Clinical trial NCT02575807
Conditions: Platinum-resistant Ovarian Cancer Platinum-resistant Fallopian Cancer Platinum-resistant Peritoneal Cancer
Keywords: Ovarian cancer Fallopian cancer Primary peritoneal cancer
Sponsor: Aduro Biotech, Inc.
Start date: 2016-03-08; Completion date: 2018-05-08
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This 2-part, Phase 1/2 study will test investigational cancer drugs known as CRS-207, epacadostat (IDO), and pembrolizumab (pembro). The purpose of this study is to find out how safe it is to give the investigational drugs to women with platinum-resistant ovarian, fallopian tube, or peritoneal cancer and if it helps patients with these types of cancer live longer or can help shrink or slow the growth of cancer.

Detailed description:

Arms: arm 1: CRS-207 administered in 3-week cycles.

\* CRS-207 (1 x 10e9 colony forming units \[CFU\]) administered by intravenous (IV) infusion. For Cycle 1 through Cycle 6, CRS-207 will be administered on Day 1 of each cycle. After 6 cycles, CRS-207 will be administered on Day 1 once every 6 weeks (every other cycle). arm 2: CRS-207 administered in 3-week cycles, IDO administered twice daily (BID).

* CRS-207 (1 x 10e9 CFU) administered by IV infusion. For Cycle 1 through Cycle 6, CRS-207 administered on Day 1 of each cycle. After 6 cycles, CRS-207 administered on Day 1 once every 6 weeks (every other cycle).
* IDO (100 milligrams \[mg\]) administered by mouth (PO) BID, starting on Day 2 of the first CRS-207 treatment cycle. arm 3: CRS-207 administered in 3-week cycles, IDO administered BID.

* CRS-207 (1 x 10e9 CFU) administered by IV infusion. For Cycle 1 through Cycle 6, CRS-207 administered on Day 1 of each cycle. After 6 cycles, CRS-207 administered on Day 1 once every 6 weeks (every other cycle).
* IDO (300 mg) administered PO BID, starting on Day 2 of the first CRS-207 treatment cycle. arm 4: CRS-207 and pembrolizumab (pembro) administered in 3-week cycles, IDO administered BID.

* CRS-207 (1 x 10e9 CFU) administered by IV infusion. For Cycle 1 through Cycle 6, CRS-207 administered on Day 2 of each cycle. After 6 cycles, CRS-207 administered on Day 2 once every 6 weeks (every other cycle).
* Pembro (200 mg) administered by IV infusion on Day 1 in 3-week cycles.
* IDO (300 mg) administered PO BID, starting on Day 3 of the first CRS-207 treatment cycle. arm 5: CRS-207 and pembro administered in 3-week cycles.

* CRS-207 (1 x 10e9 CFU) administered by IV infusion. For Cycle 1 through Cycle 6, CRS-207 administered on Day 2 of each cycle. After 6 cycles, CRS-207 administered on Day 2 once every 6 weeks (every other cycle).
* Pembro (200 mg) administered by IV infusion on Day 1 in 3-week cycles.
Interventions: intervention 1: CRS-207 intervention 2: Epacadostat intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: via IV infusion intervention 2: PO BID intervention 3: via IV infusion

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Phase 1/2, Open-Label Safety and Efficacy Evaluation of CRS-207 
in Combination with Epacadostat in Adults with Platinum-Resistant 
Ovarian, Fallopian, or Peritoneal Cancer 
Investigational Products: CRS-207, epacadostat, and pembrolizumab 
Protocol Number: ADU-CL-11 
Sponsor: 
Aduro Biotech, Inc. 
740 Heinz Avenue 
Berkeley, CA 94710-2224 USA 
Telephone: +1 510-848-4400 
Facsimile: +1 510-848-5614 
Original Protocol:  28 October 2015 
Amendment 1:  22 April 2016 
Amendment 2:  15 November 2016 
Amendment 3:  18 February 2017 
IND: 16,702 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Aduro Biotech, Inc. except to the extent that disclosure would be required by law and 
for the purpose of evaluating and/or conducting a clinical study for Aduro Biotech, Inc. You are 
allowed to disclose the contents of this document only to your Institutional Review Board (IRB) 
or Independent Ethics Committee (IEC) and study personnel directly involved with conducting 
this protocol. Persons to whom the information is disclosed must be informed that the information 
is confidential and proprietary to Aduro Biotech, Inc. and that it may not be further disclosed to 
third parties. 




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Clinical Study Protocol ADU-CL-11 
 
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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this amended protocol. I approve this document and I agree that it contains all necessary 
details for carrying out the study as described. I will conduct this study in accordance with the 
design and specific provision of this protocol and will make a reasonable effort to complete the 
study within the time designated. I will provide copies of this protocol and access to all information 
furnished by Aduro Biotech, Inc. to study personnel under my supervision. I will discuss this 
material with them to ensure they are fully informed about the study product and study procedures. 
I will let them know that this information is confidential and proprietary to Aduro Biotech, Inc. 
and that it may not be further disclosed to third parties. I understand that the study may be 
terminated or enrollment suspended at any time by Aduro Biotech, Inc., with or without cause. I 
have the right to suspend enrollment of subjects at my study site if necessary to protect the best 
interests of the study subjects. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations and ICH Guidelines for Good Clinical 
Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
  
 
 


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SYNOPSIS 
TITLE:  A Phase 1/2, Open-Label Safety and Efficacy Evaluation of CRS-207 in Combination 
with Epacadostat in Adults with Platinum-Resistant Ovarian, Fallopian, or Peritoneal Cancer  
PROTOCOL NUMBER: ADU-CL-11 
INVESTIGATIONAL PRODUCTS:  
CRS-207, epacadostat (IDO), and pembrolizumab (pembro) 
OBJECTIVES AND ENDPOINTS: 
The objectives and endpoints for this study are as follows: 
Phase 1: Dose Evaluation, Assigned Arms 
Objective(s) 
Endpoints 
Primary 
• Determine the RP2D of epacadostat 
administered with CRS-207 in subjects 
with platinum-resistant ovarian, fallopian 
or peritoneal cancer 
• Assess safety and tolerability of CRS-207 
alone and CRS-207 in combination with 
epacadostat in subjects with platinum-
resistant ovarian, fallopian or peritoneal 
cancer 
Primary 
• Hematologic and non-hematologic DLTs; 
• Adverse events by CTCAE grade; vital signs, physical 
exam findings, changes in ECG readings and changes in 
chemistry and hematology and coagulation parameters  
 
Secondary 
• Characterize the PK of epacadostat 
• Evaluate the preliminary anti-tumor 
activity of each study drug regimen 
• Characterize pharmacological effects on 
immune biomarkers in peripheral blood 
and tumor tissue 
• Characterize shedding and clearance of 
CRS-207 when given alone or with 
epacadostat 
 
Secondary 
• Plasma concentration of epacadostat and derived PK 
parameters; 
• ORR, defined as CR or PR as determined by mRECIST, 
RECIST v1.1, and GCIG CA-125 criteria; 
• PFS, defined as the time from the date of first dose to PD 
or death due to any cause. PFS is measured through the 
last tumor assessment or commencement of a new 
systemic therapy. PD is determined by mRECIST, 
RECIST v1.1 and GCIG CA-125 criteria; 
• Disease control rate, defined as CR+PR+SD as determined 
by mRECIST, RECIST v1.1, and GCIG CA-125 criteria; 
• Duration of response, defined as the time from first CR or 
PR until PD as determined by mRECIST, RECIST v1.1, 
and GCIG CA-125 criteria; 
• OS, defined as the time from first dose until date of death 
due to any cause; 
• Ratio of tumor infiltrating lymphocytes CD8/Treg (FoxP3); 
• Plasma kynurenine/tryptophan ratio;  
• Other immunological and tumor biomarker endpoints: 
o Cytokine/chemokine responses 
o Antibody responses 
o Modulation of immune cell populations and functions 
in PBMCs and tumor, and 
o CA-125, mesothelin, IDO-1, PD-L1 and additional 
tumor biomarkers; and  
• Detection of CRS-207 in urine, saliva, feces, and blood 


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CA-125 = cancer antigen-125; CR = complete response; CTCAE = Common Terminology Criteria for Adverse Events; 
DLT = dose-limiting toxicity; GCIG = Gynecologic Cancer Intergroup; IDO = epacadostat; mRECIST = modified Response 
Evaluation Criteria in Solid Tumors; ORR = objective response rate; OS = overall survival; PBMC = peripheral blood 
mononuclear cells; PD = disease progression; PD-L1 = programmed death receptor ligand 1; pembro = pembrolizumab; 
PFS = progression-free survival; PK = pharmacokinetics; PR = partial response; RECIST = Response Evaluation Criteria in 
Solid Tumors; RP2D = recommended Phase 2 dose; SD = stable disease; Treg = regulatory T cells. 
Phase 2: Randomized, 2-stage 
Objective(s) 
Endpoints 
Primary 
• Assess safety of CRS-207/pembrolizumab 
administered with or without epacadostat 
• Assess tumor response and PFS  
Primary 
• Adverse events, vital signs, physical exam findings, 
changes in ECG readings, and changes in chemistry, 
hematology, and coagulation parameters  
• ORR, defined as CR or PR as determined by mRECIST 
• PFS, defined as the time from the date of first dose to PD 
or death due to any cause. PFS is measured through the 
last tumor assessment or commencement of a new 
systemic therapy. PD is determined by mRECIST. 
Secondary 
• Assess disease control rate and duration 
of response  
• Assess OS 
Secondary 
• Disease control rate, defined as CR+PR+SD as determined 
by mRECIST, RECIST v1.1, and GCIG CA-125 criteria 
• Duration of response, defined as the time from first CR or 
PR until PD as determined by mRECIST, RECIST v1.1, 
and GCIG CA-125 criteria 
• ORR as determined by RECIST v1.1 and GCIG CA-125 
criteria 
• OS, defined as the time from first dose until date of death 
due to any cause 
• PFS where PD is determined by RECIST v1.1 and GCIG 
CA-125 criteria 
Additional 
• Assess the association of clinical efficacy 
(ORR, PFS, and OS) with immunologic 
and tumor biomarkers  
• Characterize the PK of epacadostat 
• Characterize shedding and clearance of 
CRS-207/pembrolizumab administered 
with or without epacadostat  
 
Additional 
Immunological and tumor biomarker endpoints: 
• Cytokine/chemokine and antibody responses 
• Modulation of immune cell populations and functions in 
PBMCs and tumor 
• Mesothelin, IDO-1 and PD-L1 expression 
• CA-125 and additional candidate tumor biomarkers 
Pharmacokinetic endpoints: 
• Plasma concentration of epacadostat and derived PK 
parameters 
• Detection of CRS-207 in urine, saliva, feces, and blood 
  
STUDY DESIGN: 
The study is designed to assess the safety and efficacy of the following investigational treatment 
regimens in adult females with epithelial ovarian, fallopian, or primary peritoneal cancer that is 
platinum-resistant (i.e. has progressed within 6 months after completing platinum-based 
chemotherapy):  
• CRS-207/epacadostat/pembrolizumab (CRS-207/IDO/pembro)  
• CRS-207/pembrolizumab (CRS-207/pembro)  


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The study will be conducted in 2 phases as depicted in the study schematic. Phase 1 seeks to 
evaluate safety and tolerability and is aimed at determining the recommended Phase 2 dose 
(RP2D) of epacadostat administered with CRS-207 for further evaluation in Phase 2. The 
randomized Phase 2 portion of the study will begin with a safety-run in to evaluate the addition 
of pembrolizumab, followed by a 2-stage design to evaluate safety and efficacy in subjects who 
have received no more than 3 prior chemotherapy regimens for locally advanced or metastatic 
disease.  
Study Schematic 
The Schedules of Events for Phases 1 and 2 are provided in Appendix F and Table 1, 
respectively. The study consists of a 28-day screening period, followed by administration of 
study drug(s) in 3-week cycles. Treatment will continue for as long as there is adequate safety 
and potential for clinical benefit with the exception that pembrolizumab may be given for up to 
24 months to subjects without disease progression. After 6 cycles, CRS-207 will be administered 
every 6 weeks (Q6W); all other assigned treatments remain the same.  
Archived tumor tissue and paired tumor biopsies (collected at Screening and Cycle 2 Day 15) 
will be used to explore the association of programmed death receptor ligand-1 (PD-L1) 
expression, mesothelin expression, and tumor-infiltrating lymphocyte (TIL) characteristics with 
clinical responses. Tumor evaluation by radiographic imaging will be performed within 28 days 


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prior to treatment and every 9 weeks while on treatment and until disease progression. Peripheral 
blood will be collected to assess immune responses directed against L. monocytogenes, 
mesothelin, and other tumor-associated antigens. Circulating levels of Cancer antigen 125 (CA-
125) will be assessed at Screening and on Day 1 of each 3 week cycle while on treatment, and 
every 9 weeks thereafter until disease progression is confirmed. CRS-207 shedding and 
clearance will be assessed during Phase 1 and during the Safety Run-in of Phase 2 at US sites 
only. Urine, rectal swab, oral swab, and whole blood will be collected from subjects treated with 
CRS-207. Additional assessments will be performed if results are positive for CRS-207 at the 
Day 8 time point. 
An End-of-Treatment (EOT) Visit will be scheduled once treatment has been discontinued. 
Blood will be collected at EOT to assess clearance of CRS-207 and at 
 
. To eliminate any 
potentially residual CRS-207, subjects will be administered antibiotics at the EOT Visit; the 
antibiotic regimen should be completed prior to receiving any subsequent cancer-related therapy. 
An additional Safety Follow-up Visit will occur 30 days after the last dose of study drug. If the 
subject begins another anticancer therapy before the end of the 30-day period, the subject should 
complete all of the Safety Follow-up Visit assessments prior to commencing the new therapy.  
After the Safety Follow-up Visit, subjects will return to the clinic every 9 weeks for tumor 
evaluation and CA-125 until radiographic disease progression is confirmed, at which time 
subjects will be followed every 12 weeks by phone/email (if no recent medical charting 
available) to collect data on survival and any subsequent anti-cancer treatment that may have 
been administered. Follow-up will continue until death, withdrawal of consent, or the end of the 
study, whichever occurs first. At the conclusion of the study, all remaining subjects who have 
received at least 1 dose of study treatment will be offered enrollment in a long-term follow-up 
study and continue to be followed for survival. 
Additional guidelines specific to the Phase 1 and 2 portions of the study are provided below. 
Phase 1: Dose Evaluation, Assigned Arms 
The epacadostat dose will be evaluated based on a 3+3 design utilizing protocol defined DLT 
criteria: 
Cohort3 
0/3 subjects have 
DLT1 
1/3 subjects have 
DLT1 
<2/6 subjects have 
DLT1 
>2 in a cohort have 
DLT1,2 
Dose Cohort 1 4 
CRS-207 + 100 mg 
BID IDO 
Escalate to Dose 
Cohort 2 
Expand Dose 
Cohort 1 to 
6 subjects 
Escalate to Dose 
Cohort 2 
De-escalate to Dose 
Cohort -1 (CRS-207 
+ 50 mg BID IDO)3 
Dose Cohort 2 
CRS-207 + 300 mg 
BID IDO 
Expand cohort to 12 
subjects with paired 
biopsies 
Expand Dose 
Cohort 2 to 
6 subjects 
Expand cohort to 12 
subjects with paired 
biopsies 
Dose expand with 
100 mg BID IDO 
1. 
DLT period is 21 days after first dose of CRS-207. 
2. 
In the case that a cohort is closed to enrollment, subjects who are ongoing at that dose level without DLTs may continue 
treatment at the assigned dose level at the discretion of the Investigator. 
3. 
Evaluation of Dose Cohort -1 will enable the same 3+3 rules for dose cohort expansion or de-escalation to 25 mg (Dose 
Cohort -2). Evaluation of Dose Cohort -2 will enable the same 3+3 rules for dose cohort expansion. If Dose Cohort -2 is 
not tolerated, the Arm will be terminated. 
4. 
As an added safety measure, Dose Cohort 1 will have a staggered enrollment of no more than 1 new subject treated per 
week during the dose escalation phase. Thereafter, a decision to further stagger combination enrollment will be made by 
the Safety Review Committee (SRC) and will be based on emergent safety data. 
BID = twice daily; DLT = dose-limiting toxicity 


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A Safety Review Committee (SRC) will be convened for the study, consisting of the 
Investigators who enrolled subjects in the study, the Lead Investigator, Study Medical Monitor, 
and Sponsor representatives. Adverse events, DLTs and safety data for all subjects will be 
reviewed on an ongoing basis by the SRC. Dose escalation and reduction decisions, 
determination of the recommended dose for expansion, and R2PD will be made by the SRC.  
Additionally, up to 12 subjects will be enrolled in in the CRS-207 alone arm to assess the safety 
and tolerability of CRS-207 in subjects with platinum-resistant ovarian, fallopian or peritoneal 
cancer. 
Phase 2: Randomized, 2-stage 
Phase 2 will begin by assessing safety of the addition of pembrolizumab to CRS-207 and CRS-
207/epacadostat; pembrolizumab will be administered at the 200 mg fixed dose level (as 
approved in other cancer indications). Phase 2 will initiate after the RP2D of CRS-
207/epacadostat is determined in Phase 1 and approximately 12 subjects with paired biopsies 
have been dosed at that level.  
A Safety Run-in will be completed since there are no precedent data on the addition of 
pembrolizumab to the planned drug combinations. Treatment of the first 6 randomized subjects 
in each treatment arm will be staggered, with no more than 1 subject treated per week, per arm. 
Subjects will be monitored during the Safety Run-in Period [the first 21 days] using the protocol 
defined DLT criteria. In the event ≥2 subjects in up to 6 (per arm) experience DLTs, the SRC 
will convene to determine if subsequent subjects enrolled will require a different dose level (per 
dose reduction table), or if additional subjects should be enrolled at a specified dose level to 
further assess safety and tolerability. In the event >2 subjects in the next 6 subjects (per arm) 
treated experience DLTs, the SRC will reconvene to determine if the dose will be further 
modified for the remaining subjects to be enrolled. The SRC may convene at any time during the 
Safety Run-in Period to review and evaluate available safety data as warranted by emerging 
safety data.  
Safety Run-in Dose Levels and Dose Reduction Table 
Dose level 
pembrolizumab  
 
epacadostat 
CRS-207 
  
1 
200 mg 
300 mg BID 
1 × 109 CFU 
-1 
200 mg 
100 mg BID 
1 × 109 CFU 
-2 
Further dose reductions will be discussed and confirmed by the SRC 
based on emergent safety data. 
 
Phase 2 will utilize a 2-stage design. Subjects will be randomized 1:1 into 2 treatment arms. In 
the first stage, once the final dose is confirmed in the Safety Run-in, a total of 13 subjects will be 
randomized into each arm (total 26 subjects). If the phase 2 dose is modified, at least 13 subjects 
will be enrolled and treated at the final dose level in each arm. If the pre-specified objective 
response-rate (ORR) and progression-free survival (PFS) criteria for advancement in the 2-stage 


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design are met (≥1 response or median PFS ≥ 4.8 months) for an arm, an additional 14 subjects 
will be enrolled in that arm, for a potential total of 27 subjects per arm (up to 54 subjects total if 
both arms advance to stage 2). 
In the event that during the safety run in there are 2 DLTs in 6 patients in the CRS-
207/pembrolizumab arm but the CRS-207/pembrolizumab/epacadostat has 0 or 1 DLTs in 6 
patients using the same dose levels as in the 2 arm combination, the SRC will review the data 
and may allow enrollment of another 3 subjects in each run-in to better define the toxicities. 
DOSING, DOSAGE FORMS, AND ROUTE OF ADMINISTRATION: 
CRS-207, live, attenuated, double-deleted Listeria monocytogenes encoding human mesothelin 
(Lm ∆actA/∆inlB hMeso), is formulated as 1 × 109 CFU suspended in 
 
, filled into a single-use 2-mL glass vial with a gray butyl 
stopper and aluminum crimp seal with a flip off cap. 1.0 mL CRS-207 is diluted in sterile saline 
prior to IV infusion.  
Epacadostat, an indoleamine 2,3-dioxygenase (IDO) 1 inhibitor, is available as 25 mg and 100 mg 
tablets packaged in high-density polyethylene bottles. Epacadostat will be dispensed for 3-week 
cycles for the duration of the study. Tablets are taken at the assigned dose BID in the morning and 
evening, approximately 12 hours apart. 
Pembrolizumab, Pembrolizumab can be in liquid or lyophilized powder format in single-use vials. 
Refer to the package insert for dose preparation instructions.  
 
