monitoring Plan for a Multicenter Institutional Study (For Lead-In Phase) 
and Appendix 3 Data and Safety Monitoring Plan for a Multicenter Study (Phase II or III 
study).


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11.7
Expedited Reporting
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of epacadostat, pembrolizumab, or tavo-EP and it is determined to be related either 
to the epacadostat, pembrolizumab, or tavo-EP or to a study procedure, the Investigator or his/her 
designee must notify the DSMC Chair (or qualified alternate) within 1 business day of knowledge 
of the event.  The contact may be by phone or e-mail.
Reporting to UCSF Committee on Human Research (Institutional Review Board)
The Principal Investigator must report events meeting the UCSF CHR definition of “Unanticipated 
Problem” (UP) within 10 business days of his/her awareness of the event.
Expedited Reporting to the Food and Drug Administration
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all three 
definitions: 

Suspected adverse reaction 

Unexpected 

Serious 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the information 
is available (21 CFR 312.32(d)(2)). 
Reporting to Incyte, Merck and OncoSec:
All SAEs, including pregnancy and lactation exposure cases, must be reported to Incyteand 
OncoSec within 24 hours.  For secondary institutions, they will notify our site within 24hour of the 
SAE and we will notify the appropriate sponsor contacts within 24 hours of our awareness of the 
event.

Submit the completed SAE Report Form to:
o
Incyte/Telerx via e-mail 
or fax (
 
within 24 hours of awareness that the SAE has occurred. 
o
Also submit these forms to OncoSec via email 
. within 24 
hours of awareness that the SAE has occurred


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
Transmit one e-mail or fax per SAE Report Form.  Send each SAE Report Form 
separately, with a separate SAE Notification Cover Sheet (e.g., transmit two SAE reports 
as two separate e-mails/faxes, with two cover sheets)

Complete the SAE Report Form in English. 

If hand-written, use black ink and BLOCK PRINT, and make sure that it is legible.   

Avoid the use of abbreviations on the report form.   

Tick all applicable boxes on the SAE Report Form. 

Rather than leaving a field blank, use ‘N/A’ (not applicable), ‘ND’ (not done), or ‘None’.   

Ensure that the information provided on the SAE Report Form is consistent with the data 
recorded in the Case Report Form (CRF)/electronic Case Report Form (eCRF) and the 
source data. 

Do not provide medical records (e.g., discharge summary, test results) unless specifically 
requested by Incyte or OncoSec; instead, record the information that is relevant to the 
SAE on the SAE Report Form. 

Provide clinically significant follow-up information regarding SAEs to Incyte/Telerx and 
OncoSec within 24 hours of becoming aware of the information, via the same process as 
for the initial report.  

If you amend the original SAE Report Form, annotate all corrections or additions with the 
date and your initials.  Strike through (with a single line) any information that no longer 
applies.  Otherwise, complete a new SAE Report Form with the new or updated 
information. 

When providing follow-up information, indicate whether the information should be added 
to previously reported information or if the information should replace previously reported 
information.  For example, when different medical terms are reported in Section 8 on the 
initial and follow-up reports, please indicate whether the SAE term(s) on the follow-up 
report is in addition to or replaces the term(s) on the initial report form.  If the term is being 
replaced, strike through (with a single line) the SAE term that no longer applies and include 
the date and your initials.   

If follow-up information is provided on a new SAE Report Form and fields are left blank, it 
will be assumed by Incyte/Telerx and OncoSec that there is no change in the information 
from the previous report form. 

Where an SAE is followed by reports of recurrent episodes, complications, or progression 
of the initial SAE, all such reports must be submitted as follow-up to the original episode.   