ADU-CL-11 Treatment Cycles by Arm 
 
Phase 
 
Arm 
Dose 1 / Route 
Treatment Cycle 
 
 
1 
CRS-207/ 
IDO 
CRS-207:  1 × 109 CFU by IV infusion 
over ~ 1 hour 
IDO:         100 mg or 300 mg BID Oral 
CRS-207:  Day 1 of each cycle (Cycles 1-
6); Q6W thereafter 
IDO:          BID starting Cycle 1 Day 2 
CRS-207 
CRS-207: 1 × 109 CFU by IV infusion 
over ~ 1 hour  
CRS-207:  Day 1 of each cycle (Cycles 1-
6); Q6W thereafter 
 
 
 
 
 
 
2 
CRS-207/ 
Pembro/ 
IDO 
Pembro:    200 mg by IV infusion over 
30 min 
CRS-207:  1 × 109 CFU by IV infusion 
over ~ 1 hour 
IDO:         300 mg Oral BID 1 
Pembro:    Day 1 of each cycle 
CRS-207:  Day 2 of each cycle (Cycles 1-
6); Q6W thereafter 
IDO:          BID starting Cycle 1 Day 3 
CRS-207/ 
Pembro 
Pembro:   200 mg by IV infusion over 
30 min 
CRS-207: 1 × 109 CFU by IV infusion 
over ~ 1 hour 
Pembro:    Day 1 of each cycle 
CRS-207:  Day 2 of each cycle (Cycles 1-
6); Q6W thereafter 
 
BID = twice daily; CFU = colony-forming units; IDO = epacadostat; IV = intravenous; pembro = pembrolizumab; Q6W = 
once every 6 weeks 
1 RP2D of epacadostat based on Phase 1 dose-evaluation parameters and determined by the SRC; the phase 2 
dose may be further adjusted during Phase 2 Safety Run-in 


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DOSE-LIMITING TOXICITY: 
During Phase 1, the DLT evaluation period is defined as Cycle 1 (21 days).  
During the Phase 2 Safety Run-in, the DLT evaluation period is defined as Cycle 1 (the first 21 
days).  
Non-Hematologic Events 
For non-hematological events, a DLT is defined as any treatment-emergent adverse event (TEAE) 
not attributable to disease or disease-related processes that occurs during the DLT observation 
period (Cycle 1) and is Grade 3 or higher according to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v4. 
In addition, any use of systemic steroids or a study drug dose interruption lasting more than 7 days 
for an adverse event with an unclear relationship to study drug will be considered a DLT even if 
the other DLT criteria are not fulfilled. 
The following non-hematological adverse events are NOT considered DLTs: 
• Grade 3 aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline 
phosphatase levels persisting for <7 days; 
• Grade 3 fatigue lasting <3 days; 
• Grade 3 nausea or vomiting that has resolved to ≤ Grade 2 within 48 hours with standard 
antiemetic therapies;  
• Grade 3 diarrhea that has resolved to ≤ Grade 2 within 48 hours with standard antidiarrheal 
therapies;  
• Grade 3 fever; 
• Grade 3 or 4 laboratory finding that is asymptomatic and rapidly reversible (returned to 
baseline or ≤ Grade 1 within 7 days) unless identified as clinically significant by the 
Investigator; 
• Any Grade 3 or lower change in cholesterol or triglycerides or asymptomatic change in lipid 
profile; and/or 
• Singular or non-fasting elevations in blood glucose (i.e. blood glucose excursions will be 
considered a DLTs if fasting blood glucose is elevated (Grade 3 or higher) on 2 separate 
occasions). 
Hematologic Events 
For hematologic events, a DLT is defined as follows: 
• Grade 4 neutropenia lasting >7 days; 
• Grade ≥3 febrile neutropenia; 
• Grade 4 anemia; 
• Grade 4 thrombocytopenia or ≥ Grade 3 thrombocytopenia lasting >7 days or associated with 
bleeding; and/or 
• Dose delay >7 days secondary to myelosuppression. 
Toxicities will be monitored throughout the study, and if the toxicity levels in any Arm are 
unacceptable (>33% of subjects), then dosing will be suspended until further review and 
consideration by the SRC. 


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INCLUSION AND EXCLUSION CRITERIA: 
Inclusion Criteria 
Individuals must meet all of the following requirements to be eligible to enroll in this study: 
1. Female, 18 years of age or older 
2. Histologically-confirmed disease 
For Phase 1: Individuals with epithelial ovarian cancer, fallopian tube carcinoma, or primary 
peritoneal carcinomas who are considered to have platinum-resistant disease (defined as 
progression within 6 months from completion of platinum-based chemotherapy). The date 
should be calculated from the last administered dose of platinum therapy. 
For Phase 2: Individuals with epithelial ovarian cancer, fallopian tube carcinoma, or primary 
peritoneal carcinomas who are considered to have platinum-resistant disease (defined as 
progression within 6 months from completion of a minimum of 4 platinum therapy cycles). 
The date should be calculated from the last administered dose of platinum therapy. 
3. Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1  
Phase 1 only:  Individuals who do not have measurable disease (according to RECIST v1.1) 
but have assessable disease according to the Gynecologic Cancer Intergroup (GCIG) CA-125 
criteria and require treatment, may be included if they meet all other criteria.  
4. Agree to provide core tissue biopsies at baseline and at Cycle 2 Day 15 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
6. Available archived tumor tissue for central analysis 
7. Adequate organ and marrow function, as defined by: 
• White blood cells ≥3000/µL 
• Absolute neutrophil count (ANC) ≥1500/µL 
• Absolute lymphocyte count ≥ 800/µL 
• Platelet count ≥100,000/µL 
• Serum albumin ≥3 g/dL 
• AST and ALT ≤2.5 × upper limit of normal (ULN) (<5 × ULN for subjects with liver 
metastases)  
• Total bilirubin < the institutional ULN or conjugated bilirubin ≤ 1.2 × ULN (need 
only be tested if total bilirubin exceeds ULN) or ≤ 3 × institutional ULN if due to 
Gilbert’s disease 
• Serum creatinine ≤1.5 × ULN or calculated creatinine clearance (CrCl) (estimated 
glomerular filtration rate [eGFR] can also be used in place of creatinine or CrCl) 
>50 mL/min for serum creatinine >1.5 × ULN  
• Hemoglobin ≥9 g/dL  
• International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN. 
Activated partial thromboplastin time (aPTT) ≤1.5 × ULN (unless receiving 


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anticoagulant therapy in which case values should be within therapeutic range of 
intended use) 
Any other Grade 3 or higher lab abnormalities should be discussed and approved by 
the Study Medical Monitor prior to enrollment (even if not considered clinically 
significant) 
8. Women of childbearing potential must agree to take appropriate precautions to avoid 
pregnancy, including the use of a medically acceptable method of highly effective 
contraception throughout the study and for 120 days after their final study drug 
administration. A barrier method of contraception must be employed regardless of other 
methods. Permitted methods that are at least 99% effective in preventing pregnancy 
should be communicated to the subject and their understanding confirmed. 
9. Functional gastrointestinal tract (defined as no enterocutaneous fistulas and no proximal 
stomas). Individuals with a venting gastrostomy tube must be able to tolerate clamping 
for 2 hours following oral drug administration. 
10. Provides informed consent and is willing and able to comply with all study procedures. 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study: 
1. Platinum-refractory disease (defined as progression during the first platinum-based 
chemotherapy)  
2. Major surgical procedure within 4 weeks prior to dosing 
3. Inaccessible tumors or for whom biopsy is contraindicated  
4. Clinically significant ascites 
5. Phase 2 only: Previous treatment with >3 chemotherapy regimens for locally advanced 
or metastatic disease 
• Repeat exposure to the same regimen separated in time by more than 3 months 
counts as 2 regimens 
• Regimens given as adjuvant therapy or as maintenance therapy after disease 
relapse are not included 
• Targeted agents will be included in the count  
• Bevacizumab will not count if administered as a single agent 
(There is no limit on the number of prior regimens for subjects entered into Phase 1) 
6. Active bowel obstruction, or hospitalization for bowel obstruction within 2 months prior 
to screening  
7. Requires parenteral nutrition or other agents aimed at improving performance status  
8. Hospitalization within 2 weeks prior to screening  
9. Received any anticancer medication or therapy in the 21 days prior to first dose of study 
drug or any unresolved toxicity > Grade 1 from previous anticancer therapy, except for 


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stable chronic toxicities that are not expected to resolve (i.e. peripheral neurotoxicity, 
alopecia, fatigue, etc.). Palliative radiotherapy is allowed if completed at least 2 weeks 
prior to first dose of study treatment. 
10. Prior monoclonal antibody treatment within 4 weeks before first dose of study drug, or 
not recovered (≤ Grade 1 or at baseline) from adverse events due to agents administered 
more than 4 weeks earlier 
11. History of listeriosis or previous treatment with a Listeria-based immunotherapy 
12. Known allergy to both penicillin and sulfa antibiotics  
13. Any immunodeficiency disease or immune-compromised state (e.g. use of 
immunosuppressive agents) or had systemic steroids, TNF pathway inhibitors, or PI3 
kinase inhibitors administered within 14 days prior to initiating study drug (use of 
inhaled or topical steroids or systemic corticosteroids <10 mg is permitted) 
14. Received prior immune checkpoint inhibitors (e.g. anti-CTLA-4, anti-PD-1, anti-PD-L1, 
and any other antibody or drug specifically targeting T cell costimulation) or an IDO 
inhibitor. Individuals who have received experimental vaccines or other 
immunotherapies must obtain approval from the Study Medical Monitor to confirm 
eligibility. 
15. Pregnant or breastfeeding; or intends to conceive a child from the start of screening 
through 120 days after the last dose of study drug 
16. Clinically significant heart disease (such as unstable angina, myocardial infarction 
within 6 months of study initiation, congestive heart failure, or New York Heart 
Association Class III or IV heart failure, or arrhythmia requiring therapy) 
17. Valvular heart disease that requires antibiotic prophylaxis for prevention of 
endocarditis, consistent with American Heart Association guidelines  
18. History of any autoimmune disease which required systemic therapy in the past 2 years 
including but not limited to: 
• Inflammatory bowel disease (including ulcerative colitis and Crohn’s Disease) 
• Rheumatoid arthritis 
• Systemic progressive sclerosis (scleroderma) 
• Systemic lupus erythematosus 
• Autoimmune vasculitis (e.g. Wegener’s granulomatosis) 
• Central nervous system or motor neuropathy considered of autoimmune origin 
(e.g. Guillain-Barre Syndrome, Myasthenia gravis, multiple sclerosis) 
Individuals with vitiligo, Sjogren’s Syndrome, interstitial cystitis, Graves’ or 
Hashimoto’s Disease, celiac disease, diabetes mellitus type 1, psoriasis, or 
hypothyroidism stable on hormone replacement will be allowed with Study Medical 
Monitor’s approval 
19. Diagnosed with another malignancy within the past 3 years (excluding a history of 
carcinoma in situ of the cervix, superficial non-melanoma skin cancer, superficial 
bladder cancer, or endometrial cancer that has been adequately treated) 


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20. Individuals with treated (surgically excised or irradiated) and stable brain metastases are 
eligible as long as the treatment was at least 4 weeks prior to initiation of study drug and 
baseline brain computed tomography (CT) with contrast or magnetic resonance imaging 
(MRI) within 2 weeks of initiation of study drug is negative for new brain metastases. 
Individuals with stable brain metastases must not require therapy with corticosteroids. 
21. History of interstitial lung disease  
22. Evidence of interstitial lung disease or active, noninfectious pneumonitis including 
symptomatic and/or pneumonitis requiring treatment.  
23. Active infection requiring systemic therapy 
24. History of organ transplant that requires use of immunosuppressive therapy 
25. Received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including G-CSF, GM-CSF or 
recombinant erythropoietin) within 4 weeks prior to first dose of study drug.  
26. Intercurrent illness that is either life-threatening or of clinical significance such that it 
might limit compliance with study requirements 
27. History of alcohol dependence or use of illicit drugs (e.g. opioids, cocaine, 
amphetamines, or hallucinogens) that could potentially interfere with adherence to study 
procedures or requirements 
28. Received a diagnosis of human immunodeficiency virus or human T-lymphotropic 
virus, or has a known history of, or is positive for, Hepatitis B (HBsAg reactive) or 
Hepatitis C (HCV RNA [qualitative] is detected) 
29. Received any prophylactic vaccine within 14 days of first dose of study drug or received 
a live vaccine within 30 days of first dose of study drug 
30. Has implanted medical devices that pose high risks for colonization and cannot be easily 
removed (e.g. artificial heart valves, pacemakers, prosthetic joints, orthopedic screw(s), 
metal plate(s)) if infection occurs. Other common devices such as venous access devices 
(e.g. Port-a-Cath or Mediport) may be permitted as well as arterial and venous stents 
and dental and breast implants that were placed more than 3 months prior to first dose of 
study drug. 
31. Known or suspected allergy or hypersensitivity to yeast or any other component of 
CRS-207 (e.g. glycerol); or known allergy or reaction to any component of epacadostat 
formulation; or any history of severe hypersensitivity reactions to pembrolizumab, its 
excipients or any monoclonal antibody therapy 
32. Currently receiving therapy with a UDP-glucuronosyltransferase 1A9 (UGT1A9) 
inhibitor including diclofenac, imipramine, ketoconazole, mefenamic acid, and 
probenecid. Individual may enter screening if therapy is able to be discontinued (a 7 
days washout period is required prior to first dose of epacadostat, or 5 half-lives have 
elapsed for the specific UGT1A9).  
33. Presence of a gastrointestinal condition that may affect drug absorption 


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34. Receiving monoamine oxidase inhibitors (MAOIs) or a drug which has significant 
MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before 
screening 
35. Any history of Serotonin Syndrome after receiving serotonergic drugs 
36. History or presence of an abnormal electrocardiogram (ECG) that, in the Investigator's 
opinion, is clinically meaningful. Screening QTcF interval >480 ms is excluded. In the 
event that a single QTcF is >480 ms, the subject may enroll if the average QTcF for the 
3 ECGs is <480 ms. For subjects with an intraventricular conduction delay (QRS 
interval >120 ms), the JTc interval may be used in place of the QTcF with Sponsor 
approval. The JTc must be <340 ms if JTc is used in place of the QTcF. Individuals with 
an intraventricular delay due to a left bundle branch block are excluded. 
Note: QTcF prolongation due to pacemaker may enroll if the JTc is normal. 
37. Uses more than 4 g/day of acetaminophen 
38. Has an unhealed surgical wound 
39. Insufficient peripheral venous access to permit completion of the study dosing and 
compliance with study phlebotomy regimen 
40. Participated in any other study in which receipt of an investigational new drug occurred 
within 28 days of first dose of study drug  
41. Unwilling or unable to follow the study schedule for any reason 
Dose Eligibility 
CRS-207 
Subjects must have adequate organ function as defined by the laboratory values in the table 
below prior to each dosing cycle where CRS-207 is administered. The Study Medical Monitor 
will be notified of any dose delays due to safety concerns (eg if the subject is recovering from an 
AE or pembrolizumab infusion reaction) and to discuss a plan to resume treatment. If a dose is 
delayed beyond 7 days post pembrolizumab infusion, the dose of CRS-207 should be withheld 
until the next Cycle. If a dose is delayed more than 2 weeks, contact the Study Medical Monitor 
for further instruction on continued dosing. 
The dosing eligibility requirements for CRS-207 are as follows: 
Hematologic 
Renal 
Hepatic 
WBC ≥3000/µL 
ANC ≥1000/µL 
Platelets ≥100,000/µL 
Hemoglobin ≥8 g/dL 
Creatinine ≤1.5 × ULN  
AST/ALT ≤5 × ULN 
Bilirubin ≤ 1.5× ULN OR ≤ 3 × 
ULN if due to Gilbert’s disease 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; ULN = upper limit of 
normal; WBC = white blood cell 
Epacadostat & Pembrolizumab 
If the subject meets eligibility criteria for the study and is assigned or randomized to receive 
epacadostat BID and/or pembrolizumab, dosing may initiate and should continue per protocol. 
The Study Medical Monitor will be notified of any dose interruptions due to safety concerns 
(Section 5.4.1). 


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Pembrolizumab dosing may be delayed up to 2 weeks, after which time it will be considered 
missed and the subject would continue onto the next scheduled dose. If a dose is delayed more 
than 2 weeks, contact the Sponsor Medical Monitor for further instruction on continued dosing. 
Subject Discontinuation 
A subject may be removed from treatment for any of the following reasons: 
• Occurrence of an adverse event that presents an unacceptable consequence or risk to the 
subject 
• Subject has received treatment, and there is no longer potential for clinical benefit 
(treatment should continue beyond initial progression of disease if there is potential for 
clinical benefit) 
• Noncompliance (failure to receive clinical study medication or treatment as mandated by 
the protocol, or failure to comply with protocol requirements)  
• A subject becoming pregnant while on study drug 
• Consent is withdrawn by the subject or legal representative 
• Study is discontinued by the Sponsor 
Subjects may withdraw consent or discontinue from the study at any time for any reason. Every 
effort will be made to follow all subjects for PD and survival. 
DURATION OF SUBJECT PARTICIPATION: 
The Screening Period may last up to 28 days. Treatment will continue as long as there is 
potential for clinical benefit except that pembrolizumab may be administered up to a maximum 
of 24 months. 
 
. Subjects will be observed for survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. At the conclusion of the study, all 
remaining subjects who have received at least 1 dose of study treatment will be offered 
enrollment in a long-term observational study and continue to be followed for survival. 
EFFICACY ASSESSMENTS:  
• Tumor evaluation by radiographic imaging 
o CT with contrast or MRI in case of contrast dye allergy  
o Tumor response assessed using RECIST v1.1, modified Response Evaluation 
Criteria in Solid Tumors (mRECIST), and GCIG CA-125 criteria 
• Circulating CA-125 tumor biomarker levels 
• Survival (vital status) 
• Pharmacokinetics and pharmacodynamics 
• Immunological and tumor biomarker analysis on tumor biopsies, peripheral blood 
mononuclear cells, plasma, and serum 


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o Number of tumor infiltrating lymphocytes and ratio of CD8 to regulatory 
T lymphocytes (FoxP3) 
o PD-L1 and mesothelin expression along with additional markers may be 
evaluated to explore the relationship to clinical response.  
SAFETY ASSESSMENTS: 
Safety parameters include serious adverse events, TEAEs, ECOG performance status, vital sign 
measurements, standard clinical laboratory parameters (serum chemistry, hematology, endocrine 
function, coagulation parameters, pregnancy testing and urinalysis), physical exam findings, and 
ECG parameters. Shedding (urine, oral swab, and rectal swab) and clearance (blood) of CRS-
207 will also be monitored. 
 
. Adverse events will be graded according 
to the NCI CTCAE v4. 
STATISTICAL ANALYSES: 
During Phase 1, dose escalation will be based on traditional escalation guidelines (3+3) to 
determine the RP2D and evaluate safety data (including DLTs and adverse events) of each 
planned treatment.  
Phase 2 will be an open-label, randomized study design conducted in 2 stages to achieve up to 
27 treated subjects per Arm. After 13 subjects in an Arm are randomized at the confirmed dose 
following the Safety Run-in (stage 1), an additional 14 subjects will be enrolled in that Arm 
(stage 2) if 1 or more subjects respond or if the median PFS is at least 4.8 months. If the criteria 
for either ORR or PFS are not met, the preliminary anti-tumor activity in the Arm will be 
rejected and no further subjects will be randomized to the Arm. If the Arm goes on to stage 2, a 
total of 27 treated subjects will be studied in that Arm. The Arm will be considered successful if 
4 or more subjects respond or the median PFS is at least 4.8 months. If the criteria for either 
ORR or PFS are not met, the Arm will be rejected. This design is applied to each Arm 
independently. There are no formal comparisons planned between Arms. This is an exploratory 
study of each Arm where the sample size and ORR and PFS criteria for each stage are based on 
clinical judgement. The ORR criteria and number of subjects for each stage are based on a 
Simon minimax 2-stage design (null hypothesis that ORR ≤5% versus the alternative that ORR ≥ 
20% with alpha = 0.05 and power = 0.80). The PFS criteria are based on the lower limit of the 
95% CI based on a meta-analysis in the 3rd relapse patient population where the median PFS is 
5.6 months, (95% CI: 4.8 to 6.2 months) (Hanker, 2012). 
Descriptive statistics will be provided for selected demographic, safety, pharmacokinetic, and 
immunogenicity data by dose and time as appropriate. Descriptive statistics on continuous data 
will include means, medians, standard deviations, and ranges, while categorical data will be 
summarized using frequency counts and percentages. Graphical summaries of the data may be 
presented. Response will be assessed using RECIST v1.1, mRECIST, and GCIG CA-125. PFS 
will be assessed using mRECIST, RECIST v1.1, and GCIG CA-125. OS will also be analyzed 
using Kaplan-Meier methods. 
 
 


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Table 1 
SCHEDULE OF EVENTS: Phase 2 ONLY (Phase 1 Schedule of Events in Appendix F) 
Study Phase 
Screen
ing  
Treatment Period 1 
Follow-up Period 
Screen
ing 
 
 
Cycle 1  
 
 
 
 
Cycle 2  
 
 
Cycle 3 and 
4  
Cycles 5 and Beyond 
EOT 2 
Safety 
Follow-
up3 
Survival 
Follow-
up  
Odd 
Numbere
d Cycles 
(5, 7, etc.) 
Even 
Numbere
d Cycles 
(6, 8, etc.) 
Study Day 
-28 to 
-1 
1 
2 
3 
8 
15 
1 
2 
3 
8 
15 
1 
2 
8 
1 
2 
1 
2 
ASAP 
After 
Last 
Dose 
30 Days 
After 
Last 
Dose 
Every 
12 
Weeks 
Visit Window (Days) 
- 
- 
- 
- 
±1 
±1 
±
3 
- 
 
±
1 
±1 
±
3 
 
±1 
±3 
- 
±3 
- 
 
+5 
±7 
Study Procedures 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs, Height, Weight 
5 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
Physical Examination 6 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
X 
X 
 
 
 
X 
X 
 
 
X 
 
X 
 
 
X 
 
Electrocardiogram 7 
X 
X 
X 
 
 
X 7 
X 
X 
 
 
 
X  
X 
 
X 
X 
 
 
 
X  
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior and Concomitant 
Medications and Therapies 8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival and Additional 
Cancer Treatment Status 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory/Sample Collection 
Virology Screen 10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CD4 Count 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 11 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
Clinical Hematology, Serum 
Chemistry, Liver Function 12 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Coagulation Panel 13 
X 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
CA-125 Assessment 14 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 9 
HLA-Typing 16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Phase 
Screen
ing  
Treatment Period 1 
Follow-up Period 
Screen
ing 
 
 
Cycle 1  
 
 
 
 
Cycle 2  
 
 
Cycle 3 and 
4  
Cycles 5 and Beyond 
EOT 2 
Safety 
Follow-
up3 
Survival 
Follow-
up  
Odd 
Numbere
d Cycles 
(5, 7, etc.) 
Even 
Numbere
d Cycles 
(6, 8, etc.) 
Study Day 
-28 to 
-1 
1 
2 
3 
8 
15 
1 
2 
3 
8 
15 
1 
2 
8 
1 
2 
1 
2 
ASAP 
After 
Last 
Dose 
30 Days 
After 
Last 
Dose 
Every 
12 
Weeks 
Visit Window (Days) 
- 
- 
- 
- 
±1 
±1 
±
3 
- 
 
±
1 
±1 
±
3 
 
±1 
±3 
- 
±3 
- 
 
+5 
±7 
Endocrine/Thyroid Testing 
17 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Plasma for epacadostat PK 
19/PD 30 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for epacadostat 
epigenetics 29 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood for PBMC 18 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
 
Serum/Plasma for Immune 
Monitoring 15 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
Shedding and Clearance 20 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsy 21 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Archived Tumor Specimen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Evaluation 22 
X 
Every 9 weeks (± 7 days) 
 
X 
X  
Blood for CRS-207 
Surveillance 28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Investigational Product Administration 
Pembrolizumab 27 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
CRS-207 23 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
23 
 
X 
 
 
 
Epacadostat 24 
 
 
 
X 
 BID  
 
 
 
Epacadostat Compliance & 
Accountability 25 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Other Concomitant Medication 
Antibiotics 26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 


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Footnotes 
1. 
Treatment will continue for as long as there is potential for clinical benefit except that pembrolizumab will continue for a maximum of 24 months. At Cycle 5 and beyond, 
additional clinic visits between administrations of pembrolizumab and CRS-207 will be conducted based on Investigator’s discretion and clinical indication.  
2. 
EOT Visit will occur as soon as determined that the subject will permanently discontinue study treatment, and at least 7 days after the last dose of CRS-207. If the EOT visit 
coincides with a regular study visit, the EOT evaluations will supersede those of that scheduled visit, and the data should be entered in the EOT page in the eCRF. If the EOT 
Visit occurs >21 days after the last administration of study drug, procedures from the EOT and Safety Follow-up visits may be collected as a single Safety Follow-up Visit.  
3. 
Safety Follow-up Visit will be scheduled 30 days (+5 days) post last dose of study treatment. If the subject begins another anticancer therapy before the Safety Follow-up 
Visit, every effort will be made to complete all of the Safety Follow-up Visit assessments prior to commencing the new therapy. If there is an adverse event in need of 
monitoring beyond the Safety Follow-up Visit, the subject will be followed until resolution or confirmed stability of the adverse event. If a CT scan was collected within 
9 weeks (±7 days) of the Safety Follow-up Visit, then a CT scan at the Safety Follow-up Visit will not be mandatory. 
4. 
Randomization: An IRT system will be used for randomization. Randomization may be done up to 3 days prior to Day 1. During the Safety run-in, enrollment will be 
staggered with no more than 1 new subject treated per week, per treatment arm. Thereafter, a decision to further stagger combination enrollment will be made by the SRC and 
will be based on emergent safety data. 
5. 
Vital signs: measurements consist of seated BP, pulse, respiratory rate, and temperature. Pulse oximetry will be measured if clinically indicated. Weight will be taken on Day 
1 of each cycle. Height is required at screening only. During CRS-207 infusion, vital signs will be obtained pre-infusion (- 5 minutes), then every 30 minutes (+/- 5 minutes) 
during infusion and every hour (+/- 5 minutes) during post-infusion follow-up. During pembrolizumab infusion, obtain vital signs prior to (-5 minutes) and immediately 
following (+ 5 minutes) each infusion. 
6. 
Physical examinations: A complete physical exam will be conducted at screening and Safety Follow-up Visits; symptom-directed physical examinations will be conducted 
on Day 1 of all other cycles and at the EOT visit. Physical exams may be conducted up to 3 days before dosing with CRS-207.  
7. 
Electrocardiogram: Perform routine 12-lead ECGs with the subject in recumbent or semi-recumbent position after 5 minutes rest prior to each CRS-207 and pembrolizumab 
infusion, immediately after the infusion, and at 1-hour post infusion. If abnormal at 1-hour post-infusion, repeat until baseline achieved. After Cycle 7 frequency may be 
reduced to every 12 weeks unless clinically indicated. In order not to confound interpretation of the ECG, if anti-emetics or other prophylactic agents are given then these 
should be given after the pre-dose ECG rather than before. Obtain ECG [heart rate, PR interval, QT interval, QRS duration, QTcF (Fridericia's correction) in triplicate 
(collected within approximately a 5-minute window). For subjects randomized to receive epacadostat serial ECGs will be collected pre-dose and approximately 60 to 90 
minutes after the first dose of epacadostat. Additional ECGs may be performed if clinically indicated and at the Safety Follow-up Visit.  
8. 
Concomitant medications and cancer-related therapies and procedures will be recorded within 28 days before study treatment begins and 30 days after the last dose of study 
drug, or until the subject completes the Safety Follow-up Visit. In addition, all prior and post-study treatment anticancer therapy will be recorded in the eCRFs. 
9. 
Survival Status: Once a subject has radiographic confirmed PD, discontinues study treatment or starts a new anticancer therapy, the subject moves into the Survival Follow-
up phase. Subject will be contacted every 12 weeks (by phone/email is permissible if no recent (with 14 days) medical charting is available) to collect data on survival and any 
additional cancer-related therapies that may have been administered. Follow-up will continue until death, withdrawal of consent, or the end of the study, whichever occurs 
first. 
10. Virology screen will include HIV antibody, hepatitis B (HBsAg), and hepatitis C (HCV-RNA, Qualitative). Virology screen will be performed by the site’s local laboratory. 
11. Pregnancy test is required for women of child bearing potential. Pregnancy testing will be performed by the site’s local laboratory. 
12. Safety Labs: Refer to Appendix A for complete list of clinical hematology, chemistry analytes. Day 1 blood draws may be taken up to 3 days before dosing with 
pembrolizumab and then again after the pembrolizumab infusion and before the infusion with CRS-207; additional time points may be obtained if clinically indicated. To 
avoid inadvertent contamination of a central line (e.g. infusion ports, PICC lines), blood draws MUST NOT be collected from a central line for at least 4 days after 
infusion of CRS-207 has started. If LFTs are found to be abnormal (>Grade 2), frequency of monitoring should be increased to once per week until LFTs have resolved to 
baseline at which time chemistry test monitoring will be performed according to institutional standards or approximately weekly, whichever is shorter. Liver function does not 
need to be monitored once per week indefinitely for persistent low-grade abnormalities. Appropriate liver function monitoring intervals should be discussed with the Study 
Medical Monitor. Hematology, chemistry and liver panel will be performed by the site’s local laboratory. 
13. Coagulation panel will include the following: D-dimer, fibrinogen, INR of PT, and aPTT; and will be collected pre-CRS-207 dose and one day post CRS-207 dose. INR 
should be monitored weekly for the first 4 weeks after initiation of coumarin-based anticoagulants (see Section 5.6.2 for anticoagulant restrictions) and upon discontinuation 
of epacadostat. Coagulation testing will be performed by the site’s local laboratory. Additional tests should be performed as clinically indicated  


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Amendment 3, 18 Feb 2017 
14. CA-125 will be assessed at screening as close to but no more than 14 days before the first study treatment, then on Day 1 of each cycle while on treatment (or every 3 weeks 
if subject dosing is delayed). Subjects who discontinue treatment for reasons other than PD should continue to have CA-125 assessed every 9 weeks until the start of a new 
anticancer therapy, documented PD, death, or the end of the study, whichever occurs first. Additional CA-125 time points collected per institutional standard should also be 
entered into the eCRF. Subjects considered CA-125 evaluable should have CA-125 repeated no earlier than 28 days if a CA-125 is reduced by 50% from baseline. See 
Appendix C for more details. 
15. Immune Monitoring: Whole blood for immune monitoring will be drawn and processed into serum and plasma. Refer to the Laboratory Manual for collection and 
processing instructions. Samples will be sent to the central laboratory. 
16. HLA-typing: should include type A and B of class I antigens, low resolution. HLA will be performed by the site’s local laboratory. 
17. Thyroid panel: collected at Screening, Cycle 1 Day 1, then on Day 1 of odd numbered Cycles only (Cycle 3, Cycle 5, Cycle 7, etc.) and will include: triiodothyronine (T3) or 
free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH); additional thyroid function testing may be performed if clinically indicated. Blood 
draws may be taken up to 3 days before pembrolizumab infusion. Additional endocrine testing for subjects receiving epacadostat: collected at Screening, Cycle 1 Day 1, 
Cycle 3 Day 1 and then every 12 weeks thereafter (on Day 1 of Cycle 7, Cycle 11, Cycle 15, etc.) will include: adrenocorticotropic hormone, serum cortisol (taken between 8-
9 AM), luteinizing hormone and prolactin.  
18. Whole Blood for PBMC: Approximately 70 mL of whole blood to be processed as described in the Laboratory Manual. PBMCs will be drawn at the following timepoints: 
Day 1 and Day 8 of Cycle 1, Cycle 2, Cycle 4, then Day 1 of Cycle 5, Cycle 7 and at the EOT visit. 
19. Epacadostat PK sample: (3.5 mL) plasma for epacadostat will be taken pre epacadostat-dose on Cycle 2 Day 1. Epacadostat will be administered in clinic on Cycle 2 Day 1 
in order to collect pre-dose blood sample for PK.  
20. Shedding/clearance: For subjects in the Safety Run-in at US sites only: urine, rectal swab, oral swab, and whole blood will be collected pre-CRS-207 dose, and at 6 hours, 18 
to 24 hours, and Day 7 post-CRS-207 infusion end time on Cycle 1 and Cycle 2. DO NOT use the central line for blood sample collection. Additional assessments will be 
performed if results are positive for CRS-207 at the Day 7 time point. Samples will be sent to IHMA Central Laboratory. 
21. Tumor biopsies: will be collected during the screening period (pre-first dose) and on Cycle 2 Day 15 (+7 days). Fine needle aspiration will not be acceptable. Samples will be 
sent to the Central Laboratory. Tumor biopsy should NOT be performed on the same day as CRS-207 or pembrolizumab administration. If additional biopsies are performed 
by Investigator for standard of care during the course of study, a sample should be retained for Sponsor research evaluation. 
22. Tumor evaluations: will be performed using CT with contrast of the abdomen and pelvis (or MRI in case of contrast dye allergy) within 28 days prior to treatment, and 
repeated every 9 weeks (±7 days) after initiation of study drug using the same assessment technique. Subjects who discontinue treatment for reasons other than PD should 
continue to have their disease assessed by CT every 9 weeks (±7 days) until the start of a new anticancer therapy, documented PD, death, withdrawal of consent, or the end of 
study, whichever occurs first. Data from any standard of care CT scans may also be collected for tumor evaluation. 
23. CRS-207: will be administered on Day 2 of each cycle via IV infusion over approximately 1 hour (no in-line IV filter should be used). After Cycle 6, CRS-207 will be 
administered every six weeks, at even numbered visits (Cycle 8, Cycle 10, etc.) Study Medical Monitor must be notified for dose delays as noted in Section 4.3.1. Before each 
CRS-207 infusion, subjects will be pre-medicated with acetaminophen and saline will be given immediately before and after infusion with CRS-207 (Section 5.5.2.1). 
Subjects will be observed for at least 4 hours after each infusion. Subjects who are not stable enough to be released at 4 hours after infusion should continue to be monitored 
until stable. Presence of fever alone does not indicate subject is not clinically stable. Document the time subject becomes stable in the medical records. To avoid inadvertent 
contamination of a central line (e.g. infusion ports, PICC lines), DO NOT administer CRS-207 or saline through a central line during infusion or for 4 days 
following infusion. DO NOT flush the central line for any reason during and for 4 days after CRS-207 infusion.  
24. Epacadostat: Epacadostat will be administered orally starting on Day 3 and BID thereafter. Tablets will be taken at the assigned dose in the morning and evening, 
approximately 12 hours apart. Epacadostat will be administered in clinic on Cycle 2 Day 1 and Day 2 in order to collect pre-dose blood sample for PK. Epacadostat dosing 
does not apply to CRS-207/pembro arm. 
25. Epacadostat Diary: At each visit, provide a dosing diary and instructions on recording each dose of epacadostat. Collect unused epacadostat and review competed dosing 
diary with subject at following visit.  
26. Antibiotics: A 7-day course of antibiotics will be administered at the EOT visit AFTER blood has been collected for CRS-207 culture to ensure clearance of CRS-207. 
Antibiotic regimen must be completed prior to initiation of any other cancer-related therapy. Subjects with a central line port will receive 1 dose of IV antibiotics followed by 
6 days of oral antibiotics; all other subjects will receive 7 days of oral antibiotics (refer to Section 5.6.3). Site personal will contact the subject by to confirm compliance with 
the antibiotic treatment and document in source and CRFs.  
27. Pembrolizumab: will be administered on Day 1 of each cycle via IV infusion over 30 minutes (-5/+10 minutes).  


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28. CRS-207 surveillance: At EOT, blood for culture will be collected prior to initiation of antibiotics (if applicable, blood must also be collected through the central line port) to 
assess CRS-207 clearance. After EOT, blood for culture will be collected for CRS-207 surveillance at 
 
 
.  
29. Epacadostat epigenetics: A baseline whole blood sample for epigenetics (to characterize cell populations at baseline) will be collected prior to subject’s first dose of 
epacadostat for subjects randomized to receive epacadostat. 
30. Epacadostat pharmacodynamics: the PD sample for kynurenine/tryptophan determination should be collected pre-epacadostat dose, fasted overnight (at least 8 hours) on 
Cycle 1 Day 1 and Cycle 2 Day 1 only for subjects randomized to receive epacadostat.


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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2 
INVESTIGATOR AGREEMENT.................................................................................................. 3 
SYNOPSIS ...................................................................................................................................... 4 
LIST OF TABLES ........................................................................................................................ 28 
LIST OF FIGURES ...................................................................................................................... 28 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 29 
1 
INTRODUCTION AND BACKGROUND INFORMATION ........................................ 32 
1.1 
Background ................................................................................................................. 32 
1.1.1 Immune Resistance in Cancers ............................................................................. 33 
1.1.2 CRS-207 ................................................................................................................ 33 
1.1.3 Epacadostat ........................................................................................................... 35 
1.2 
Rationale for CRS-207, Epacadostat, and Pembrolizumab Immunotherapy in 
Advanced Ovarian Cancers......................................................................................... 39 
1.3 
Potential Risks and Benefits of the Treatment Regimen ............................................ 40 
1.3.1 CRS-207 ................................................................................................................ 40 
1.3.2 Pembrolizumab ..................................................................................................... 41 
1.3.3 Epacadostat ........................................................................................................... 41 
1.3.4 CRS-207 and Pembrolizumab, and Epacadostat Regimens ................................. 42 
2 
STUDY OBJECTIVES ..................................................................................................... 44 
2.1 
Phase 1: Dose Evaluation, Assigned Arms ................................................................. 44 
2.2 
Phase 2: Randomized, 2-stage .................................................................................... 45 
3 
STUDY DESIGN.............................................................................................................. 46 
3.1 
Phase 1:  Dose Evaluation, Assigned Arms ................................................................ 48 
3.2 
Phase 2:  Randomized, 2-Stage ................................................................................... 48 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS .................................................... 50 
4.1 
Inclusion Criteria ........................................................................................................ 50 
4.2 
Exclusion Criteria ....................................................................................................... 51 
4.3 
Dose Eligibility ........................................................................................................... 54 
4.3.1 CRS-207 ................................................................................................................ 54 
4.3.2 Epacadostat and Pembrolizumab .......................................................................... 55 
4.4 
Subject Discontinuation .............................................................................................. 55 


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5 
STUDY TREATMENTS .................................................................................................. 56 
5.1 
Treatment Arms .......................................................................................................... 56 
5.2 
Treatment Assignment ................................................................................................ 56 
5.3 
Dose Limiting Toxicities ............................................................................................ 56 
5.3.1 Non-Hematologic Events ...................................................................................... 57 
5.3.2 Hematologic Events .............................................................................................. 57 
5.4 
Other Adverse Event Considerations .......................................................................... 58 
5.4.1 Dose Interruption, Modification, and Management of Events Associated with 
Study Treatments .................................................................................................. 58 
5.4.2 Criteria and Procedures for Dose Modification .................................................... 58 
5.4.3 Immune-related Adverse Events ........................................................................... 61 
5.4.4 Management of Infusion Reactions Associated with Pembrolizumab ................. 66 
5.4.5 Supportive Care .................................................................................................... 66 
5.4.6 Procedures for Subjects Exhibiting Serotonin Syndrome ..................................... 67 
5.5 
Drug Supplies.............................................................................................................. 67 
5.5.1 Formulation, Packaging, Preparation, and Dispensing ......................................... 67 
5.5.2 Study Drug Administration ................................................................................... 69 
5.5.3 Treatment Compliance .......................................................................................... 70 
5.5.4 Investigational Product Storage ............................................................................ 71 
5.5.5 Investigational Product Accountability ................................................................. 71 
5.6 
Prior and Concomitant Medications and/or Procedures ............................................. 72 
5.6.1 Permitted Medications and/or Procedures ............................................................ 72 
5.6.2 Restricted Medications and/or Procedures ............................................................ 73 
5.6.3 Antibiotic Administration ..................................................................................... 74 
5.6.4 Documentation of Prior and Concomitant Medication and Therapy Use ............. 76 
6 
STUDY ASSESSMENTS ................................................................................................ 77 
6.1 
Screening Period ......................................................................................................... 77 
6.2 
Treatment Period ......................................................................................................... 77 
6.3 
End-of-Treatment Visit (EOT) ................................................................................... 78 
6.4 
Safety Follow-up Visit ................................................................................................ 78 
6.5 
Disease Follow-up ...................................................................................................... 78 
6.6 
Survival Follow-up and CRS-207 Surveillance .......................................................... 78 
6.7 
Unscheduled Visit ....................................................................................................... 79 


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7 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ................................. 80 
7.1 
Study Enrollment ........................................................................................................ 80 
7.2 
Demographics and Medical History ........................................................................... 80 
7.3 
Distribution of Subject Dosing Diary and Reminder Cards ....................................... 80 
7.4 
Blood Cultures for CRS-207 Surveillance .................................................................. 80 
7.5 
Tumor Biopsy ............................................................................................................. 81 
7.6 
Exploratory Laboratory Evaluations ........................................................................... 81 
7.6.1 Immune Monitoring, Pharmacokinetic, and Pharmacodynamic Assessments ..... 81 
7.6.2 Unused Research Samples .................................................................................... 82 
8 
EFFICACY ASSESSMENTS .......................................................................................... 83 
8.1 
Tumor Imaging and Assessment ................................................................................. 83 
8.1.1 Initial Tumor Imaging ........................................................................................... 83 
8.1.2 Tumor Imaging During the Study ......................................................................... 83 
8.1.3 Tumor Response ................................................................................................... 84 
8.2 
Tumor Biomarker CA-125 .......................................................................................... 85 
8.3 
Pharmacokinetics, Pharmacodynamics, and Tumor Biomarker Analysis .................. 85 
9 
SAFETY ASSESSMENTS ............................................................................................... 86 
9.1 
Adverse Events ........................................................................................................... 86 
9.1.1 Assessment of Adverse Events by the Investigator .............................................. 87 
9.1.2 Adverse Events of Special Interest ....................................................................... 88 
9.2 
Serious Adverse Events .............................................................................................. 88 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators.............................. 89 
9.4 
Pregnancy Reporting ................................................................................................... 90 
9.5 
Expedited Reporting ................................................................................................... 90 
9.6 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor ....................................................................................................................... 91 
9.7 
Clinical Laboratory Evaluations ................................................................................. 91 
9.7.1 Chemistry and Hematology .................................................................................. 91 
9.7.2 Liver Function Tests ............................................................................................. 91 
9.7.3 Urinalysis .............................................................................................................. 92 
9.7.4 Coagulation ........................................................................................................... 92 
9.7.5 Endocrine and Thyroid Function Testing ............................................................. 92 
9.7.6 Pregnancy Testing ................................................................................................. 92 


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9.7.7 Additional Laboratory Assessments ..................................................................... 92 
9.7.8 Shedding and Clearance of CRS-207 ................................................................... 92 
9.7.9 Blood Cultures for CRS-207 Surveillance ............................................................ 93 
9.8 
Vital Signs, Weight, and Height ................................................................................. 93 
9.9 
Physical Examinations ................................................................................................ 93 
9.9.1 Comprehensive Physical Examination ................................................................. 93 
9.9.2 Symptom-Directed Physical Examination ............................................................ 93 
9.10 
ECOG Performance Status ......................................................................................... 93 
9.11 
Electrocardiograms ..................................................................................................... 93 
10 
STATISTICS .................................................................................................................... 95 
10.1 
Analysis Populations ................................................................................................... 95 
10.2 
Statistical Methods ...................................................................................................... 95 
10.2.1 Analysis of Efficacy .............................................................................................. 95 
10.2.2 Analysis of Safety ................................................................................................. 97 
10.2.3 Interim Analysis .................................................................................................... 97 
10.2.4 Sample Size Determination................................................................................... 97 
11 
DATA MANAGEMENT AND RECORD KEEPING..................................................... 99 
11.1 
Data Management ....................................................................................................... 99 
11.1.1 Data Handling ....................................................................................................... 99 
11.1.2 Computer Systems ................................................................................................ 99 
11.1.3 Data Entry ............................................................................................................. 99 
11.1.4 Medical Information Coding................................................................................. 99 
11.1.5 Data Validation ..................................................................................................... 99 
11.2 
Record Keeping ........................................................................................................ 100 
12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ........................... 101 
12.1 
Ethical Conduct of the Study .................................................................................... 101 
12.2 
Institutional Review Board and Institutional Biosafety Committee ......................... 101 
12.3 
Informed Consent...................................................................................................... 101 
12.4 
Study Monitoring Requirements ............................................................................... 101 
12.5 
Disclosure of Data..................................................................................................... 102 
12.6 
Retention of Records................................................................................................. 102 
12.7 
Publication Policy ..................................................................................................... 102 