If a new SAE that occurs at a different time interval is considered completely non-
associated to a previously reported SAE, complete and submit a new SAE Report Form 
as an initial report.
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1.
Quality or quantity of data recording is inaccurate or incomplete
2.
Poor adherence to protocol and regulatory requirements
3.
Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4.
Plans to modify or discontinue the development of epacadostat, pembrolizumab, or tavo-EP


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12 Study Management
12.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable 
regulatory requirements.
Before initiating this trial, the Investigator will have written and dated approval from the Institutional 
Review Board for the protocol, written informed consent form, subject recruitment materials, and 
any other written information to be provided to subjects before any protocol related procedures 
are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable regulatory 
requirements.
12.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant information related 
to the study (e.g. advertisements used to recruit participants) will be reviewed and approved by 
the UCSF CHR (UCSF Institutional Review Board).  Prior to obtaining CHR approval, the protocol 
must be approved by the Helen Diller Family Comprehensive Cancer Center Site Committee and 
by the Protocol Review Committee (PRC).  The initial protocol and all protocol amendments must 
be approved by the IRB prior to implementation.  
12.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants must 
sign the CHR-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  The 
original signed copy of the consent document must be retained in the medical record or research 
file. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial.
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable opinion 
in advance of use.  The subject or his/her legally acceptable representative should be informed 
in a timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial.  The communication of this information will be 
provided and documented via a revised consent form or addendum to the original consent form 


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that captures the subject’s dated signature or by the subject’s legally acceptable representative’s 
dated signature.
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements.
12.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by PRC and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the 
Investigator must then notify the IRB in writing within five (5) working days after implementation.  
The Study Chair and the UCSF study team will be responsible for updating any participating sites.
12.5
Handling and Documentation of Clinical Supplies
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs.  The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
epacadostat, pembrolizumab, or tavo-EP has been dispensed by patient number and initials will 
be included. The sponsor-investigator will maintain written records of any disposition of 
epacadostat, pembrolizumab, and tavo-EP.
The Principal Investigator shall not make the investigational drug available to any individuals other 
than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol.
12.6
Case Report Forms (CRFs)
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into OnCore® via standardized CRFs 
in accordance with the CTMS study calendar, using single data entry with a secure access 
account.  The Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible 
upon completion of the study visit; the Investigator will review and approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by UCSF 
personnel.  All source documentation should be kept in separate research folders for each patient.
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.


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The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the database 
will be locked.  Any changes to the data entered into the CRFs after that time can only be made 
by joint written agreement among the Study Chair, the Trial Statistician, and the Protocol Project 
Manager.
Each participating site will complete study specific CRFs for safety monitoring and data analysis.  
Each site will enter the study data into OnCore® via standardized CRFs in accordance with the 
CTMS study calendar, using single data entry with a secure access account. The participating 
site’s Clinical Research Coordinator (CRC) will complete the CRFs; the Investigator will review 
and approve the completed CRFs – this process must be completed within 3 business days of 
the visit. Study data from the participating site will be reported and reviewed in aggregate with 
data from patients enrolled at the coordinating center, UCSF.  All source documentation and 
CTMS data will be available for review/monitoring as needed.
12.7
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring entity 
for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-approved Data 
and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse events and 
suspected adverse reactions considered “serious”.  The DSMC will audit study-related activities 
to ensure that the study is conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant results of the DSMC 
audit will be communicated to the IRB and the appropriate regulatory authorities at the time of 
continuing review, or in an expedited fashion, as applicable.  See Appendix 2 Data and Safety 
Monitoring Plan for a Multicenter Institutional Study (For Lead-In Phase) and Appendix 3 
Data and Safety Monitoring Plan for a Multicenter Study (Phase II or III study), for additional 
information.
12.8
Multicenter communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center for Phase II studies will also coordinate, at minimum, monthly conference 
calls with the participating sites at the completion of each cohort or more frequently as needed to 
discuss risk assessment.  The following issues will be discussed as appropriate:

Enrollment information

Cohort updates

Adverse events (i.e. new adverse events and updates on unresolved adverse events and 
new safety information)

Protocol violations

Other issues affecting the conduct of the study
12.9
Record Keeping and Record Retention
The Principal Investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by subjects, as well as written records of the disposition of the 
drug when the study ends.  
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 


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individual administered the investigational drug or employed as a control in the investigation. Case 
histories include the case report forms and supporting data including, for example, signed and 
dated consent forms and medical records including, for example, progress notes of the physician, 
the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall 
document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study.
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it is 
being investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and FDA is notified.
12.10 Coordinating Center Documentation of Distribution
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that the 
Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, 
drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed.
12.11 Regulatory Documentation
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by the 
UCSF Committee on Human Research (CHR). Prior to implementing this protocol at the 
participating sites, approval for the UCSF CHR approved protocol must be obtained from the 
participating site’s IRB. 
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants: 

Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 

Participating Site IRB approved consent form 

Participating Site IRB membership list 

Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 

Curriculum vitae and medical license for each investigator and consenting professional 


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
Documentation of Human Subject Research Certification training for investigators and key 
staff members at the Participating Site 

Participating site laboratory certifications and normal ranges.
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment.
13 Protection of Human Subjects
13.1
Protection from Unnecessary Harm
Each clinical site is responsible for protecting all subjects involved in human experimentation. This 
is accomplished through the CHR mechanism and the process of informed consent. The CHR 
reviews all proposed studies involving human experimentation and ensures that the subject’s 
rights and welfare are protected and that the potential benefits and/or the importance of the 
knowledge to be gained outweigh the risks to the individual. The CHR also reviews the informed 
consent document associated with each study in order to ensure that the consent document 
accurately and clearly communicates the nature of the research to be done and its associated 
risks and benefits. 
13.2
Protection of Privacy
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the individuals 
described in the informed consent document.


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33. Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E. & Prendergast, G. C. 
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Appendices
Appendix 1 Performance Status Criteria
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity
Fully active, able to carry on all pre-disease performance without restriction
1
Symptoms, but ambulatory
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light housework, office work)
2
In bed < 50% of the time
Ambulatory and capable of all self-care, but unable to carry out any work 
activities
Up and about more than 50% of waking hours
3
In bed > 50% of the time
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
100% bedridden
Completely disabled
Cannot carry on any self-care
Totally confined to bed or chair
5
Dead


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Appendix 2 Data and Safety Monitoring Plan for a Multicenter Institutional Study 
(For Lead-In Phase)
1.
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and patient safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes: 
•
Review of patient data in each cohort. 
•
Review of serious adverse events.
•
Approval of dose escalation by DSMC Chair or Vice Chair.
•
Real time monitoring (depending on study accrual).
•
Minimum of a yearly regulatory audit.
2.
Monitoring and Reporting Guidelines
The data is monitored by a DSMC monitor once a month as patients are enrolled and includes 
all visits through the first post-Dose Limiting Toxicity (DLT) period.  At the time of dose 
escalation, a written report will be submitted to the DSMC Chair outlining the cohort dose, all 
adverse events and serious adverse event reports, and any Dose Limiting Toxicity as described 
in the protocol.  The report will be reviewed by the DSMC Chair or qualified alternate and written 
authorization to proceed or a request for more information will be issued within two business 
days of the request.  The report is then reviewed at the subsequent DSMC meeting.  In the 
event that the committee does not concur with the DSMC Chair’s decision, further study accrual 
is held while further investigation takes place.  
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites.  The Study Chair will conduct continuous review of data 
and patient safety and discuss each patient’s treatment at weekly UCSF Site Committee 
meetings.  The discussions are documented in the UCSF Site Committee meeting minutes.  For 
each dose level, the discussion will include the number of patients, significant toxicities in 
accordance with the protocol, doses adjustments, and observed responses.
Multicenter communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites.  
The following issues will be discussed as appropriate:

Enrollment information.

Cohort updates (i.e., DLTs).

Adverse events (i.e. new adverse events and updates on unresolved adverse events 
and new safety information).

Protocol violations.

Other issues affecting the conduct of the study.


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Dose Level Considerations
The PI/Study Chair, participating investigators, and research coordinators from each site will 
review enrollment for each dose level cohort during the regularly scheduled conference calls.  
The dose level for ongoing enrollment will be confirmed for each patient scheduled to be 
enrolled at a site.  Dose level assignments for any patient scheduled to begin treatment must be 
confirmed by the UCSF Coordinating Center via e-mail.
If a Dose Limiting Toxicity (DLT) arises in a patient treated at a participating site, all sites must 
be notified immediately by the UCSF Coordinating Center.  The Study Chair has 1 business day 
(after first becoming aware of the event at either the UCSF Coordinating Center or the 
participating site) in which to report the information to all participating sites.  If the DLT occurs at 
a participating site, the local investigator must report it to the UCSF Coordinating Center within 
one business day, after which the UCSF Coordinating Center will notify the other participating 
sites.
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites as per the 
study-specific guidelines listed in Appendix H.  The data (i.e., redacted copies of source 
documents) from the participating sites will be downloaded into the PC console of OnCore prior 
to the monitoring visits in order for the DSMC to monitor the participating site’s compliance with 
the protocol and FDA guidelines.
3.
Review and Oversight Requirements
3.1
Adverse Event Monitoring
All clinically significant adverse events (AEs), whether or not considered to be expected 
or unexpected and whether or not considered to be associated with the use of study drug, 
will be entered into OnCore®, UCSF’s Clinical Trial Management System.  
Adverse Events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation Program 
(CTEP) of the National Cancer Institute.  Adverse Events are further given an assignment 
of attribution or relationship to treatment or medical procedure.  Attribution categories 
are:

Definite – The adverse event is clearly related to the investigational agent(s) or 
medical procedure.

Probable – The adverse event is likely related to the investigational agent(s) or 
medical procedure.

Possible – The adverse event may be related to the investigational agent(s) or 
medical procedure.

Unlikely – The adverse event is doubtfully related to the investigational 
agent(s)or medical procedure.

Unrelated – the adverse event is clearly not related to the investigational 
agent(s) or medical procedure.


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All adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Coordinating Center’s Site Committee.  All clinically significant adverse events 
must be reported to the UCSF Coordinating Center by the participating sites within 1 
business days of becoming aware of the event.  The Site Committee will review and 
discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the 
adverse event to the administration of the study drug(s) from the UCSF Coordinating 
Center and the participating sites.
3.2
Serious Adverse Event Reporting
By definition, an adverse event is defined as a serious adverse event (SAE) according 
to the following criteria:

Death.

Life-threatening (i.e. results in an immediate risk of death).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Permanent or significant disability/incapacity.

Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that 
may require medical or surgical intervention to prevent one of the outcomes 
listed above.

Event occurring in a gene therapy study.

Event that changes the risk/benefit ratio of a study.

Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with the UCSF IRB Regulations 
and Code of Federal Regulation Title 21 Part 312.32.  The SAE will be reported on a 
Med Watch form.
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event
FDA website for guidance in reporting serious adverse events:
www.fda.gov/Safety/MedWatch/HowToReport/default.htm
Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All serious adverse events are entered into OnCore®, as well as submitted to the IRB 
(per IRB guidelines) via iRIS®.  All SAEs, whether expected or unexpected, must be 
reported to the UCSF Coordinating Center within 10 business days of becoming aware 
of the event or during the next scheduled conference all, whichever is sooner.  The 
SAEs are reviewed and monitored by the Data and Safety Monitoring Committee on an 
ongoing basis and discussed at DSMC meetings, which take place every six weeks.  
The date the SAE was sent to all required reporting agencies will be documented in 
OnCore®.
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be possibly, probably, or 
definitely related either to the investigational drug or any research related procedure, the 


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Study Chair at the UCSF Coordinating Center or the assigned designee must be notified 
within 1 business day from the participating site(s) and the Study Chair must then notify 
the DSMC Chair or qualified alternate within 1 business day of this notification.  The 
reporting procedure is by communication via e-mail, with a copy of the e-mail to the 
DSMC Manager.
3.3
Review of Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in 
the Investigator Brochure or package insert) is noted in the study, the Study Chair at the 
UCSF Coordinating Center is responsible for notifying the DSMC at the time the 
increased rate is identified.  The report will indicate if the incidence of adverse events 
observed in the study is above the range stated in the Investigator’s Brochure or package 
insert.
If at any time the Study Chair stops enrollment or stops the study due to safety issues, 
the DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail 
and the IRB must be notified via 10 business days via an iRIS Reporting Form.
Data and Safety Monitoring Committee Contacts:
 (DSMC Chair)
UCSF HDFCCC
San Francisco, CA 94158
DSMC Monitors 
UCSF HDFCCC
San Francisco, CA 
94143