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12.8 
Financial Disclosure.................................................................................................. 103 
13 
STUDY ADMINISTRATIVE INFORMATION ........................................................... 104 
13.1 
Protocol Amendments ............................................................................................... 104 
13.2 
Address List .............................................................................................................. 104 
13.2.1 Sponsor ............................................................................................................... 104 
13.2.2 Contract Research Organization ......................................................................... 104 
13.2.3 Drug Safety ......................................................................................................... 104 
13.2.4 Biological Specimens.......................................................................................... 104 
14 
REFERENCES ............................................................................................................... 105 
APPENDIX A: 
CLINICAL LABORATORY ANALYTES .................................................. 109 
APPENDIX B: 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS VERSION 1.1 
QUICK REFERENCE .................................................................................................... 110 
APPENDIX C: 
GYNECOLOGICAL CANCER INTERGROUP DEFINITIONS FOR 
RESPONSE AND PROGRESSION BASED ON CA-125 QUICK REFERENCE ...... 112 
APPENDIX D: 
PROHIBITED MONOAMINE OXIDASE INHIBITORS AND DRUGS 
ASSOCIATED WITH SIGNIFICANT MONOAMINE OXIDASE INHIBITORY 
ACTIVITY ...................................................................................................................... 121 
APPENDIX E: 
INFORMATION REGARDING EFFECTIVENESS OF CONTRACEPTIVE 
METHODS ..................................................................................................................... 122 
APPENDIX F: 
SCHEDULE OF EVENTS (PHASE 1 ONLY) ............................................ 123 
 
 
 


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LIST OF TABLES 
Table 1 
SCHEDULE OF EVENTS: Phase 2 ONLY (Phase 1 Schedule of Events in  
Appendix F) ................................................................................................................ 18 
Table 2 
Phase 1 Dose Evaluation Plan..................................................................................... 48 
Table 3 
Safety Run-in Dose Levels and Dose Reduction ........................................................ 49 
Table 4 
Dosing Eligibility Requirements for CRS-207 ........................................................... 54 
Table 5 
ADU-CL-11 Treatment Cycles by Arm ..................................................................... 56 
Table 6 
Dose Modification Guidance for Epacadostat ............................................................ 59 
Table 7 
Pembrolizumab Dose Modification Guidelines for Drug-Related Adverse Events ... 61 
Table 8 
General Guidelines for Immune-Related Adverse Events Due to Epacadostat .......... 65 
Table 9 
Pembrolizumab Infusion Reaction Treatment Guidelines .......................................... 66 
Table 10 Signs and Symptoms of Serotonin Syndrome ............................................................ 67 
Table 11 Warfarin Dose Modifications ..................................................................................... 74 
Table 12 Imaging and Treatment After First Radiologic Evidence of Progressive Disease ..... 84 
 
LIST OF FIGURES 
Figure 1 
 Study Schematic......................................................................................................... 46 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ActA 
Actin assembly-inducing protein A 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
APC 
Antigen presenting cells 
aPTT 
Activated partial thromboplastin time 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
BP 
Blood pressure 
CA-125 
Cancer antigen 125 
CFU 
Colony-forming units 
CI 
Confidence interval 
Cmax 
Plasma concentrations attained the peak values 
CR 
Complete response 
CrCl 
Creatinine clearance 
CRA 
Clinical Research Associate 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DC 
Dendritic cell 
DILI 
Drug-induced liver injury 
DKA 
Diabetic ketoacidosis 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOT 
End-of-Treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCIG 
Gynecologic Cancer Intergroup 
GCP 
Good Clinical Practice 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GVAX pancreas 
Irradiated, whole-cell, allogeneic tumor immunotherapy 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
hMeso 
Human mesothelin 
IB 
Investigator’s Brochure 


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Abbreviation 
Definition 
IBC 
Institutional Biosafety Committee 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDO 
Indoleamine 2,3-dioxygenase 
IHC 
Immunohistochemistry 
IL 
Interleukin 
InlB 
Internalin B 
INR 
International normalized ratio 
irAE 
Immune-related adverse events 
IRB 
Institutional Review Board 
irRC 
Immune-related Response Criteria 
IRT 
Interactive Response Technology 
IV 
Intravenous 
Kyn 
Kynurenine 
LFT 
Liver function test 
LLO 
Listeriolysin O 
Lm 
Listeria monocytogenes 
MAOI 
Monoamine oxidase inhibitors 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRECIST 
Modified Response Evaluation Criteria in Solid Tumors 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute  
NK 
Natural killer 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Disease progression 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PR 
Partial response 
PT 
Prothrombin time 
Q3W 
Every 3 weeks 
QD 
Once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 


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Abbreviation 
Definition 
SAF 
Safety Set 
SAP 
Statistical analysis plan 
SCCHN 
Squamous cell carcinoma of the head and neck 
SD 
Stable disease 
SNRI 
Serotonin/norepinephrine reuptake inhibitors 
SRC 
Safety Review Committee 
SS 
Serotonin Syndrome 
SSRI 
Selective serotonin reuptake inhibitors 
T1DM 
Type 1 diabetes mellitus 
TCR 
T cell receptor 
TEAE 
Treatment-emergent adverse event 
Treg 
Regulatory T lymphocyte 
Trp 
Tryptophan  
UGT1A9 
UDP-glucuronosyltransferase 1A9 
ULN 
Upper limit of normal 
US 
United States 
 


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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background 
In the United States (US), ovarian cancer is the fifth leading cause of cancer-related death in 
women.1,2 Approximately 21,290 patients were diagnosed with ovarian cancer in the US in 2015.3 
Epithelial ovarian cancer is the most common and lethal form of ovarian cancer.4 Prognosis for 
survival depends on the stage of the disease at diagnosis. However, most women are diagnosed 
with advanced stage ovarian cancer, with a 5-year survival of only 30%.1,2,5 
For patients with advanced stage ovarian cancer, surgical removal of the tumor is generally 
performed. Standard of care for these patients is then platinum-based combination chemotherapy. 
However, of the 60% to 80% of patients who present with advanced disease and who respond to 
first-line chemotherapy, more than 75% will develop resistant or recurrent disease.6 Ultimately, 
almost all patients develop platinum resistance.6 
Platinum-free interval, or the interval of time before disease recurrence, is a strong predictor of 
treatment outcome.7 Outcome following platinum-based chemotherapy is categorized as follows:  
• Platinum-sensitive – Patients whose disease responds but recurs >6 months from completion 
of platinum-based chemotherapy;  
• Platinum-resistant – Patients whose disease responds but recurs <6 months from completion 
of platinum-based chemotherapy; or  
• Platinum-refractory – Patients whose disease fails to respond. 
Patients with platinum-sensitive disease can be re-treated with a platinum-based chemotherapy. 
However, treatment options for platinum-resistant patients are limited. The most active single 
agent therapies for patients with platinum-resistant disease include pegylated liposomal 
doxorubicin, paclitaxel, and topotecan.8 Tumor response rates are in the range of 10% to 15% and 
overall survival (OS) is approximately 12 months.9 When given in combination, these agents result 
in increased toxicity with no demonstrable improvement in outcome.6,10-12 
The AURELIA trial6 studied the addition of bevacizumab to single agent chemotherapy in patients 
with platinum-resistant disease. An improvement in progression-free survival (PFS) but not OS 
was noted. Objective response rate (ORR), determined using Response Evaluation Criteria in Solid 
Tumors (RECIST), in patients receiving bevacizumab-containing therapy was 27.3%, compared 
with 11.8% in subjects receiving chemotherapy alone. Importantly, the hazard ratio for PFS was 
0.48 (95% confidence interval [CI]: 0.38 to 0.60), and the OS hazard ratio was 0.85 (95% CI: 0.66 
to 1.08) when compared with chemotherapy alone. In November 2014, the US Food and Drug 
Administration (FDA) approved treatment of platinum-resistant recurrent ovarian cancer with 
bevacizumab and pegylated liposomal doxorubicin, paclitaxel, or topotecan. 
Five-year survival rates for patients treated with platinum-based regimens are approximately 20% 
to 25%.13 While this is a substantial improvement over the 5% to 10% survival rate reported for 
patients with advanced disease in the pre-platinum era, ovarian cancer still remains a formidable 
challenge and new treatment approaches are needed. For patients with platinum-resistant disease, 
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1.1.1 
Immune Resistance in Cancers 
The importance of immune surveillance in controlling the outgrowth of neoplastically transformed 
cells has been known for decades.14 The inability of the immune system to control tumor growth 
does not appear to result from an inability to recognize the tumor as foreign. Tumor cells have 
been shown to evade immune destruction despite displaying recognizable antigens on their surface 
and despite the presence of high-avidity T cells that are specific for these antigens.15,16 Histologic 
evaluation of many human cancers shows extensive infiltration by inflammatory and immune 
cells,17 suggesting that the immune system responds to malignancy, albeit less effectively than 
needed to eradicate the tumors. These observations have led to the hypothesis that failure of the 
immune system to generate an effective response to malignancy could be the result of inadequate 
stimulation or exaggerated negative regulation. A combination of immunotherapy agents that 
stimulate an immune response targeted to tumor cells combined with the relief of negative 
regulation should synergize in allowing the immune system to generate a response leading to 
enhanced tumor rejection. 
In recent years, several immune-targeted agents have been approved by the FDA for cancer 
treatment. While single agent activity has consistently been reported, combining immunotherapies 
that target distinct immune pathways has the potential to further enhance the depth and breadth of 
the anti-tumor immune response over single agents. Multiple immune mechanisms have been 
shown to be present concurrently in the tumor microenvironment, suggesting that combination 
therapies may be required for optimal therapeutic effect.18,19 Several areas of opportunity exist 
where therapeutic intervention could be effective when combined. These areas include 
(1) promoting the antigen recognition and presentation functions of antigen presenting cells 
(APCs), (2) promoting the production of protective T cell responses, and (3) overcoming immune 
suppression in the tumor bed.20 
 
1.1.2 
CRS-207 
1.1.2.1 
Mesothelin as an Immunotherapy Target 
Mesothelin is a tumor-associated antigen with limited expression on the surface of mesothelial 
cells lining the pleura, peritoneum, and pericardium, but highly expressed in several human 
tumors, including ovarian cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), and 
mesotheliomas, but not in normal cells from the pancreas and ovary.21 While mesothelin 
expression was detected in 20/21 of ovarian cancers in an earlier limited immunohistochemistry 
(IHC) study,22 another study with 70 ovarian tumor samples using a combination of expression 
profiling, reverse transcription polymerase chain reaction confirmation, and IHC methods 
demonstrated that strong mesothelin expression was observed in approximately 65% of all samples 
evaluated, ranging from Grade 1 to 3 epithelial ovarian cancer, clear cell, endometrioid, and serous 
tumor types.23 In contrast, in the same study, mesothelin expression was observed in 20/21 serous 
tumors evaluated, demonstrating the strong correlation between expression of this 
tumor-associated antigen and ovarian malignancy. This identifies mesothelin as an attractive target 
for active tumor-specific immunotherapy.  


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1.1.2.2 
Listeria monocytogenes-Based Immunotherapy 
Listeria monocytogenes (Lm) is an attractive platform for the presentation of tumor-associated 
antigens and activation of an immune response directed against cancer cells. Lm provides both a 
potent stimulation of innate immunity and also stimulates an adaptive immune response through 
recruitment and activation of CD4+ and CD8+ T cell immunity specific for the encoded 
heterologous antigens.24-27 However, since wild-type Lm is a food-borne pathogen, the 
live-attenuated double-deleted Lm platform strain (Lm ΔactA/ΔinlB), known as ANZ-100, has 
deletions of 2 genes, actA and inlB. These genes encode the virulence-determinant proteins actin 
assembly-inducing protein A (ActA) and Internalin B (InlB), the 2 proteins which facilitate 
cell-to-cell spread and invasion of non-phagocytic cells, in particular hepatocytes. Deletion of actA 
and inlB in ANZ-100 results in the retention of the immunostimulatory potency of the fully virulent 
pathogen but with 1,000-fold attenuation of virulence in mice as compared with wild-type Lm.28 
Uptake of ANZ-100 by macrophages and other phagocytic cells in the liver and spleen is still 
retained and results in a local inflammatory response as well as activation and recruitment of 
natural killer (NK) cells and T cells to the liver. ANZ-100 underwent clinical evaluation in a Phase 
1 dose-escalation study of intravenous (IV) administration in adults with carcinoma and liver 
metastases and was found to be well tolerated at doses up to 3 × 108 colony-forming units (CFU).29  
ANZ-100 was subsequently engineered to express mesothelin, resulting in CRS-207 
(Lm ΔactA/ΔinlB/human mesothelin [hMeso]). CRS-207 contains an hMeso expression cassette 
integrated at the inlB locus. After uptake of CRS-207 by DCs and macrophages, mesothelin is 
expressed and released into the cytosolic compartment and subsequently processed through the 
endogenous major histocompatibility complex Class I presentation pathway, resulting in activation 
of mesothelin-specific cell-mediated immunity. Other mechanisms to activate mesothelin-specific, 
cell-mediated immunity may include uptake and cross-presentation of antigens by DCs and other 
cells after infection by CRS-207 and apoptosis. 
1.1.2.3 
Summary of Nonclinical Studies for CRS-207 
Refer to the current CRS-207 Investigator’s Brochure (IB) for additional details regarding 
nonclinical study data. 
1.1.2.4 
Summary of Clinical Studies for CRS-207 
CRS-207 is being evaluated in multiple clinical studies and multiple oncologic indications. CRS-
207, either alone or in combination (sequential or concomitant) with other investigational or 
approved agents, has been administered to more than 350 subjects with advanced cancers. CRS-
207 administered with pembrolizumab is being evaluated in multiple oncologic indications; no 
safety or efficacy data is currently available. Initial data from an ongoing clinical study of CRS-
207 with agents targeting the PD-1 blockade (i.e. nivolumab) in patients with pancreatic cancer 
suggests an acceptable tolerability profile.  
A complete summary of current clinical information on CRS-207 is provided in the IB.  
A Phase 1, first-in-human, multiple-dose, dose-escalation trial (VAC07001) was completed in 
adults with treatment-refractory malignant mesothelioma, advanced NSCLC, or advanced 
carcinoma of the ovary or pancreas. The maximum tolerated dose (MTD) was 1 × 109 CFU; CRS-
207 was generally well tolerated. While the study enrolled subjects with multiple disease types 


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and was not powered to assess survival, 6/17 subjects (with prior immunotherapy or subsequent 
radiation) survived at least 15 months after receiving the first dose of CRS-207. 
1.1.3 
Epacadostat 
Indoleamine 2,3-dioxygenase (IDO) 1 is an enzyme that contributes to tumor-derived immune 
suppression. Overexpression and upregulation of IDO1 depletes tryptophan (Trp) and increases 
Trp catabolites, including kynurenine (Kyn), which have been implicated in dendritic cell (DC) 
maturation and T cell growth arrest and cell death.30 Inhibition of IDO1 may enhance the function 
of APCs, increase the number of CD8+ T cells, and, at the same time, decrease the number of 
regulatory T lymphocytes (Tregs) infiltrating the tumor. Blocking IDO1 may also allow host Tregs 
to be "reprogrammed," resulting in enhanced CD8+ T cell responses.31 Therefore, adjuvant 
strategies designed to circumvent the endogenous immunosuppressive pathways, such as the IDO1 
pathway, could offer ways to enhance immunotherapy efficacy.  
Epacadostat (also referred to as INCB024360) is a novel, potent, and selective inhibitor of the 
enzyme IDO1. In cell-based assays, epacadostat potently inhibits IDO1 in both human tumor cells 
and human DCs resulting in reduced Trp to Kyn conversion (half maximal inhibitory concentration 
[IC50] values: 7.1 to 12.7 nM). Epacadostat does not significantly inhibit other proteins that could 
impact Trp catabolism.  
1.1.3.1 
IDO Inhibition as a Target for Cancer 
Recent interest has focused on the role of IDO1 as a mechanism of induction of tolerance to 
malignancy.32 IDO1 is a heme-containing, monomeric oxidoreductase that catalyzes the 
degradation of the essential amino acid Trp to N-formyl-kynurenine. Kyn can be subsequently 
metabolized through a series of enzymatic steps to nicotinamide adenine dinucleotide. IDO1 is the 
first rate-limiting enzyme in one of the breakdown pathways of Trp. In another pathway, Trp 
hydroxylase catalysis of Trp leads to the formation of serotonin and melatonin. 
The expression and activity profiles of IDO1 are distinct from those of Trp dioxygenase, an 
enzyme predominantly expressed in the liver that catalyzes the same enzymatic reaction as IDO1 
and maintains proper Trp balance in response to dietary uptake. In contrast to Trp dioxygenase, 
IDO1 is expressed in a variety of tissues, with particularly high levels found in areas of contact 
with potential sources of immune challenge (e.g. gut, respiratory tract, placenta, and spleen), 
consistent with a role for regulating Trp metabolism in a local microenvironment.33 Within the 
immune system, IDO1 activity is specifically induced in cells such as DCs and macrophages at 
localized sites of inflammation.34 
IDO1-driven oxidation of Trp results in a strong inhibitory effect on the development of 
T cell-mediated responses by blocking T cell activation and inducing T cell apoptosis.35 Both the 
reduction in local Trp levels and the production of Trp catabolites that are inhibitory to cell 
proliferation contribute to the immunosuppressive effects.36 IDO1 activity also promotes the 
differentiation of naïve T cells to cells with a regulatory phenotype (Treg).37 Since increased Treg 
activity has been shown to promote tumor growth and Treg depletion has been shown to allow an 
otherwise ineffectual anti-tumor immune response to occur,38 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- Trp, 


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maintains immune tolerance to allo-antigens present in the fetus, and allows pregnancy to persist, 
whereas IDO inhibition results in immune-mediated fetal loss.39 A critical role for IDO1 in 
immunomodulation has been confirmed in numerous animal models, including models of allograft 
tolerance, inflammation, and cancer.33 While IDO1 inhibition can exacerbate disease in models of 
autoimmune disorders,33 IDO1 null mice show no evidence of susceptibility to developing 
spontaneous autoimmunity or alterations in immune system development,35 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 tumors.40,41 In addition, studies with 
1-methyl-tryptophan, demonstrate that IDO1 inhibition dramatically increases the efficacy of 
various 
chemotherapeutic 
agents 
(e.g. 
platinum 
compounds, 
taxane 
derivatives, 
cyclophosphamide) without increased toxicity.41 Although the specific mechanisms responsible 
for this potentiation remain to be fully elucidated, the effects were not observed in T cell deficient 
animals, suggesting that improved therapeutic efficacy may result from disablement of 
immunosuppressive mechanisms within the tumor microenvironment. 
Based on studies examining serum levels of Trp and Kyn, IDO1 appears to be chronically activated 
in patients with cancer, and IDO1 activation correlates with more extensive disease.42,43 IDO1 is 
overexpressed in a wide variety of human tumor cell types, as well as by the DCs that localize to 
the tumor-draining lymph nodes.40,44 Increased expression of IDO1 in tumor cells has been shown 
to be an independent prognostic variable for reduced OS in subjects with melanoma, ovarian, 
colorectal, and pancreatic cancers.45-50 
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. 
1.1.3.2 
Summary of Nonclinical Studies for Epacadostat 
Refer to the current epacadostat IB for details on nonclinical study data. 
1.1.3.3 
Summary of Clinical Studies for Epacadostat 
At least 10 Phase 1 and 2 Incyte-sponsored clinical studies have either been completed or are 
ongoing. Five investigator-sponsored clinical studies have either been completed or are ongoing. 
At least 890 subjects have been enrolled and received at least 1 dose of epacadostat in Incyte-
sponsored studies, and 47 subjects were enrolled and received at least 1 dose of epacadostat in 
investigator-sponsored studies. 
In the initial Phase 1 multicenter, open-label, dose-escalation study in subjects with refractory solid 
tumors by Incyte Corporation (study INCB 24360-101), epacadostat (INCB024360) was generally 
well tolerated in subjects with refractory solid tumors at doses of up to 700 mg BID, and there 
appeared to be no correlation of dose with toxicity. Of the 52 subjects who were administered 
INCB024360, the median duration of treatment was 51.5 days. Eight subjects (15.4%) had an AE 
leading to death; of these 8 subjects, the cause of death was disease progression for 7 subjects and 


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hypoxia for the remaining subject. Twenty-five subjects (48.1%) had an SAE during the study. 
Serious adverse events were observed in all 8 treatment groups. The most frequently reported SAE 
was disease progression (4 subjects, 7.7%), followed by abdominal pain, nausea, and hypoxia (3 
subjects each, 5.8%). Treatment-emergent AEs were reported in all subjects. Fatigue and nausea 
were the most frequently reported treatment-related AEs (25 subjects each, 48.1%). The incidence 
and severity of fatigue were not dose related. Thirty subjects (57.7%) had treatment-emergent AEs 
≥ grade 3 in severity and 7 subjects (13.5%) had a treatment-emergent AE leading to 
discontinuation of study drug and withdrawal from the study. Two dose limiting toxicities (DLTs) 
occurred; 1 DLT of radiation pneumonitis at the 300 mg BID dose level and 1 DLT of fatigue at 
the 400 mg BID dose level. A maximum tolerated dose (MTD) was not determined. There were 
no clinically meaningful changes or trends noted in clinical hematology, chemistry, or urinalysis 
results or for vital signs, electrocardiograms, or physical examinations. 
In Study INCB 24360-201 (epacadostat + ipilimumab), 50 subjects were enrolled by the data cutoff 
(29 OCT 2015) and were treated with epacadostat 300 mg BID (i.e. subjects treated with 300 mg 
BID and subjects treated with 300 mg BID who subsequently reduced to 100 mg BID), 100 mg 
BID, 25 mg BID, 50 mg BID, 75 mg TDD (50 mg AM and 25 mg PM), and 50 mg BID intermittent 
doses (2 weeks on and 1 week off), all in combination with the anti−CTLA-4 antibody ipilimumab 
(3 mg/kg IV every 3 weeks). 
In the initial Phase 1 dose-escalation portion, 5 of the 7 subjects receiving epacadostat 300 mg BID 
in combination with ipilimumab developed clinically significant ALT elevations; therefore, the 
study was amended to evaluate lower epacadostat doses. A preliminary analysis of epacadostat 
exposure parameters and liver function tests (LFTs) was performed, and there was no evidence of 
a relationship between steady-state peak exposure or AUC and ALT level for subjects in this 
cohort. 
Based on the preliminary unaudited data as of the data cutoff (29 Oct 2015), 5 subjects (10%) had 
treatment-emergent AEs leading to death. Four of the 5 subjects had a single treatment-emergent 
AE (sepsis syndrome, intracranial hemorrhage, osteomyelitis, and multi-system failure) leading to 
death. One of the 5 subjects had multiple treatment-emergent AEs (hypotension, confusion, atrial 
fibrillation, bradycardia, acute kidney injury, cardiogenic shock) leading to death. None of these 
deaths were considered by the investigator to be causally related to treatment with epacadostat. 
Twenty-seven subjects (54.0%) had an SAE. Serious AEs were observed in the 300 mg BID, 25 
mg BID, 50 mg BID, 50 mg BID intermittent, and 75 mg TDD dose groups. The system organ 
classes with the most frequently reported SAEs were gastrointestinal disorders (10 subjects, 
20.0%), infections and infestations (7 subjects, 14%), and general disorders and administration site 
condition and investigations (6 subjects each 12.0%). The most frequently reported SAEs were 
increased ALT and AST (5 subjects in the 300 mg BID and 1 subject in the 50 mg BID group) 
followed by colitis (4 subjects total with 2 subjects in the 25 mg BID group, 1 subject in the 50 mg 
BID, and 1 subject in the 50 mg BID intermittent group). In the 75 mg TDD group 2 SAEs occurred 
in 1 subject each (fall and rash).  
Treatment-emergent AEs were reported in 49 subjects (98.0%). Fatigue was the most frequently 
reported treatment-emergent AE (33 subjects, 66.0%) followed by rash (27 subjects, 54.0%; 
includes the preferred terms rash, rash generalized, rash macular, rash maculopapular, and rash 
pruritic). More than half of subjects (64.0%) had treatment-emergent AEs ≥ grade 3 in severity.  