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Appendix 3 Data and Safety Monitoring Plan for a Multicenter Study (Phase II or III 
study)
1.
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and patient safety for 
all HDF CCC institutional clinical studies.  A summary of DSMC activities for this study includes: 
•
Review of patient data.
•
Review of serious adverse events.
•
Monitoring every six months (depending on patient accrual).
•
Minimum of a yearly regulatory audit.
2.
Monitoring and Reporting Guidelines
All institutional Phase II or III therapeutic studies are designated with a moderate risk 
assessment (see Appendix H).   The data is monitored by a DSMC Monitor twice per year with 
twenty percent of the patients monitored (or at least three patients if the calculated value is less 
than three).   
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites to 
communicate the review of adverse events, safety data, and other study matters.
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites.  The Study Chair will conduct continuous review of data 
and patient safety and discuss each patient’s treatment at monthly UCSF Site Committee 
meetings.  The discussions are documented in the UCSF Site Committee meeting minutes.  
Multicenter communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites.  
The following issues will be discussed as appropriate:
•
Enrollment information. 
•
Adverse Events (i.e., new adverse events and updates on unresolved adverse events 
and new safety information).
•
Protocol Violations.
•
Other issues affecting the conduct of the study.
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites as per the 
study-specific guidelines listed in Appendix H.  The data (i.e., copies of source documents) from 


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the participating sites will be downloaded into the PC console of OnCore prior to the monitoring 
visits in order for the DSMC to monitor the participating site’s compliance with the protocol and 
FDA regulations.
3
Review and Oversight Requirements
3.1
Adverse Event Monitoring
All Grade 3-5 Adverse Events (AEs), regardless of being unexpected or considered to be 
associated with the use of the study drug will be entered into OnCore®, UCSF’s Clinical Trial 
Management System.  
Adverse Events are graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the 
National Cancer Institute.  Adverse Events are further given an assignment of attribution or 
relationship to treatment or medical procedure.  
Attribution categories are:
•  
Definite – The adverse event is clearly related to the investigational agent(s) or 
medical procedure.
•  
Probable – The adverse event is likely related to the investigational agent(s) or 
medical procedure.
• 
Possible – The adverse event may be related to the investigational agent(s) or 
medical procedure.
• 
Unlikely – The adverse event is doubtfully related to the investigational agent(s) 
or medical procedure.
• 
Unrelated – the adverse event is clearly not related to the investigational
agent(s) or medical procedure.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Site Committee meetings.  All adverse events entered into OnCore® will be reviewed on 
a monthly basis at the UCSF Coordinating Center Site Committee meetings.  All clinically 
significant adverse events must be reported to the UCSF Coordinating Center by the 
participating sites within 10 business days of becoming aware of the event or during the next 
scheduled monthly conference call, whichever is sooner.  The UCSF Site Committee will review 
and discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the 
adverse event to the administration of the study drug(s) from the UCSF Coordinating Center 
and the participating sites. 
3.2
Serious Adverse Event Reporting
By definition, an Adverse Event is defined as a Serious Adverse Event (SAE) according to the 
following criteria:

Death.

Life-threatening (i.e. results in an immediate risk of death).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Permanent or significant disability/incapacity.


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
Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed above.

Event occurring in a gene therapy study.

Event that changes the risk/benefit ratio of a study.

Any other event the Principal Investigator judges to be serious or which would suggest a 
significant hazard, contraindication, side effect, or precaution.
Serious Adverse Event reporting will be in accordance with the UCSF IRB Regulations and 
Code of Federal Regulation Title 21 Part 312.32.  The SAE will be reported on a Med Watch 
form.  
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event
FDA website for guidance in reporting serious adverse events:
www.fda.gov/Safety/MedWatch/HowToReport/default.htm
Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All Serious Adverse Events are entered into OnCore®, as well as submitted to the IRB (per IRB 
guidelines) via iRIS®.  All SAEs, whether expected or unexpected, must be reported to the 
UCSF Coordinating Center within 1 business days of becoming aware of the event.  The SAEs 
are reviewed and monitored by the UCSF Data and Safety Monitoring Committee on an ongoing 
basis and discussed at DSMC meetings, which take place every six weeks.  The date the SAE 
was sent to all required reporting agencies will be documented in OnCore®.
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be possibly, probably, or definitely 
related either to the investigational drug or any research related procedure, the Study Chair at 
the UCSF Coordinating Center or the assigned designee must be notified within 1 business day 
from the participating site(s) and the Study Chair must then notify the DSMC Chair or qualified 
alternate within 1 business day of this notification.  The reporting procedure is by 
communication via phone or in person with written documentation of the one-on-one 
communication via e-mail, with a copy of the e-mail to the DSMC Manager.
3.3
Review of Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, the Study Chair at the UCSF 
Coordinating Center is responsible for notifying the DSMC at the time the increased rate is 
identified.  The report will indicate if the incidence of adverse events observed in the study is 
above the range stated in the Investigator Brochure or package insert.
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day and the IRB must be 
notified within 10 business days via an iRIS Reporting Form.