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Nineteen subjects (38.0%) had a treatment-emergent AE leading to discontinuation of epacadostat. 
Five of the 7 subjects (71.4%) treated in the 300 mg BID cohort, 4 of the 8 subjects (50.0%) treated 
in the 25 mg BID cohort, 7 of the 18 subjects (38.9%) treated in the 50 mg BID cohort, and 3 of 9 
subjects (33.3%) treated in the 50 mg BID intermittent dose cohort discontinued epacadostat 
because of treatment-emergent AEs. No subjects in either the 100 mg BID group or the 75 mg 
TDD group had a treatment-emergent AE leading to discontinuation of epacadostat. 
In a recent ongoing Incyte Corporation Phase 1 study (INCB 24360-202), safety, efficacy, and 
tolerability of the combination of pembrolizumab at a dose of 2 mg/kg IV every 3 weeks in 
combination with epacadostat at doses of 25 mg BID to 300 mg BID in subjects with various, 
advanced or metastatic solid tumors is being evaluated. A total of 60 subjects were enrolled as of 
29 October 2015: 25 mg BID (n=4) and, 50 mg BID (n=20), 100 mg BID (n=18), and 300 mg BID 
(n=18). Preliminary results from this study showed that one grade 3 rash (8%) was reported in the 
50 mg BID cohort and this was found to be DLT based on the extent of rash. The most common 
all grade immune-related AEs were rash (16%), diarrhea (16%), dyspnea (8%), pruritus (8%), and 
headache (8%). The ORR per modified RECIST v1.1 (mRECIST) was 71% (5/7), and disease 
control rate (DCR; CR+PR+stable disease) was 100% (7/7) (note: calculations included only 
evaluable subjects for response).  
Based on the preliminary, unaudited data as of the data cutoff (29 Oct 2015), no Grade 4 treatment-
related AEs were reported. Three subjects (5%) discontinued for a treatment-related AE: grade 3 
arthralgia, grade 3 AST increased, 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. 
Preliminary data from Study INCB 24360-210 (600 mg BID of epacadostat versus 20 mg BID of 
tamoxifen in Stage III or IV epithelial ovarian cancer) are available as of the data cutoff on 29 
October 2015. This phase 1 study is a completed monotherapy study in subjects with biochemically 
recurrent-only epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube carcinoma 
after complete remission with first-line chemotherapy. At the time of the cutoff, 42 Forty-two 
subjects were enrolled (22 in the epacadostat treated group and 20 in the tamoxifen-treated group); 
21 subjects (50.0%) discontinued due to disease progression, 15 subjects (35.7%) discontinued 
due to study termination, and 6 subjects (14.3%)withdrew due to treatment-emergent AEs. Based 
on the preliminary unaudited data through that date, no subject had an AE leading to death. Two 
subjects (4.8%) had an SAE. One SAE was reported in the epacadostat group (abdominal pain), 
and 1 SAE was reported in the tamoxifen group (ascites). The system organ classes with the most 
reported treatment-emergent AEs in the epacadostat group were general disorders and 
administration site conditions and gastrointestinal disorders (13 subjects each, 59.1%). Fatigue 
was the most frequently reported treatment-emergent AE in the epacadostat group (8 subjects, 
36.4%), followed by nausea (6 subjects, 27.3%) and abdominal distention, constipation, and 
vomiting (4 subjects each, 18.2%). This study was terminated by the sponsor. No safety concerns 
with epacadostat were identified. 
Epacadostat 600 mg BID was well-tolerated. Twenty-two subjects received at least 1 dose of 
epacadostat with a median exposure of 56.0 days and a median average total daily dose of 
1200 mg. Twenty subjects received at least 1 dose of tamoxifen with a median exposure of 61.0 
days and a median average total daily dose of 40 mg. No subject had an AE leading to death. Two 


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subjects (4.8%) had SAEs: 1 subject in the epacadostat group (abdominal pain) and 1 subject in 
the tamoxifen group (ascites). Treatment-emergent AEs were reported in 32 subjects (76.2%) with 
17 subjects (77.3%) in the epacadostat group and 15 subjects (75.0%) in the tamoxifen group. 
Fatigue was the most frequently reported treatment-emergent AE in the epacadostat group (8 
subjects, 36.4%), followed by nausea (6 subjects, 27.3%), rash (5 subjects, 22.7%), and abdominal 
distention, constipation, and vomiting (4 subjects each, 18.2%).  
The most frequently reported immune-related AEs in the epacadostat group were skin-related, with 
5 subjects (22.7%) reporting rash (2 with rash maculopapular, 1 with rash papular, 1 with rash 
erythematous, and 1 with rash) and 2 subjects (9.1%) reporting pruritus. Two subjects had 
maculopapular rashes that were ≥ grade 3. All other skin-related treatment-emergent AEs were < 
grade 3. 
Seven subjects in the epacadostat group (31.8%) had a treatment-emergent AE ≥ grade 3 in severity 
including maculopapular rash (2 subjects), and increased GGT, vomiting, abdominal pain, 
hypertension, and hyponatremia (1 subject each). 
The majority of subjects had normal hematology and clinical chemistry laboratory assessments at 
baseline, and the values remained normal throughout the study. Overall, no clinically meaningful 
changes or trends in vital sign measurements or 12-lead electrocardiogram findings were observed. 
• The IB provides the most current and complete information on ongoing clinical studies 
INCB24360-203, Phase 1/2 open-label study of epacadostat administered in combination 
with MEDI4736 (durvalumab) in subjects with advanced melanoma, NSCLC, pancreatic 
cancer, or SCCHN 
• INCB 24360-204, a Phase 1/2 study of the safety, tolerability, and efficacy of INCB24360 
administered in combination with nivolumab in select advanced cancers, including 
melanoma, NSCLC, CRC, SCCHN, ovarian cancer, and B cell NHL or HL (including 
DLBCL) in Phase 1 and Phase 2, and glioblastoma in Phase 2. 
1.2 
Rationale for CRS-207, Epacadostat, and Pembrolizumab Immunotherapy in 
Advanced Ovarian Cancers 
The adaptive immune system plays a key role in anti-tumor immune response by targeting 
cancer-specific antigens expressed by tumor cells.51 Histologically, cancer cells show infiltration 
by immune cells. However, immune-mediated elimination is not possible due to the 
immunosuppressive state of the ovarian cancer microenvironment, resulting from the secretion of 
interleukin (IL)-4, IL-1𝛽𝛽, vascular endothelial growth factor, and prostaglandin-E2.51 These recruit 
immunosuppressive Tregs, and inhibit CD4+ T cells.51 An increase in Treg activity has been shown 
to decrease survival.52 In the context of cancer immunotherapy, the preferential inhibition of Treg 
and an increase in tumor-infiltrating lymphocytes may enhance treatment-induced tumor-specific 
immunity, thereby improving efficacy.53 In ovarian cancer cells, the high level of IDO expression 
results in a reduction of tumor-infiltrating lymphocytes, which has been associated with poor 
prognosis.54 As IDO is a key regulator of immunosuppression, inhibition of IDO using epacadostat 
is a highly attractive strategy for ovarian cancer therapy.  
The intracellular lifecycle of the live-attenuated double-deleted Lm platform strain used to create 
CRS-207 enables effective stimulation of CD4+ and CD8+ T cell immunity, known to be important 
for reducing tumor burden.55 Multiple pathogen-associated molecular pattern receptors are 


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triggered in response to interaction with Lm macromolecules upon infection. This results in the 
pan-activation of innate immune effectors and release of Th-1-polarizing cytokines, exerting a 
profound impact in supporting the development of a CD4+ and CD8+ T cell response.56-59  
Thus, CRS-207 and epacadostat may have a synergistic advantage: epacadostat inhibition of IDO1 
can inhibit the immunosuppressive nature of the tumor microenvironment, thus allowing CRS-207 
to most effectively initiate an anti-cancer immune response. The addition of a checkpoint inhibitor 
may enhance the immunotherapeutic potential of these agents by relieving the adaptive resistance 
mechanism on tumor-specific T cells. 
 
 
 
 
Initial data from an ongoing clinical 
study of CRS-207 with agents targeting the PD-1 blockade (i.e. nivolumab) suggests an acceptable 
tolerability profile.  
With the addition of pembrolizumab, it is hypothesized the reactivation and expansion of tumor-
specific T cells in context of blocking the PD-1/PD-L1 inhibitory pathway may ultimately provide 
further enhanced anti-tumor activity. The current study is designed to evaluate whether CRS-207 
with epacadostat and pembrolizumab effectively primes and sustains tumor-specific T cell 
responses and results in clinical benefit for patients with previously treated disease.  
1.3 
Potential Risks and Benefits of the Treatment Regimen  
This study is the first to investigate the safety and immunogenicity of CRS-207 when administered 
with epacadostat and pembrolizumab in adults with platinum-resistant ovarian, fallopian, or 
peritoneal cancer. 
1.3.1 
CRS-207 
The proposed dose level for this study (1 × 109 CFU) is the MTD as determined in the Phase 1 
solid tumor dose escalation study (Protocol VAC07001), which included 2 ovarian cancer patients. 
It is also the dose administered in ongoing studies in other oncologic indications, which are 
demonstrating further safety and tolerance of this dose.  
Treatment emergent adverse events (TEAEs) temporally related to CRS-207 administration which 
are common and may vary in degree of severity include fevers, chills, nausea, vomiting, fatigue, 
headache and changes in blood pressure; generally, these were reported as immediate, transient, 
and mild and resolve within 48 hours following CRS-207 infusion. Changes in hepatic enzyme 
levels and hematological parameters (lymphopenia) are also anticipated to varying degrees of 
severity. These effects are likely a consequence of the mechanism of action of CRS-207 through 
the activation of the innate immune system and release of proinflammatory cytokines and 
chemokines. Some of these infusion-related events may be mitigated by pre-medication with 
acetaminophen and administration of saline prior to and following CRS-207 infusion. Based on 
available results from clinical studies, continued clinical development of CRS-207 is warranted.  


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1.3.2 
Pembrolizumab 
1.3.2.1 
Checkpoint Inhibitors 
Programmed Death receptor-1 (PD-1) is a checkpoint protein on T cells that normally inhibits T 
cells from attacking other cells in the body. Overexpression of the ligand PD-L1 on cancer cells 
further evades immune attack by T cells. Checkpoint inhibitors, including antibodies targeting PD-
1, block the PD-1/PD-L1 interaction and boost the immune response against cancer cells. 
Monoclonal antibodies targeting PD-1, including pembrolizumab and nivolumab, have been 
approved for use in multiple tumor types and are currently being studied in several additional 
indications. 
1.3.2.2 
Summary of Clinical Indications for Pembrolizumab 
Pembrolizumab (Keytruda [US]), a humanized monoclonal antibody against the programmed 
death receptor-1 (PD-1) protein, has been developed by Merck & Co for the treatment of patients 
with cancer. Pembrolizumab is approved for treatment of patients with melanoma in several 
countries; in the US and EU it is approved for the treatment of adults with advanced, unresectable 
or metastatic malignant melanoma. Pembrolizumab has also been approved in several countries 
for the treatment of patients with NSCLC; in the US it is indicated for the treatment of metastatic 
NSCLC whose tumors express programmed death receptor ligand-1 (PD-L1) as determined by an 
FDA-approved test and who have disease progression on or after platinum-containing 
chemotherapy. Patients with NSCLC and EGFR or ALK genomic tumor aberrations should also 
have disease progression on FDA-approved therapy for these aberrations prior to receiving 
pembrolizumab. Pembrolizumab is also approved in the US for the treatment of patients with 
recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on 
or after platinum-containing chemotherapy.  
Pembrolizumab is not currently approved for treatment of platinum-resistant ovarian, fallopian, or 
peritoneal cancer and is being used as an investigational agent in this study. However, the approved 
package insert should be consulted for additional product information on storage, preparation and 
administration, contraindications, warnings/precautions, adverse reactions, and drug interactions. 
The planned dose of pembrolizumab is 200 mg Q3W. As described in the approved label, existing 
exposure-response data and population pharmacokinetic modeling suggest 200 mg once Q3W is 
an appropriate fixed dose for pembrolizumab. 
1.3.3 
Epacadostat 
As of 29 OCT 2015, 253 unique subjects have been exposed to INCB024360 as monotherapy (91 
subjects) and/or in combination with checkpoint inhibitors (anti−PD-1 targeted therapy: 79 
subjects; anti−PD-L1 targeted therapy: 33 subjects; and anti−CTLA-4 targeted therapy: 50 
subjects). The most common expected treatment-emergent adverse events include diarrhea, 
nausea, vomiting, fatigue, and rash; increased hepatic enzyme levels are also expected. Of these, 
diarrhea, nausea, and vomiting are considered common serious events expected for epacadostat 
monotherapy. Consult the epacadostat IB for full reference safety information. 


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Theoretically, inhibition of IDO1 could cause an increase in serotonin levels that could precipitate 
a cluster of adverse events termed Serotonin Syndrome (SS) when administered alone or in 
combination with other serotonergic agents. This rare syndrome has been associated with some 
monoamine oxidase inhibitors (MAOIs) and combinations of serotonergic drugs.60 The clinical 
manifestations of SS range from barely perceptible to lethal; onset is rapid (within 12 hours of 
drug[s] administration).  
Based on preliminary studies in the rat, concentrations of epacadostat in the cerebrospinal fluid 
were below the quantifiable limit of detection (2 nM) after IV dosing, and total brain homogenate 
concentrations were approximately 15% of corresponding plasma concentrations. Therefore, 
epacadostat exhibits apparent limited penetration across the blood-brain barrier and is likely not 
associated with significant effects on Trp metabolism in the brain that might affect brain serotonin 
levels. In the INCB 24360-201 study, 12 of the 48 subjects enrolled as of 29 October 2014 received 
concomitant treatment with a selective serotonin reuptake inhibitors (SSRI) and epacadostat and 
0 of 12 subjects exhibited SS. Although this represents a hypothetical risk only and has not been 
observed in clinical studies of epacadostat, use of MAOIs will be prohibited during the study. 
Subjects will be provided with an informative subject leaflet describing the signs and symptoms 
of the syndrome along with instructions to seek immediate medical care if any of these signs or 
symptoms is observed. 
1.3.4 
CRS-207 and Pembrolizumab, and Epacadostat Regimens 
This is the first study to investigate the administration of CRS-207 with epacadostat and 
pembrolizumab. As of November 3, 2016, 8 subjects have been treated with CRS-207 in 
combination with epacadostat (4 subjects with 100mg BID epacadostat, and 4 subjects with 300mg 
BID epacadostat) in the Phase 1 portion of this study. No DLTs have been observed and the 
combination was well-tolerated at both dose levels tested. 
CRS-207 is currently being evaluated with the PD-1 inhibitor nivolumab in an investigator-
sponsored Phase 2 study in subjects with previously-treated pancreatic cancer (ADU-CL-06; 
NCT02243371). As of December 5, 2016, approximately 51 subjects have been treated with a 
combination that includes CRS-207 and nivolumab. Initial data from this ongoing clinical study 
suggests an acceptable tolerability profile of both agents at full dose (CRS-207 1 × 109 CFU with 
nivolumab at 3 mg/kg). Refer to the CRS-207 Investigators Brochure for additional information. 
An ongoing study (INCB24360-202) with epacadostat and pembrolizumab showed that the 
combination was well-tolerated at all dose levels tested, including the 300mg BID dose of 
epacadostat.   
Although there was a somewhat higher incidence of grade 3 rash observed in the 300 mg BID 
cohort compared to the 100 mg BID cohort, these events did not qualify as protocol-specified 
DLTs. A dose of 300 mg epacadostat in combination with pembrolizumab is currently being 
investigated in additional clinical studies. 
In the aforementioned study (INCB24360-202), there was evidence of improved efficacy in 
melanoma subjects at all doses of epacadostat examined (50 to 300 mg BID). A Phase 3 study 
(INCB24360-301) is ongoing in subjects with unresectable or metastatic melanoma; in this study 
the dose of 100 mg bid epacadostat with pembrolizumab is based upon a benefit/risk assessment 
specific to the study population and indication. Given melanoma is considered responsive to 


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immunotherapy, and lower doses of epacadostat appeared to have similar activity, the 100 mg BID 
dose combination was selected to lower the potential of dose interruptions and dose reductions 
relative to a higher dose. 
In other tumor types (including ovarian, peritoneal, and fallopian tube carcinomas), which may be 
less responsive to known immunotherapies, greater target coverage for inhibition of IDO1 may be 
necessary. PK/PD modelling suggests doses of 100 mg BID epacadostat achieve an average IC50 
at trough in most subjects. At 300 mg BID, epacadostat achieves target inhibition above the IC90 
at trough thereby shifting the benefit/risk in favor of the higher epacadostat dose for tumor types 
generally considered less responsive to immunotherapy. 
For these reasons the proposed combinations in this study will be evaluated with Phase 1 dose 
evaluation and provision in Phase 2 to adjust the dose of epacadostat in the event of unacceptable 
toxicity following the addition of pembrolizumab to the CRS-207/IDO combination. 
 


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2 
STUDY OBJECTIVES 
2.1 
Phase 1: Dose Evaluation, Assigned Arms 
Objective(s) 
Endpoints 
Primary 
• Determine the RP2D of epacadostat 
administered with CRS-207 in subjects 
with platinum-resistant ovarian, fallopian 
or peritoneal cancer 
• Assess safety and tolerability of CRS-207 
alone and CRS-207 in combination with 
epacadostat in subjects with platinum-
resistant ovarian, fallopian or peritoneal 
cancer 
 
Primary 
• Hematologic and non-hematologic DLTs; 
• Adverse events by CTCAE grade; vital signs, physical 
exam findings, changes in ECG readings and changes in 
chemistry and hematology and coagulation parameters  
 
Secondary 
• Characterize the PK of epacadostat 
• Evaluate the preliminary anti-tumor 
activity of each study drug regimen 
• Characterize pharmacological effects on 
immune biomarkers in peripheral blood 
and tumor tissue 
• Characterize shedding and clearance of 
CRS-207 when given alone or with 
epacadostat 
 
Secondary 
• Plasma concentration of epacadostat and derived PK 
parameters; 
• ORR, defined as CR or PR as determined by mRECIST, 
RECIST v1.1, and GCIG CA-125 criteria; 
• PFS, defined as the time from the date of first dose to PD 
or death due to any cause. PFS is measured through the 
last tumor assessment or commencement of a new 
systemic therapy. PD is determined by mRECIST, 
RECIST v1.1 and GCIG CA-125 criteria; 
• Disease control rate, defined as CR+PR+SD as determined 
by mRECIST, RECIST v1.1, and GCIG CA-125 criteria; 
• Duration of response, defined as the time from first CR or 
PR until PD as determined by mRECIST, RECIST v1.1, 
and GCIG CA-125 criteria; 
• OS, defined as the time from first dose until date of death 
due to any cause; 
• Ratio of tumor infiltrating lymphocytes CD8/Treg (FoxP3); 
• Plasma kynurenine/tryptophan ratio;  
• Other immunological and tumor biomarker endpoints: 
o Cytokine/chemokine responses 
o Antibody responses 
o Modulation of immune cell populations and functions 
in PBMCs and tumor, and 
o CA-125, mesothelin, PD-L1 and additional tumor 
biomarkers; and  
• Detection of CRS-207 in urine, saliva, feces, and blood 
CA-125 = cancer antigen-125; CR = complete response; CTCAE = Common Terminology Criteria for Adverse Events; 
DLT = dose-limiting toxicity; GCIG = Gynecologic Cancer Intergroup; IDO = epacadostat; mRECIST = modified Response 
Evaluation Criteria in Solid Tumors; ORR = objective response rate; OS = overall survival; PBMC = peripheral blood 
mononuclear cells; PD = disease progression; PD-L1 = programmed death receptor ligand 1; pembro = pembrolizumab; 
PFS = progression-free survival; PK = pharmacokinetics; PR = partial response; RECIST = Response Evaluation Criteria in 
Solid Tumors; RP2D = recommended Phase 2 dose; SD = stable disease; Treg = regulatory T cells. 
 
 
 


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2.2 
Phase 2: Randomized, 2-stage 
Objective(s) 
Endpoints 
Primary 
• Assess safety of CRS-207/pembrolizumab 
administered with or without epacadostat 
• Assess tumor response and PFS  
Primary 
• Adverse events, vital signs, physical exam findings, 
changes in ECG readings, and changes in chemistry, 
hematology, and coagulation parameters  
• ORR, defined as CR or PR as determined by mRECIST 
• PFS, defined as the time from the date of first dose to PD 
or death due to any cause. PFS is measured through the 
last tumor assessment or commencement of a new 
systemic therapy. PD is determined by mRECIST. 
Secondary 
• Assess disease control rate and duration 
of response  
• Assess OS 
Secondary 
• Disease control rate, defined as CR+PR+SD as determined 
by mRECIST, RECIST v1.1, and GCIG CA-125 criteria 
• Duration of response, defined as the time from first CR or 
PR until PD as determined by mRECIST, RECIST v1.1, 
and GCIG CA-125 criteria 
• ORR as determined by RECIST v1.1 and GCIG CA-125 
criteria 
• OS, defined as the time from first dose until date of death 
due to any cause 
• PFS where PD is determined by RECIST v1.1 and GCIG 
CA-125 criteria 
Additional 
• Assess the association of clinical efficacy 
(ORR, PFS, and OS) with immunologic 
and tumor biomarkers  
• Characterize the PK of epacadostat 
• Characterize shedding and clearance of 
CRS-207/pembrolizumab administered 
with or without epacadostat  
 
Additional 
Immunological and tumor biomarker endpoints: 
• Cytokine/chemokine and antibody responses 
• Modulation of immune cell populations and functions in 
PBMCs and tumor 
• Mesothelin and PD-L1 expression 
• CA-125 and additional candidate tumor biomarkers 
Pharmacokinetic endpoints: 
• Plasma concentration of epacadostat and derived PK 
parameters 
• Detection of CRS-207 in urine, saliva, feces, and blood 
 
 
 


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3 
STUDY DESIGN 
The study is designed to assess the safety and efficacy of the following investigational treatment 
regimens in adult females with epithelial ovarian, fallopian, or primary peritoneal cancer that is 
platinum-resistant (i.e. has progressed within 6 months after completing platinum-based 
chemotherapy):  
• CRS-207/epacadostat/pembrolizumab (CRS-207/IDO/pembro)  
• CRS-207/pembrolizumab (CRS-207/pembro)  
The study will be conducted in 2 phases as depicted in the study schematic (Figure 1). Phase 1 
seeks to evaluate safety and tolerability and is aimed at determining the recommended Phase 2 
dose (RP2D) of epacadostat administered with CRS-207 for further evaluation in Phase 2. The 
randomized Phase 2 portion of the study will begin with a safety-run in to evaluate the addition of 
pembrolizumab, followed by a 2-stage design to evaluate safety and efficacy in subjects who have 
received no more than 3 prior chemotherapy regimens for locally advanced or metastatic disease. 
Figure 1  
Study Schematic 
 
 
 


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The Schedules of Events for Phases 1 and 2 are provided in Appendix F and Table 1, respectively. 
The study consists of a 28-day screening period, followed by administration of study drug(s) in 3-
week cycles. Treatment will continue for as long as there is adequate safety and potential for 
clinical benefit with the exception that pembrolizumab may be given for up to 24 months to 
subjects without disease progression. After 6 cycles, CRS-207 will be administered every 6 weeks 
(Q6W); all other assigned treatments remain the same.  
Archived tumor tissue and paired tumor biopsies (collected at Screening and Cycle 2 Day 15) will 
be used to explore the association of programmed death receptor ligand-1 (PD-L1) expression, 
mesothelin expression, and tumor-infiltrating lymphocyte (TIL) characteristics with clinical 
responses. Tumor evaluation by radiographic imaging will be performed within 28 days prior to 
treatment and every 9 weeks while on treatment and until disease progression. Peripheral blood 
will be collected to assess immune responses directed against L. monocytogenes, mesothelin, and 
other tumor-associated antigens. Circulating levels of Cancer antigen 125 (CA-125) will be 
assessed at Screening and on Day 1 of each 3 week cycle while on treatment, and every 9 weeks 
thereafter until disease progression is confirmed. CRS-207 shedding and clearance will be assessed 
during Phase 1 and during the Safety Run-in of Phase 2 at US sites only. Urine, rectal swab, oral 
swab, and whole blood will be collected from subjects treated with CRS-207. Additional 
assessments will be performed if results are positive for CRS-207 at the Day 7 time point. 
An End-of-Treatment (EOT) Visit will be scheduled once treatment has been discontinued. Blood 
will be collected at EOT to assess clearance of CRS-207 and at 
 
. To eliminate any potentially 
residual CRS-207, subjects will be administered antibiotics at the EOT Visit; the antibiotic 
regimen should be completed prior to receiving any subsequent cancer-related therapy. An 
additional Safety Follow-up Visit will occur 30 days after the last dose of study drug. If the subject 
begins another anticancer therapy before the end of the 30-day period, the subject should complete 
all of the Safety Follow-up Visit assessments prior to commencing the new therapy.  
After the Safety Follow-up Visit, subjects will return to the clinic every 9 weeks for tumor 
evaluation and CA-125 until radiographic disease progression is confirmed, at which time subjects 
will be followed every 12 weeks by phone/email (if no recent medical charting available) to collect 
data on survival and any subsequent anti-cancer treatment that may have been administered. 
Follow-up will continue until death, withdrawal of consent, or the end of the study, whichever 
occurs first. At the conclusion of the study, all remaining subjects who have received at least 1 
dose of study treatment will be offered enrollment in a long-term follow-up study and continue to 
be followed for survival. 
Additional guidelines specific to the Phase 1 and 2 portions of the study are provided below. 


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3.1 
Phase 1:  Dose Evaluation, Assigned Arms 
The epacadostat dose will be evaluated based on a 3+3 design utilizing protocol defined DLT 
criteria (Table 2). 
Table 2 
Phase 1 Dose Evaluation Plan 
Cohort3 
0/3 subjects have 
DLT1 
1/3 subjects have 
DLT1 
<2/6 subjects have 
DLT1 
>2 in a cohort have 
DLT1,2 
Dose Cohort 1 
CRS-207 + 100 mg 
BID IDO 
Escalate to Dose 
Cohort 2 
Expand Dose 
Cohort 1 to 
6 subjects 
Escalate to Dose 
Cohort 2 
De-escalate to Dose 
Cohort -1 (CRS-207 
+ 50 mg BID IDO)3 
Dose Cohort 2 
CRS-207 + 300 mg 
BID IDO 
Expand cohort to 12 
subjects with paired 
biopsies 
Expand Dose 
Cohort 2 to 
6 subjects 
Expand cohort to 12 
subjects with paired 
biopsies 
Dose expand with 
100 mg BID IDO 
1. 
DLT period is 3 weeks after first dose of CRS-207. 
2. 
In the case that a cohort is closed to enrollment, subjects who are ongoing at that dose level without DLTs may continue 
treatment at the assigned dose level at the discretion of the Investigator. 
3. 
Evaluation of Dose Cohort -1 will enable the same 3+3 rules for dose cohort expansion or de-escalation to 25 mg (Dose 
Cohort -2). Evaluation of Dose Cohort -2 will enable the same 3+3 rules for dose cohort expansion. If Dose Cohort -2 is 
not tolerated, Treatment Arm will be terminated. 
BID = twice daily; DLT = dose-limiting toxicity 
 
Additionally, approximately 12 subjects with paired biopsies will be enrolled in the CRS-207 alone 
arm to assess the safety and tolerability of CRS-207 alone in subjects with platinum-resistant 
ovarian, fallopian or peritoneal cancer. 
A Safety Review Committee (SRC) will be convened for the study, consisting of the Investigators 
who enrolled subjects in the study, the Lead Investigator, Study Medical Monitor, and Sponsor 
representatives. Adverse events, DLTs and safety data for all subjects will be reviewed on an 
ongoing basis by the SRC. Dose escalation and reduction decisions, determination of the 
recommended dose for expansion, and R2PD will be made by the SRC. 
3.2 
Phase 2:  Randomized, 2-Stage 
Phase 2 will begin by assessing safety the addition of pembrolizumab to CRS-207 and CRS-
207/epacadostat; pembrolizumab will be administered at the 200 mg fixed dose level (as approved 
in other cancer indications). Phase 2 will initiate after the RP2D of CRS-207/epacadostat is 
determined and approximately 12 subjects with paired biopsies have been dosed at that level.  
A Safety Run-in will be completed since there are no precedent data on the addition of 
pembrolizumab to the planned drug combinations. Treatment of the first 6 randomized subjects in 
each treatment arm will be staggered, with no more than 1 subject treated per week, per arm. 
Subjects will be monitored during the Safety Run-in Period [the first 21 days] using the protocol 
defined DLT criteria. In the event ≥2 subjects in up to 6 (per arm) experience DLTs, the SRC will 
convene to determine if subsequent subjects enrolled will require a different dose level (Table 3), 
or if additional subjects should be enrolled at a specified dose level to further assess safety and 
tolerability. In the event >2 subjects in the next 6 subjects (per arm) treated experience DLTs, the 
SRC will reconvene to determine if the dose will be further modified for the remaining subjects to 
be enrolled. The SRC may convene at any time during the Safety Run-in Period to review and 
evaluate available safety data as warranted by emerging safety data. 


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Table 3 
Safety Run-in Dose Levels and Dose Reduction 
Dose level 
pembrolizumab  
 
epacadostat 
CRS-207 
  
1 
200 mg 
300 mg BID 
1 × 109 CFU 
-1 
200 mg 
100 mg BID 
1 × 109 CFU 
-2 
Further dose reductions will be discussed and confirmed by the SRC 
based on emergent safety data. 
 
Phase 2 will utilize a 2-stage design. Subjects will be randomized 1:1 into 2 treatment arms. In the 
first stage, once the final dose is confirmed in the Safety Run-in, a total of 13 subjects will be 
randomized into each arm (total 26 subjects). If the phase 2 dose is modified, at least 13 subjects 
will be enrolled and treated at the final dose level in each arm. If the pre-specified objective 
response-rate (ORR) and progression-free survival (PFS) criteria for advancement in the 2-stage 
design are met (≥1 response or median PFS ≥ 4.8 months) for an arm, an additional 14 subjects 
will be enrolled in that arm, for a potential total of 27 subjects per arm (up to 54 subjects total if 
both arms advance to stage 2). 
In the event that during the safety run in there are 2 DLTs in 6 patients in the CRS-
207/pembrolizumab arm but the CRS-207/pembrolizumab/epacadostat has 0 or 1 DLTs in 6 
patients using the same dose levels as in the 2 arm combination, the SRC will review the data and 
may allow enrollment of another 3 subjects in each run-in to better define the toxicities.  
 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Individuals must meet all of the following requirements to be eligible to enroll in this study: 
1. Female, 18 years of age or older 
2. Histologically-confirmed disease 
For Phase 1: Individuals with epithelial ovarian cancer, fallopian tube carcinoma, or primary 
peritoneal carcinomas who are considered to have platinum-resistant disease (defined as 
progression within 6 months from completion of platinum-based chemotherapy). The date 
should be calculated from the last administered dose of platinum therapy. 
For Phase 2: Individuals with epithelial ovarian cancer, fallopian tube carcinoma, or primary 
peritoneal carcinomas who are considered to have platinum-resistant disease (defined as 
progression within 6 months from completion of a minimum of 4 platinum therapy cycles). 
The date should be calculated from the last administered dose of platinum therapy. 
3. Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1  
Phase 1 only:  Individuals who do not have measurable disease (according to RECIST v1.1) 
but have assessable disease according to the Gynecologic Cancer Intergroup (GCIG) CA-125 
criteria and require treatment, may be included if they meet all other criteria.  
4. Agree to provide core tissue biopsies at baseline and at Cycle 2 Day 15   
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
6. Available archived tumor tissue for central analysis 
7. Adequate organ and marrow function, as defined by: 
• White blood cells ≥3000/µL 
• Absolute neutrophil count (ANC) ≥1500/µL 
• Absolute lymphocyte count ≥ 800/µL 
• Platelet count ≥100,000/µL 
• Serum albumin ≥3 g/dL 
• AST and ALT ≤2.5 × upper limit of normal (ULN) (<5 × ULN for subjects with liver 
metastases)  
• Total bilirubin < the institutional ULN or conjugated bilirubin ≤ 1.2 × ULN (need 
only be tested if total bilirubin exceeds ULN) or ≤ 3 × institutional ULN if due to 
Gilbert’s disease 
• Serum creatinine ≤1.5 × ULN or calculated creatinine clearance (CrCl) (estimated 
glomerular filtration rate [eGFR] can also be used in place of creatinine or CrCl) 
>50 mL/min for serum creatinine >1.5 × ULN  
• Hemoglobin ≥9 g/dL  
• International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN. 
Activated partial thromboplastin time (aPTT) ≤1.5 × ULN (unless receiving 


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anticoagulant therapy in which case values should be within therapeutic range of 
intended use) 
Any other Grade 3 or higher lab abnormalities should be discussed and approved by 
the Study Medical Monitor prior to enrollment (even if not considered clinically 
significant) 
8. Women of childbearing potential must agree to take appropriate precautions to avoid 
pregnancy, including the use of a medically acceptable method of highly effective 
contraception throughout the study and for 120 days after their final study drug 
administration. A barrier method of contraception must be employed regardless of other 
methods. Permitted methods that are at least 99% effective in preventing pregnancy 
should be communicated to the subject and their understanding confirmed. 
9. Functional gastrointestinal tract (defined as no enterocutaneous fistulas and no proximal 
stomas). Individuals with a venting gastrostomy tube must be able to tolerate clamping 
for 2 hours following oral drug administration. 
10. .Provides informed consent and is willing and able to comply with all study procedures. 
4.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in 
the study: 
1. Platinum-refractory disease (defined as progression during the first platinum-based 
chemotherapy)  
2. Major surgical procedure within 4 weeks prior to dosing 
3. Inaccessible tumors or for whom biopsy is contraindicated  
4. Clinically significant ascites 
5. Phase 2 only: Previous treatment with >3 chemotherapy regimens for locally advanced 
or metastatic disease 
• Repeat exposure to the same regimen separated in time by more than 3 months 
counts as 2 regimens 
• Regimens given as adjuvant therapy or as maintenance therapy after disease 
relapse are not included 
• Targeted agents will be included in the count  
• Bevacizumab will not count if administered as a single agent 
(There is no limit on the number of prior regimens for subjects entered into Phase 1) 
6. Active bowel obstruction, or hospitalization for bowel obstruction within 2 months prior 
to screening  
7. Requires parenteral nutrition or other agents aimed at improving performance status  
8. Hospitalization within 2 weeks prior to screening  


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9. Received any anticancer medication or therapy in the 21 days prior to first dose of study 
drug or any unresolved toxicity > Grade 1 from previous anticancer therapy, except for 
stable chronic toxicities that are not expected to resolve (i.e. peripheral neurotoxicity, 
alopecia, fatigue, etc.). Palliative radiotherapy is allowed if completed at least 2 weeks 
prior to first dose of study treatment. 
10. Prior monoclonal antibody treatment within 4 weeks before first dose of study drug, or 
not recovered (≤ Grade 1 or at baseline) from adverse events due to agents administered 
more than 4 weeks earlier 
11. History of listeriosis or previous treatment with a Listeria-based immunotherapy 
12. Known allergy to both penicillin and sulfa antibiotics  
13. Any immunodeficiency disease or immune-compromised state (e.g. use of 
immunosuppressive agents) or had systemic steroids, TNF pathway inhibitors, or PI3 
kinase inhibitors administered within 14 days prior to initiating study drug (use of 
inhaled or topical steroids or systemic corticosteroids <10 mg is permitted) 
14. Received prior immune checkpoint inhibitors (e.g. anti-CTLA-4, anti-PD-1, anti-PD-L1, 
and any other antibody or drug specifically targeting T cell costimulation) or an IDO 
inhibitor. Individuals who have received experimental vaccines or other 
immunotherapies must obtain approval from the Study Medical Monitor to confirm 
eligibility. 
15. Pregnant or breastfeeding; or intends to conceive a child from the start of screening 
through 120 days after the last dose of study drug 
16. Clinically significant heart disease (such as unstable angina, myocardial infarction 
within 6 months of study initiation, congestive heart failure, or New York Heart 
Association Class III or IV heart failure, or arrhythmia requiring therapy) 
17. Valvular heart disease that requires antibiotic prophylaxis for prevention of endocarditis, 
consistent with American Heart Association guidelines  
18. History of any autoimmune disease which required systemic therapy in the past 2 years 
including but not limited to: 
• Inflammatory bowel disease (including ulcerative colitis and Crohn’s Disease) 
• Rheumatoid arthritis 
• Systemic progressive sclerosis (scleroderma) 
• Systemic lupus erythematosus 
• Autoimmune vasculitis (e.g. Wegener’s granulomatosis) 
• Central nervous system or motor neuropathy considered of autoimmune origin 
(e.g. Guillain-Barre Syndrome, Myasthenia gravis, multiple sclerosis) 
Individuals with vitiligo, Sjogren’s Syndrome, interstitial cystitis, Graves’ or 
Hashimoto’s Disease, celiac disease, diabetes mellitus type 1, psoriasis, or 
hypothyroidism stable on hormone replacement will be allowed with Study Medical 
Monitor’s approval 


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19. Diagnosed with another malignancy within the past 3 years (excluding a history of 
carcinoma in situ of the cervix, superficial non-melanoma skin cancer, superficial 
bladder cancer, or endometrial cancer that has been adequately treated) 
20. Individuals with treated (surgically excised or irradiated) and stable brain metastases are 
eligible as long as the treatment was at least 4 weeks prior to initiation of study drug and 
baseline brain computed tomography (CT) with contrast or magnetic resonance imaging 
(MRI) within 2 weeks of initiation of study drug is negative for new brain metastases. 
Individuals with stable brain metastases must not require therapy with corticosteroids. 
21. History of interstitial lung disease  
22. Evidence of interstitial lung disease or active, noninfectious pneumonitis including 
symptomatic and/or pneumonitis requiring treatment 
23. Active infection requiring systemic therapy 
24. History of organ transplant that requires use of immunosuppressive therapy 
25. Received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant 
erythropoietin) within 4 weeks prior to first dose of study drug.  
26. Intercurrent illness that is either life-threatening or of clinical significance such that it 
might limit compliance with study requirements 
27. History of alcohol dependence or use of illicit drugs (e.g. opioids, cocaine, 
amphetamines, or hallucinogens) that could potentially interfere with adherence to study 
procedures or requirements 
28. Received a diagnosis of human immunodeficiency virus or human T-lymphotropic 
virus, or has a known history of, or is positive for, Hepatitis B (HBsAg reactive) or 
Hepatitis C (HCV RNA [qualitative] is detected) 
29. Received any prophylactic vaccine within 14 days of first dose of study drug or received 
a live vaccine within 30 days of first dose of study drug 
30. Has implanted medical devices that pose high risks for colonization and cannot be easily 
removed (e.g. artificial heart valves, pacemakers, prosthetic joints, orthopedic screw(s), 
metal plate(s)) if infection occurs. Other common devices such as venous access devices 
(e.g. Port-a-Cath or Mediport) may be permitted as well as arterial and venous stents and 
dental and breast implants that were placed more than 3 months prior to first dose of 
study drug. 
31. Known or suspected allergy or hypersensitivity to yeast or any other component of 
CRS-207 (e.g. glycerol); or known allergy or reaction to any component of epacadostat 
formulation; or any history of severe hypersensitivity reactions to pembrolizumab, its 
excipients or any monoclonal antibody therapy 
32. Currently receiving therapy with a UDP-glucuronosyltransferase 1A9 (UGT1A9) 
inhibitor including diclofenac, imipramine, ketoconazole, mefenamic acid, and 
probenecid. Individual may enter screening if therapy is able to be discontinued (a 7 
days washout period is required prior to first dose of epacadostat, or 5 half-lives have 
elapsed for the specific UGT1A9).  


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33. Presence of a gastrointestinal condition that may affect drug absorption 
34. Receiving monoamine oxidase inhibitors (MAOIs) or a drug which has significant 
MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before 
screening 
35. Any history of Serotonin Syndrome after receiving serotonergic drugs 
36. History or presence of an abnormal electrocardiogram (ECG) that, in the Investigator's 
opinion, is clinically meaningful. Screening QTcF interval >480 ms is excluded. In the 
event that a single QTcF is >480 ms, the subject may enroll if the average QTcF for the 
3 ECGs is <480 ms. For subjects with an intraventricular conduction delay (QRS 
interval >120 ms), the JTc interval may be used in place of the QTcF with Sponsor 
approval. The JTc must be <340 ms if JTc is used in place of the QTcF. Individuals with 
an intraventricular delay due to a left bundle branch block are excluded. 
Note: QTcF prolongation due to pacemaker may enroll if the JTc is normal. 
37. Uses more than 4 g/day of acetaminophen 
38. Has an unhealed surgical wound 
39. Insufficient peripheral venous access to permit completion of the study dosing and 
compliance with study phlebotomy regimen 
40. Participated in any other study in which receipt of an investigational new drug occurred 
within 28 days of first dose of study drug  
41. Unwilling or unable to follow the study schedule for any reason. 
4.3 
Dose Eligibility 
4.3.1 
CRS-207 
Subjects must have adequate organ function as defined by the laboratory values in Table 4 prior 
to each dosing cycle where CRS-207 is administered. The Study Medical Monitor will be notified 
of any dose delays due to safety concerns (eg if the subject is recovering from an AE or 
pembrolizumab infusion reaction) and to discuss a plan to resume treatment. If a dose is delayed 
beyond 7 days post pembrolizumab, the dose of CRS-207 should be withheld until the next Cycle. 
If dose is delayed more than 2 weeks, contact the Medical Monitor for further instruction on 
continued dosing. 
Table 4 
Dosing Eligibility Requirements for CRS-207 
Hematologic 
Renal 
Hepatic 
WBC ≥3000/µL 
ANC ≥1000/µL 
Platelets ≥100,000/µL 
Hemoglobin ≥8 g/dL 
Creatinine ≤1.5 × ULN  
AST/ALT ≤ 5 × ULN 
Bilirubin ≤ 1.5 × ULN OR ≤ 3 × 
ULN if due to Gilbert’s disease 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; ULN = upper limit of 
normal; WBC = white blood cell. 