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Data and Safety Monitoring Committee Contacts:
UCSF HDFCCC
San Francisco, CA 94158
DSMC Monitors 
UCSF HDFCCC
San Francisco, CA 
94143
*  DSMP approved by NCI 09/February2012


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Appendix 4TranslationalMedicine Methods and Statistical Analysis
Compare of inflammatory genes expression by Nanostring before and after initiation of 
treatment on study
 
RNA is isolated from FFPE tumor tissue using Qiagen RecoverAll kits. RNA is run on NanoString’s 
Human Immunology Panel v2 as described by the vendor. Analysis of the data is performed using 
NSolver software provided by NanoString. Samples that do not reach NanoString’s Quality 
Control benchmarks are removed from analysis. Counts or Log2 Fold Change from screen to a 
post-treatment time-point are used to compare samples.
 
Compare relative proportion of effector versus regulatory T-cells in pre-treatment and 
post-treatment tumor specimens
 
PBMCs are thawed, washed, and rested overnight. Cells are then stained with surface markers 
and viability dye. After being fixed and permeabilized, any necessary intercellular staining is 
performed. Cells are analyzed on a BD Biosciences LDS Fortessa X-20 and resulting data is 
analyzed by FlowJo (TreeStar). 
 
Compare pre-treatment to post-treatment in cytokine expression, T-cell repertoire, 
clonality
 
To assess a patient’s clonality and T cell fraction, Adaptive analysis is done on DNA isolated from 
PBMC or FFPE tissue sample from tumor. DNA is isolated using Qiagen RecoverAll kits. 
 
Cytokine expression is measured in patient serum using MILLIPLEX MAP High Sensitivity Human 
Cytokine Magnetic Bead Kit (EMD Millipore, Billerica, MA). Analysis will be performed with 
weighted 5 Paramater Logistic curves produced by Luminex xPONENT software. Results (pg of 
analyte/mL of sample) are adjusted to pg of analyte/g of tumor and averaged to produce an 
average expression value. 
Compare pre-treatment and post-treatment populations of immune cell populations in the 
peripheral blood including short-lived effector cells (SLECs) and memory T-cells
 
PBMCs are thawed, washed, and rested overnight. Cells are then stained with surface markers 
and viability dye. After being fixed cells are analyzed on a BD Biosciences LDS Fortessa X-20 
and resulting data is analyzed by FlowJo (TreeStar). 
 
Compare pre-treatment to post-treatment functional immune responses using Elispot 
analysis
 
PBMCs are thawed, washed, and rested overnight before being plated in 96-well MultiScreen 
Filter Plates (EMD Millipore, Billerica, MA) with applicable melanoma peptides, no peptide, or a 
positive control peptide. Relevant cytokines secreted from activated cells are captured on the 
plate and visualized using Biotin/Streptavidin binding of alkaline phosphatase conjugate (ALP) 
with BCIP/NBT Phosphatase Substrate (MABtech, Nacka Strand, Sweden).  Plates are scanned 
with an ELISpot reader (Cellular Technology Limited, Shaker Heights, OH) and counted using 
CTL Immunospot 5.0 Analyzer software. Final counts of antigen specific cytokine-secreting cells 
is obtained by subtracting the number of spots in the no-antigen control wells from the test wells.


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Statistical Analysis
 
Data from all assays are graphed and analyzed for statistical significance in GraphPad Prism 
software. T-tests are used to determine statistical significance for comparisons between 2 groups. 
ANOVA tests are used to determine statistical significance for comparisons between 3 or more 
groups. Significance is considered reached if the p value is at or below 0.05.