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4.3.2 
Epacadostat and Pembrolizumab 
If the subject meets eligibility criteria for the study and is assigned or randomized to receive 
epacadostat BID and/or pembrolizumab, dosing may initiate and should continue per protocol. The 
Study Medical Monitor will be notified of any dose interruptions due to safety concerns (Section 
5.4.1). 
Pembrolizumab dosing may be delayed up to 2 weeks, after which time it will be considered 
missed and the subject would continue onto the next scheduled dose. If a dose is delayed more 
than 2 weeks, contact the Sponsor Medical Monitor for further instruction on continued dosing. 
4.4 
Subject Discontinuation 
A subject may be removed from treatment for any of the following reasons: 
• Occurrence of an adverse event that presents an unacceptable consequence or risk to the subject 
• Subject has received treatment, and there is no longer potential for clinical benefit (treatment 
should continue beyond initial progression of disease if there is potential for clinical benefit) 
• Noncompliance (failure to receive clinical study medication or treatment as mandated by the 
protocol, or failure to comply with protocol requirements)  
• A subject becoming pregnant while on study drug  
• Consent is withdrawn by the subject or legal representative 
• Study is discontinued by the Sponsor 
If a subject provides a baseline biopsy and then subsequently a second biopsy at Cycle 2 Day 15 
cannot be obtained due to safety or accessibility issues then the subject may remain on study 
treatment if they do not otherwise meet the criteria for withdrawal. 
Subjects may withdraw consent or discontinue from the study at any time for any reason. Every 
effort will be made to follow all subjects for PD and survival. If a subject withdraws prematurely 
from the study due to the above criteria or any other reason, study staff should make every effort 
to complete the full panel of assessments scheduled for the EOT and Safety Follow-up visits 
including the post-treatment monitoring for CRS-207. If the EOT Visit occurs >21 days after the 
last administration of study drug, procedures from the EOT and Safety Follow-up visits may be 
collected as a single Safety Follow-up Visit. The reason for subject withdrawal must be 
documented in the electronic Case Report Form (eCRF). 
In the case of subjects lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s study records. Sites will attempt to obtain vital status data (e.g. death 
or last date known alive) from public records or other external sources where possible if a subject 
withdraws consent from study (i.e. refuse follow-up for vital status) or is documented as lost to 
follow up. 


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5 
STUDY TREATMENTS 
5.1 
Treatment Arms 
Subjects will be assigned or randomized to the following treatment arms described in Table 5.  
Table 5 
ADU-CL-11 Treatment Cycles by Arm 
 
Phase 
 
Arm 
Dose 1 / Route 
Treatment Cycle 
 
1 
CRS-207 
CRS-207: 1 × 109 CFU by IV infusion 
over ~ 1 hour  
CRS-207:  Day 1 of each cycle (Cycles 1-
6); Q6W thereafter 
 
 
1 
CRS-207/ 
IDO 
CRS-207: 1 × 109 CFU by IV infusion 
over ~ 1 hour 
IDO:        100 mg or 300 mg BID Oral 
CRS-207:  Day 1 of each cycle (Cycles 1-
6); Q6W thereafter 
IDO:          BID starting Cycle 1 Day 2 
 
2 
CRS-207/ 
Pembro/ 
IDO 
Pembro:   200 mg by IV infusion over 30 
min 
CRS-207:  1 × 109 CFU by IV infusion 
over ~ 1 hour 
IDO:         300 mg Oral BID 1 
 
Pembro:    Day 1 of each cycle 
CRS-207:  Day 2 of each cycle (Cycles 1-
6); Q6W thereafter 
IDO:          BID starting Cycle 1 Day 3 
 
2 
CRS-207/ 
Pembro 
Pembro:   200 mg by IV infusion over 30 
min 
CRS-207: 1 × 109 CFU by IV infusion 
over ~ 1 hour 
 
Pembro:    Day 1 of each cycle 
CRS-207:  Day 2 of each cycle (Cycles 1-
6); Q6W thereafter 
 
BID = twice daily; CFU = colony-forming units; IDO = epacadostat; IV = intravenous; pembro = pembrolizumab; Q6W = 
once every 6 weeks 
1 RP2D of epacadostat based on Phase 1 dose-evaluation parameters and determined by the SRC; the Phase 2 dose may be 
further adjusted during Phase 2 Safety Run-in 
 
5.2 
Treatment Assignment 
Phase 1 of the study will be open-label and subjects will be assigned to Arms as specified in the 
study design (Section 3.1).  
Phase 2 of the study will be open-label and randomized. Subjects (including subjects enrolled in 
Safety 
Run-in) 
will 
be 
randomized 
in 
a 
1:1 
manner 
to 
receive 
CRS-207/ 
epacadostat/pembrolizumab or CRS-207/pembrolizumab.  
5.3 
Dose Limiting Toxicities 
During Phase 1, the DLT evaluation period is defined as Cycle 1 (21 days). 
During the Phase 2 Safety Run-in, the DLT evaluation period is defined as Cycle 1 (the first 21 
days). 
 


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5.3.1 
Non-Hematologic Events 
For non-hematological events, a DLT is defined as any treatment-emergent adverse event (TEAE) 
not attributable to disease or disease-related processes that occurs during the DLT observation 
period (Cycle 1) and is Grade 3 or higher according to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v4. 
In addition, any use of systemic steroids or a study drug dose interruption lasting more than 7 days 
for an adverse event with an unclear relationship to study drug will be considered a DLT even if 
the other DLT criteria are not fulfilled. 
The following non-hematological adverse events are NOT considered DLTs: 
• Grade 3 aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline 
phosphatase levels persisting for <7 days; 
• Grade 3 fatigue lasting <3 days; 
• Grade 3 nausea or vomiting that has resolved to ≤ Grade 2 within 48 hours with standard 
antiemetic therapies;  
• Grade 3 diarrhea that has resolved to ≤ Grade 2 within 48 hours with standard antidiarrheal 
therapies;  
• Grade 3 fever; 
• Grade 3 or 4 laboratory finding that is asymptomatic and rapidly reversible (returned to 
baseline or ≤ Grade 1 within 7 days) unless identified as clinically significant by the 
Investigator; 
• Any Grade 3 or lower change in cholesterol or triglycerides or asymptomatic change in lipid 
profile; and/or 
• Singular or non-fasting elevations in blood glucose (i.e. blood glucose excursions will be 
considered a DLT if fasting blood glucose is elevated (Grade 3 or higher) on 2 separate 
occasions).  
5.3.2 
Hematologic Events 
For hematologic events, a DLT is defined as follows: 
• Grade 4 neutropenia lasting >7 days; 
• Grade ≥3 febrile neutropenia; 
• Grade 4 anemia; 
• Grade 4 thrombocytopenia or ≥ Grade 3 thrombocytopenia lasting >7 days or associated with 
bleeding; and/or 
• Dose delay >7 days secondary to myelosuppression. 
Toxicities will be monitored throughout the study, and if the toxicity levels in any Arm are 
unacceptable (>33% of subjects), then dosing will be suspended until further review and 
consideration by the SRC. 


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5.4 
Other Adverse Event Considerations 
5.4.1 
Dose Interruption, Modification, and Management of Events Associated with Study 
Treatments 
In some circumstances, it may be necessary to temporarily interrupt one or more study treatments 
as a result of adverse events that may have an unclear relationship to study drug.  
Any interruptions of >2 weeks or for LFT abnormalities must be discussed with the Study Medical 
Monitor before resuming treatment. Treatment with all study drugs should be withheld for 
drug-related Grade 4 hematologic toxicities, nonhematological toxicity ≥ Grade 3 (including 
laboratory abnormalities), and severe or life-threatening adverse events. 
Except in cases of emergency, it is recommended that the Investigator consult with the Study 
Medical Monitor (or other representative of the Sponsor) before temporarily interrupting therapy 
for reasons other than protocol-mandated medication hold. Additionally, the Investigator must 
notify the Study Medical Monitor and Study Project Manager via email before restarting study 
drug that was temporarily interrupted because of an adverse event. 
Dosing interruptions may be permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g. elective surgery, unrelated medical events, vacation, and/or 
holidays) upon review and approval from the Study Medical Monitor. Subjects should be placed 
back on study therapy within 3 weeks of the scheduled interruption, unless otherwise discussed 
with the sponsor. The reason for interruption should be documented in the subject's study record. 
Pembrolizumab may be administered up to 3 days before or after the scheduled Day 1 of each 
cycle due to administrative reasons. CRS-207 must be administered one day after pembrolizumab 
administration. 
5.4.2 
Criteria and Procedures for Dose Modification 
CRS-207 has been well tolerated to date. The major safety signals have been infusion related 
reactions (Section 5.5.2.1). If a dose reduction of CRS-207 is being considered then the Study 
Medical Monitor should be contacted for further discussion. 
Epacadostat dose may be reduced according to the guidelines and dose levels described in Table 
6. Additional information related to dose changes for epacadostat for specific adverse events can 
be found in Section 5.4.3.3 for immune-related Adverse Events (irAEs) and Section 5.4.6 for an 
adverse event of SS. Dose modifications for pembrolizumab-related events are provided in 
Table 7. 
If the subject experiences a new TEAE or is recovering from a TEAE, CRS-207 administration 
may be delayed up to 7 days following pembrolizumab administration; the Sponsor must be 
notified. If a dose of CRS-207 is delayed beyond 7 days of pembrolizumab, the dose of CRS-207 
should be withheld until the next cycle. 
 
 
 
 


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Table 6 
Dose Modification Guidance for Epacadostat 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Dose Level for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Related: Reduce by 1 dose level 
Not Related: Same dose level  
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
n/a 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin1 
2 
Toxicity resolves to Grade 0-1 
Related: Reduce by 1 dose level 
Not Related: Same dose level  
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)2 
n/a  
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset)  
 
T1DM  
 
 
Hold epacadostat for new onset Type 1 
diabetes mellitus. Resume epacadostat when 
subjects are clinically and metabolically 
stable. 
Related: Reduce by 1 dose level 
Not Related: Same dose level  
Resume epacadostat when subjects are clinically and 
metabolically stable 
Hyperglycemia 
 
3-4 
 
Hold epacadostat for Grade 3-4 
hyperglycemia associated with evidence of 
beta cell failure. Resume epacadostat when 
subjects are clinically and metabolically 
stable. 
Related: Reduce by 1 dose level 
Not Related: Same dose level 
Resume epacadostat when subjects are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Therapy with epacadostat can be continued 
while endocrine replacement therapy is 
instituted. 
Related: Reduce by 1 dose level 
Not Related: Same dose level 
 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
 
Hyperthyroidism 
3 
Toxicity resolves to Grade 0-1 
Related: Reduce by 1 dose level 
Not Related: Same dose level 
 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
 
4 
Permanently discontinue 
n/a 
 
Permanently discontinue 
Hypothyroidism 
1-4 
 
Therapy with epacadostat can be continued 
while thyroid replacement therapy is 
instituted 
n/a 
Therapy with epacadostat can be continued while 
thyroid replacement therapy is instituted 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Related: Reduce by 1 dose level 
 
                                                 
1 Subjects with bone metastasis related elevations at baseline, contact sponsor to discuss clinical management and possible dose reductions of epacadostat. 
2 For subjects with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline and lasts for at 
least 1 week then subjects should be discontinued. For subjects have transient Grade 3 AST/ALT levels persisting for < 7 days and do NOT require steroids, epacadostat may 
reduce by 1 dose level once AST/ALT returns to baseline.  


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Dose Level for Restarting 
Treatment 
Treatment Discontinuation 
Not Related: Same dose level 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
n/a 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Related: Reduce by 1 dose level 
Not Related: Same dose level 
 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
 
3-4 
Permanently discontinue 
n/a 
Permanently discontinue 
All Other Drug-
Related Toxicity 
3 or Severe3 
Toxicity resolves to Grade 0-1 
Related: Reduce by 1 dose level 
Not Related: Same dose level 
 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
 
4 
 
Permanently discontinue 
 
n/a 
Permanently discontinue 
                                                 
3 Subjects with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue epacadostat for persistent Grade 2 
adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 


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Table 7 
Pembrolizumab Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-
4 hyperglycemia associated with 
evidence of beta cell failure 
Resume pembrolizumab when subjects are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab can 
be continued while endocrine 
replacement therapy is instituted 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can 
be continued while thyroid 
replacement therapy is instituted 
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted 
 
Infusion 
Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite 
adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related 
Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE that recurs or any life-
threatening event. 
a For subjects with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% 
relative to baseline and lasts for at least 1 week then subjects should be discontinued. Grade 3 AST/ALT levels persisting for < 7 days, 
pembrolizumab may resume once AST/ALT has returns to baseline. 
 
b If symptoms resolve within one 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 mL/hr). Otherwise dosing will be held until symptoms resolve and the subject should be pre-medicated for the next 
scheduled dose; Refer to Table 9 for further management details. 
c Subjects with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue 
study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 
within 12 weeks of the last dose. 
 
5.4.3 
Immune-related Adverse Events 
Subjects who develop an adverse event thought to be immune-related should have additional 
testing to rule out other etiologic causes. If laboratory results or symptoms indicate a possible 


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irAEs, then additional testing should be performed to rule out other etiologic causes. If no other 
cause is found, then it is assumed to be immune-related.  
 
5.4.3.1 
Procedures and Supportive Care Guidelines for Subjects Exhibiting Immune-Related 
Adverse Events 
The treatment guidelines outlined in this section are intended to guide the Investigator if the events 
are deemed related to epacadostat or pembrolizumab. The Study Medical Monitor is available to 
discuss procedures for treating subjects exhibiting irAEs. 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator. Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below. Note that several courses of steroid tapering 
may be necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care.  
IV systemic antibiotic treatment in order to ensure clearance of CRS-207 should be administered 
prior to initiation of systemic steroids required to treat suspected irAEs. However systemic steroids 
can be administered at the same time as systemic antibiotics if necessary due to the subject’s 
condition. 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
o For Grade 3 and Grade 4 events, immediately treat with IV steroids. Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
• Diarrhea/Colitis:  
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).  
o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion. For Grade 2 or higher diarrhea, consider gastrointestinal 
consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists >3 days, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists >1 week, treat with IV steroids followed 
by high dose oral steroids.  
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 


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• Type 1 diabetes mellitus (T1DM) (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA): 
o For T1DM or Grade 3 and Grade 4 Hyperglycemia: 
− Insulin replacement therapy is recommended for T1DM and for Grade 3 and 
Grade 4 hyperglycemia associated with metabolic acidosis or ketonuria.  
− Evaluate subjects with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
• Hypophysitis: 
o For Grade 2 events, treat with 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. 
o For Grade 3 and Grade 4 events, 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:  
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. 
o Grade 2 hyperthyroidism events (and Grade 2 to Grade 4 hypothyroidism): 
− In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
− In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o Grade 3 and Grade 4 hyperthyroidism:  
− Treat with an initial dose of IV corticosteroid 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. 
• Hepatic: 
o For Grade 2 events, monitor LFTs more frequently until returned to baseline values 
(consider weekly or twice weekly if steroids are not initiated). 
− Treat with IV or oral corticosteroids. 
o For Grade 3 and Grade 4 events, treat with IV corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 


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• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3 and Grade 4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
5.4.3.2 
Procedures for other Severe Immune-Mediated Adverse Reactions, Including Ocular 
Manifestations 
All study drugs should be permanently discontinued for severe (Grade 4) irAEs. Systemic 
corticosteroid 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 should be permanently discontinued for immune-mediated ocular disease 
that is unresponsive to local immunosuppressive therapy. 
5.4.3.3 
Discontinuation Rules and Procedures for Immune-Related Adverse Events  
Adverse events of a potential immunologic etiology or irAEs may be defined as an adverse event 
of unknown etiology, associated with drug exposure and consistent with an immune phenomenon. 
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 adverse events 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 to rule out neoplastic, infectious, metabolic, toxin, 
or other etiologic causes prior to labeling an adverse event as an irAE. If other causes exist, 
additional supportive care may be required.Subjects who develop a ≥ Grade 2 irAE should be 
discussed immediately with the Sponsor. 
General supportive care recommendations to manage irAEs due to epacadostat are detailed in 
Table 8. In addition, recommendations for prophylactic and supportive care measures of specific 
irAEs, infusion reactions, pneumonitis, hepatitis, dermatitis, immune-mediated neuropathies, 
immune-mediated endocrinopathies, and ocular manifestations are detailed throughout 
Section 5.4. 
irAEs may be attributable to one or more study drugs. If the event is clearly related to one of the 
agents, follow the instructions specific for that agent, if available. If the event is related to multiple 
agents, follow the action taken instructions provided, or consult the Study Medical Monitor. 
 
 


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Table 8 
General Guidelines for Immune-Related Adverse Events Due to Epacadostat 
irAE Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat* 
Action Taken With Respect to 
Epacadostat 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic treatment. 
Grade 2 
May withhold 
epacadostat per 
Investigator's 
discretion. 
May return to treatment if 
improves to Grade 1 or resolves 
within 6 weeks. If adverse event 
resolves within 4 weeks, subject 
may restart at the same dose and 
schedule for epacadostat. 
For an adverse event that does not 
resolve within 4 weeks, 
epacadostat should be reduced 
1 dose level. If adverse event does 
not resolve within 6 weeks, study 
treatment with epacadostat should 
be discontinued or discussed with 
Study Medical Monitor. 
Consider systemic 
corticosteroids in addition to 
appropriate symptomatic 
treatment. 
Grade 3 
Withhold or 
discontinue 
epacadostat. 
Discontinue if unable 
to reduce 
corticosteroid dose to 
<10 mg/day of 
prednisone or 
equivalent within 6 
weeks of toxicity. 
Any restart of study treatment 
must be discussed with Study 
Medical Monitor prior to restarting 
treatment. 
Systemic corticosteroids are 
indicated in addition to 
appropriate symptomatic 
treatment. May use 1 to 
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 
epacadostat. 
Not applicable. Any exceptions 
require Study Medical Monitor 
approval. 
Systemic corticosteroids are 
indicated in addition to 
appropriate symptomatic 
treatment. May use 1 to 
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. 
irAE = immune-related adverse event. 
*in any of the above scenarios where epacadostat is held or discontinued, contact the Study Medical Monitor for guidance on 
continuation of CRS-207 treatment. 
Note that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
 


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5.4.4 
Management of Infusion Reactions Associated with Pembrolizumab 
Signs and symptoms usually develop during or shortly after pembrolizumab infusion and generally 
resolve completely within 24 hours of completion of infusion. Table 9 shows treatment guidelines 
for subjects who experience an infusion reaction associated with administration of pembrolizumab. 
The Study Medical Monitor will be consulted regarding continued dosing of CRS-207 and/or 
epacadostat should any of the events listed in Table 9 occur. 
Table 9 
Pembrolizumab Infusion Reaction 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 subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
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 subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one 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 mL/hr). Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
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: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
5.4.5 
Supportive Care  
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator, including, but not limited to, the items outlined below: 


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• Nausea/vomiting: nausea and vomiting should be treated aggressively, and prophylactic 
antiemetic therapy should be used according to standard institutional practice. If a subject 
requires daily administration of an antiemetic, an alternative to dexamethasone should be used. 
Subjects should be strongly encouraged to maintain liberal oral fluid intake. 
5.4.6 
Procedures for Subjects Exhibiting Serotonin Syndrome  
As noted in Section 1.3.4, there is a theoretical chance that epacadostat could cause an increase in 
serotonin levels in the brain that might trigger SS when administered in combination with other 
serotonergic agents.60 This syndrome has been most closely associated with use of MAOIs, 
Demerol®, linezolid, or methylene blue; all of these agents are prohibited during the study (see 
Appendix D for prohibited medications associated with MAO inhibition). SSRIs and 
serotonin/norepinephrine reuptake inhibitors (SNRIs) are permitted in the study. Subjects will be 
provided with an informative subject leaflet describing the signs and symptoms of the syndrome 
along with instructions to seek immediate medical care if any of these signs or symptoms are 
observed. The following procedures will be implemented if subjects exhibit the signs/symptoms 
of SS described in Table 10, including tremor; hyperreflexia; and spontaneous, ocular, or inducible 
clonus, together with agitation, fever, diaphoresis, or muscle rigidity: 
• Immediately interrupt all study drug administration; 
• Immediately interrupt any SSRI or SNRI administration; 
• Provide appropriate medical management of the subject 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 subject chooses to remain in the study, restart treatment with epacadostat 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 treatment 
MAY NOT be restarted; and 
• If subject chooses to withdraw from the study or must restart treatment with SSRI or SNRI, 
the subject 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. 
Table 10 Signs and Symptoms of Serotonin Syndrome 
Tremor and hyperreflexia 
Spontaneous clonus 
Muscle rigidity, temperature >38°C (100.4°F), and either ocular clonus or inducible clonus 
Ocular clonus and either agitation or diaphoresis 
Inducible clonus and either agitation or diaphoresis 
5.5 
Drug Supplies 
5.5.1 
Formulation, Packaging, Preparation, and Dispensing 
5.5.1.1 
CRS-207 
CRS-207 is a formulated live-attenuated strain hMeso38 of Lm, derived by deletion of actA and 
inlB coding sequences from a Streptomycin-resistant, wild-type strain and insertion of the hMeso 
coding sequence. The CRS-207 drug product consists of attenuated Lm (1 × 109 CFU total) 


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suspended in 
. The drug 
product is filled at a volume of 1.5 mL into a single-use 2R injection glass vials with a gray butyl 
stopper and aluminum crimp seal with a flip-off cap, and stored frozen at -60ºC or colder until IV 
administration. CRS-207 is supplied by Aduro Biotech. 
5.5.1.2 
Epacadostat 
Epacadostat (INCB024360) is formulated as an immediate release tablet. For this study, 25 mg 
and 100 mg tablets will be available. 
 
 
 
 
 
 
Epacadostat will be packaged in high-density polyethylene bottles of 35 tablets. Bottles will be 
labeled in the local language, and will comply with the legal and regulatory requirements of each 
country. 
Epacadostat tablets will be dispensed on Day 1 of each indicated cycle in a sufficient amount 
required for the period of time until the next visit. Subjects will be provided a dosing diary and 
instructed to record each study drug dosing. Subjects will be instructed to return all unused study 
drug at the next visit. 
Epacadostat is supplied by Incyte Corporation. 
5.5.1.3 
Pembrolizumab 
Pembrolizumab, a humanized monoclonal antibody, is formulated and supplied as either a 
lyophilized powder or solution. 
Pembrolizumab for injection is a sterile, preservative-free, white to off-white lyophilized powder 
in single-use vials. Each vial is reconstituted and diluted for intravenous infusion. Each 2 mL of 
reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 mg), 
polysorbate 80 (0.4 mg), and sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide 
to adjust pH to 5.5. 
Pembrolizumab for injection is a sterile, preservative-free, clear to slightly opalescent, colorless to 
slightly yellow solution that requires dilution for IV infusion. Each vial contains 100 mg of 
pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and 
is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for 
Injection, USP.  


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5.5.2 
Study Drug Administration 
5.5.2.1 
CRS-207 
CRS-207 is intended for administration by IV infusion (no in-line IV filter should be used). 
Additional details for storage and preparation of CRS-207 are provided in the study Pharmacy 
Manual. 
Use of Central Lines: 
To avoid contamination of a central line (e.g. infusion ports, peripherally inserted central catheter 
lines) with CRS-207 during and after infusion: 
• 
 CRS-207 must NOT be administered through a central line or infusion ports; 
• Central lines must NOT be used or accessed for any reason once the CRS-207 infusion 
has been initiated (including blood draws, medication administration, or line flushing; 
blood draws prior to infusion through a port or central line are allowed) and through 4 
days after infusion;  
• Central lines must be clearly labeled with tape or other method indicating the date when 
the port may be used again after CRS-207 infusion. 
Pre-Medication and Post-Infusion Observation 
Before each CRS-207 infusion, subjects should be pre-medicated with 650 mg (or the maximum 
dose permitted by label) acetaminophen (paracetamol). Subjects allergic to acetaminophen may 
receive 800 mg ibuprofen. All subjects are required to receive a minimum of 500 mL of normal 
saline immediately before CRS-207 infusion; an additional 0.5 - 1 L after infusion is 
recommended, as tolerated. Additional fluids may be given for persistent tachycardia, fever, or 
hypotension based on Investigator’s discretion.  
Subjects will be observed in the clinic for at least 4 hours after the first CRS-207 infusion and at 
least 2 hours following each subsequent infusion. Subjects should continue to be monitored after 
infusion and released once they are considered clinically stable. Vital signs (blood pressure [BP], 
pulse, respiratory rate, temperature) will be obtained every 30 minutes during the CRS-207 
infusion and every hour during post-infusion follow-up. Presence of fever alone does not preclude 
the subject from being released. Hospital admissions for overnight monitoring will not be 
considered an SAE unless the event meets criteria for seriousness other than hospitalization. 
Accumulating subject experience during and after CRS-207 infusions at 1 × 109 CFU has further 
demonstrated the following clinical observations, which are to be expected: 
• Fevers: Despite the acetaminophen premedication, subjects can spike fevers up to 40°C 
starting at the end of the CRS-207 infusion generally through the next 24 hours. Oral ibuprofen 
(400 to 800 mg) and acetaminophen (650 to 1000 mg) can be used in alternate sequence every 
4 hours. Rarely, a cooling blanket has been used during the clinic stay. Fevers after 24 hours 
are uncommon and rare after 36 hours. 
• Rigors: Rigors/chills have been observed starting during or at the end of the CRS-207 infusion 
through 24 hours. IV narcotics such as morphine (use of meperidine is prohibited per protocol) 
can be administered per institutional policy.  


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• BP: Small drops in BP have been observed necessitating additional IV fluids during the 4 hour 
observation period (up to 1 or 2 L). Reasons for this include the development of may 
experience fever, compartmental shifts of fluid resulting from the CRS-207 infusion, and the 
use of narcotics. Some subjects have also been slightly hypotensive at 24 hours upon arrival to 
the clinic on Day 2. Subjects are encouraged to hydrate themselves liberally at home with oral 
fluids. 
• Appetite: Appetite is generally suppressed during the 24 hours after CRS-207 infusion related 
to the factors listed above. Liberal intake of fluids is encouraged. 
• Nausea and vomiting: Nausea and vomiting have been reported and observed infrequently 
within 24 hours after CRS-207 infusion. 
For more information, Refer to Section 5.6.1 and the IB for additional details on CRS-207 
administration and supportive care. 
5.5.2.2 
Epacadostat 
Subjects will take their dose of epacadostat in the morning and evening, approximately 12 hours 
apart without respect to food. If a dose is missed by more than 4 hours, that dose should be skipped 
and should be resumed at the scheduled time. Subjects will self-administer epacadostat except as 
specified in the Schedule of Events, when the morning dose will be given at the study site clinic. 
5.5.2.3 
Pembrolizumab 
Pembrolizumab will be diluted and administered as a dose of 200 mg using a 30-minute IV 
infusion. Sites should target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps, a window between -5 minutes and +10 minutes is 
permitted (i.e. infusion time is 30 minutes -5 min/+10 min). Do not co-administer other drugs 
through the same infusion line. Pembrolizumab infusions will be administered Q3W for up to 24 
months. The instruction for use contains specific instructions for the preparation of the 
pembrolizumab infusion and administration of infusion solution. 
5.5.3 
Treatment Compliance 
All study drugs will be administered only to subjects participating in the study and complying with 
the instructions from the Investigator. 
CRS-207 and pembrolizumab will be administered only by study personnel. 
Compliance to the epacadostat study drug regimen will be evaluated by counting unused 
epacadostat tablets and reviewing the dosing diary. The objective is 100% compliance, and 
Investigators and their staff should evaluate compliance at each visit and take appropriate steps to 
optimize compliance. During the active treatment period, if compliance is not between 80% and 
120%, inclusive, the subject will be counseled about the importance of compliance to the regimen. 
If outside these limits at 2 consecutive visits, the subject will be withdrawn from the study unless 
there is a sound reason for the compliance deviation.  


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5.5.4 
Investigational Product Storage  
5.5.4.1 
CRS-207 
CRS-207 must be stored at -60ºC or colder until just before use. 
CRS-207 Environmental Precautions 
In wild-type form, Lm is a bacterium commonly found in soil and water, and may be present in a 
variety of raw and processed foods. Listeriosis is a foodborne illness caused by wild-type Lm which 
primarily affects pregnant women and immunocompromised individuals. Direct human-to-human 
spread of Lm is believed to be limited mainly to vertical transmission from mother to neonate. 
CRS-207 is a LADD construct originating from wild-type Lm which contains deletions of 2 
virulence genes that render it greater than 1000-times less toxic than wild-type Lm in mice.28 
LADD-based immunotherapies (Lm ΔactA/ΔinlB), including CRS-207, have been designated as 
Risk Group 1 by the Aduro Institutional Biosafety Committee. Risk Group 1 is consistent with the 
guidance by the German ZKBS (Central Commission for Biological Safety) for classification of 
Lm strains with deletion in genes prFA, hly, actA, and plcB.62 Individuals who prepare CRS-207 
for infusion must take appropriate precautions (e.g. gloves, laboratory coat, face protection, needle 
stick or sharps precautions) to avoid contamination or direct contact with the agent. Once prepared 
for infusion, the chance for direct exposure to CRS-207 by study personnel should be greatly 
diminished. However, study personnel and staff should continue to adhere to the institutional 
guidelines for standard precautions.  
Based on nonclinical studies and available clearance and shedding data from clinical studies, a 
subject who receives CRS-207 is unlikely to spread an infection to others. Subjects receiving CRS-
207 should be counseled to minimize the potential risk of spreading CRS-207 by practicing good 
health hygiene (e.g. hand-washing) as with any potential infectious agent, and adhering to protocol 
requirements for barrier method of contraception during sexual intercourse. 
5.5.4.2 
Epacadostat 
Epacadostat drug product should be stored at ambient conditions (15°C to 30°C). 
5.5.4.3 
Pembrolizumab 
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. 
If supplied as solution, do not freeze or shake. 
5.5.5 
Investigational Product Accountability 
The Investigator is responsible for the control of investigational products under study. The 
investigational product must be used only in accordance with the Protocol. An investigational 
product dispensing log for CRS-207. epacadostat, and pembrolizumab must be kept current and 
should contain the following information: 
• Delivery of study drug to the study site, 
• Inventory of study drug at the site, 
• The date and quantity of investigational products administered (including pill or vial counts 
from each supply dispensed [epacadostat] and/or administered [CRS-207, pembrolizumab]) to 
the subject, 


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• Return of study drug to the Investigator or designee by subjects (for epacadostat), 
• Documentation of proper disposal of used investigational product, and 
• Documentation of proper disposal (or return, at Sponsor’s request) of unused investigational 
product.  
Inventory and accountability records must be maintained and readily available for inspection by 
the study monitor and are open to inspection at any time by any applicable regulatory authorities. 
At sites where destruction of the study drug is required before monitor inspection, the monitors 
rely on documentation of destruction per the site Standard Operating Procedures to verify drug 
accountability. 
CRS-207 and Pembrolizumab 
The investigational sites, per institutional guidelines, will destroy used CRS-207 and 
pembrolizumab vials after formulation for administration. The formulation of CRS-207 and 
pembrolizumab for administration and the destruction of each used vial will be carefully 
documented in the study Pharmacy Manual. Unused CRS-207 and pembrolizumab will be 
destroyed at the study site after final investigational product accountability and notification by 
Sponsor, unless otherwise directed by Sponsor or if Sites Drug Destruction SOPs requires return 
to the Study Sponsor.  
Epacadostat 
The Investigator or designee will be expected to collect and retain all used, unused, and partially 
used containers of epacadostat until verified by the study monitor (unless otherwise agreed to by 
the Sponsor). At the conclusion of the study, the Investigator or designee will oversee shipment of 
any remaining epacadostat back to the Sponsor or its designee for destruction according to 
institutional Standard Operating Procedures. If local procedures mandate on-site destruction of 
investigational supply, the site should (where local procedures allow) maintain the investigational 
supply until the study monitor inspects the accountability records in order to evaluate compliance 
and accuracy of accountability by the investigative site.  
5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Permitted Medications and/or Procedures 
During the course of the clinical study, subjects are anticipated to continue the use of prescribed 
medications identified during the screening procedures, consistent with study inclusion and 
exclusion criteria. Permitted concomitant medications used in this study include: 
• 7-day antibiotic regimen scheduled 7 days after the last dose of CRS-207 (Section 5.6.3) 
• Acetaminophen (paracetamol; ibuprofen if allergic to acetaminophen) prior to each CRS-207 
infusion (no more than 4 g/d of acetaminophen) 
• Antipyretics to treat fever or to prevent recurrence of fever 
• Antiemetics according to American Society for Clinical Oncology guidelines.63 If daily 
administration of an antiemetic is required, an alternative to dexamethasone should be used. 
• IV narcotics such as morphine (per institutional policy) for rigors associated with CRS-207 
dosing (use of meperidine is prohibited per protocol). 


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• Palliative (limited-field) radiation therapy is permitted for all anatomic sites except lung, but 
only for pain control to sites present at baseline and with approval by the Study Medical 
Monitor.  
 
5.6.2 
Restricted Medications and/or Procedures 
The following therapies are not permitted during the study (if administered, the subject may be 
removed from the study): 
• Non-study chemotherapy or immunotherapy (approved or investigational) 
• TNF pathway inhibitors or PI3 kinase inhibitors 
• Systemically active steroids for more than 3 days or use of any systemic steroids within 21 days 
before or after dosing, with the exception of study-prescribed steroids 
• Any other investigational product  
• Filgrastim (Neupogen® or granulocyte colony-stimulating factor) or Sargramostim (Leukine® 
or GM-CSF) should not be administered 14 days prior to or 14 days after any CRS-207 dose. 
Approval must be obtained from the Study Medical Monitor for a subject to continue dosing 
if administered within this timeframe. 
• Prophylactic vaccines (e.g. pneumococcal vaccine, influenza vaccine) should not be 
administered 14 days prior to or 14 days after any CRS-207 dose. Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed within specified timeframes. 
However, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are 
not allowed. Approval must be obtained from the Study Medical Monitor for a subject to 
continue dosing if a prophylactic vaccine is administered within this timeframe. 
• Live vaccines (examples of live vaccines include, but are not limited to: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, BCG, intranasal influenza vaccines (e.g. Flu-Mist®) 
and typhoid [oral] vaccine) and prohibited while on study treatment.  
• Any UGT1A9 inhibitor, including acitretin, amitriptyline, androsterone, cyclosporine, 
dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, estradiol (17-beta), flutamide, geftinib, 
gemfibrozil, glycyrrhetinic acid glycyrrhizin, imatinib, imipramine, ketoconazole, linoleic acid 
supplements, mefenamic acid, mycophenolic acid, niflumic acid, nilotinib, phenobartital, 
phenylbutazone, 
phenytoin, 
probenecid 
propofol, 
quinidine, 
ritonavir, 
sorafenib, 
sulfinpyrazone, valproic acid, and verapamil (note: propofol, when used for short-term 
sedation during surgical/biopsy procedures, is allowed after consultation with the Sponsor. The 
epacadostat dose may be taken on the morning of the procedure, and the evening dose held 
following the procedure. Epacadostat may be resumed the next day.) 
• 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.  
• 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 (see Appendix D). 


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• Any planned or emergency major surgery or surgical procedure; minor surgical procedures 
should be discussed with the Study Medical Monitor to determine if it is appropriate for the 
subject to continue study treatment. Placement of new implants or prosthetic devices will 
require subjects on CRS-207 to be discontinued from study treatment. 
In addition, the following therapies should not be administered during the study unless medically 
necessary and approval must be obtained from the Study Medical Monitor for a subject to continue 
dosing if therapy is given concurrently with study participation: 
• General anesthesia or deep sedation 
• Aspirin >325 mg/d (chronic daily use of aspirin ≤325 mg/d is allowed) 
• More than 4 g/d of acetaminophen  
• Systemic antibiotics 
• Use of coumarin-based anticoagulants (e.g. Coumadin) is discouraged. Low-dose Coumadin 
(1 mg) is acceptable; however, doses that increase the INR are discouraged and will require 
dose modification. If an alternative to coumarin-based anticoagulants cannot be used, dose 
adjustment of the Coumadin may be needed. Based on the observed magnitude of 
epacadostat/warfarin PK interaction and PK/PD modeling results, for an epacadostat dose of 
300 mg BID, the dose of warfarin should be reduced by approximately one-third after initiation 
of epacadostat administration based on approximately 30% to 40% reduction in S- and R-
warfarin oral clearance values. Close INR monitoring is recommended for subjects on a stable 
dose of warfarin who are starting treatment with epacadostat. Based on PK/PD modeling, 
recommendations for warfarin dose modifications for subjects receiving other epacadostat 
doses, are summarized in Table 11 below based on the INR prior to starting epacadostat. 
Table 11 Warfarin Dose Modifications 
Stable Baseline INR 
Epacadostat Dose 
≤ 100 mg BID 
200 mg BID 
300 mg BID 
INR ≤ 2.5 
Close INR 
monitoring 
Close INR monitoring 
Reduce warfarin by ~33% 
and monitor INR 
INR > 2.5 
Close INR 
monitoring 
Reduce warfarin by 20-
25% and monitor INR 
Reduce warfarin by ~ 
33% and monitor INR 
If subjects receive immunosuppressive medications on or after study, prophylactic antibiotics to 
prevent CRS-207 infection are strongly recommended for the duration of the treatment with the 
immunosuppressant (recommended oral 80 mg trimethoprim / 400 mg sulfamethoxazole once 
daily or 160 mg trimethoprim / 800 mg sulfamethoxazole (DS) three days a week). 
5.6.3 
Antibiotic Administration  
Any subject who received CRS-207 will be administered a 7-day course of antibiotics at the EOT 
visit (once blood is drawn for cultures) and prior to receiving subsequent cancer-related (non-
study) therapy. Site personnel will contact the subject to confirm compliance with antibiotic 
treatment. 
Subjects with a central line port will receive 1 dose (2 g ampicillin or 3-5 mg/kg 
trimethoprim/sulfamethoxazole [in penicillin-allergic subjects]) of IV antibiotics through the port, 
followed by 6 days of oral antibiotics (the recommended course of oral amoxicillin (500 mg at 8-


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hour intervals) or trimethoprim/sulfamethoxazole in penicillin-allergic subjects (160 mg 
trimethoprim/800 mg sulfamethoxazole at 12-hour intervals); all other subjects will receive a 7-
day course of oral amoxicillin or trimethoprim/sulfamethoxazole (in penicillin-allergic subjects).  
During or after study treatment, subjects who are confirmed to have a blood culture positive for 
CRS-207 after more than 7 days post-infusion, will receive a minimum 14-day course of IV 
antibiotics (see Section 5.6.3.2 below).  
Consult the package inserts for amoxicillin, trimethoprim, and sulfamethoxazole for product 
information on dosage and administration, contraindications, warnings/precautions, adverse 
reactions, and drug interactions. 
5.6.3.1 
Suspected Infection with CRS-207 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
5.6.3.2 
Antibiotic Treatment for CRS-207 Infection 
 
 
 
 
 
 
 
 
 
 
 


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5.6.4 
Documentation of Prior and Concomitant Medication and Therapy Use 
All concomitant medications, therapies, and measures must be recorded in the eCRF, and any 
medication or therapy received or procedure performed within 28 days before study treatment 
begins and 30 days after the last dose of study drug, or until the subject completes the Safety 
Follow-up Visit, will be recorded in the eCRF. In addition, all prior and post-study treatment 
cancer-related therapies and procedures will be recorded in the eCRFs. The generic name, dosage, 
duration, and reason for the concomitant medication or therapy should be documented.  
Any changes to concomitant medication or therapy will also be documented. The medication 
record will be maintained after signing the informed consent form (ICF) to document concomitant 
medications and therapies, including any changes to the dose or regimen. Concomitant 
medications include any prescription, over the counter medications, or natural/herbal preparations 
taken or administered during the study period. Concomitant treatments and/or procedures that are 
required to manage a subject's medical condition during the study will also be recorded in the 
eCRF.  


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6 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the Schedule of Events. The order of 
procedures is suggested by the order of mention within the schedule. See below for description 
and instructions on each assessment. Further details of study procedures and assessments can be 
found in the study reference manual.  
6.1 
Screening Period 
Before screening assessments are conducted, the subject must be given a thorough explanation of 
the purpose and evaluations of the study. Subsequently, the subject must sign and receive a copy 
of an ICF that was approved by the Institutional Review Board (IRB) or Ethics Committee and 
Institutional Biosafety Committee (IBC) and an authorization for use and disclosure of protected 
health information before any study-specific procedure is performed. The ICF must be obtained 
before performing any study-specific procedures. However, assessments done as part of standard 
of care prior to ICF may be used if they are within the required screening period. An original 
signed consent form will be retained in the subject’s source documentation at the site, and a copy 
will be provided for the subject to take home.  
The Screening Period will be up to 28 days. Screening is the interval between the signing of the 
ICF and the day the subject receives the first dose of treatment in the study (Cycle 1 Day 1). 
Potential subjects will be evaluated for entry into the study according to the stated inclusion and 
exclusion criteria. Subjects who are identified during this screening as not eligible for study 
enrollment do not need to complete all screening procedures. The reason for ineligible status will 
be documented. 
Procedures conducted as part of the subject's routine clinical management (e.g. blood count, 
imaging study) and obtained before signing of informed consent may be used for screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed in the required timeframe of the study (i.e. within 28 days of Cycle 1 Day 1). All 
information associated with eligibility requirements must be entered into the appropriate eCRF 
pages. 
Tests with results that fail eligibility requirements may be repeated once during the screening 
period if the Investigator believes the results to be in error. Additionally, a subject who fails 
screening may repeat the screening process 1 time if the Investigator believes there has been a 
change in eligibility status (e.g. after recovery from an infection). 
The screening biopsy will be obtained once all other eligibility requirements are confirmed. 
Treatment assignment (Phase 1) or randomization (Phase 2) will be the final step in the screening 
process, prior to administration of study drug(s). 
6.2 
Treatment Period 
Treatment will commence on Cycle 1 Day 1. Subjects will be considered in the Treatment Period 
until completion of the EOT visit. Treatment may continue as long as the subject has not met any 
criteria for study withdrawal; pembrolizumab may be administered a maximum of 24 months. 
Subjects may continue on treatment with radiographic PD if subject is clinically stable and the 
Investigator believes the treatment is providing benefit. 
 


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6.3 
End-of-Treatment Visit (EOT) 
If a decision is made that the subject will permanently discontinue study drug, the EOT visit should 
be conducted as soon as possible after the last dose of study drug. If the EOT visit coincides with 
a regular study visit, the EOT evaluations will supersede those of that scheduled visit, and the data 
should be entered in the EOT page in the eCRF.  
If the EOT Visit is >21 days after the last administration of study drug, procedures from the EOT 
and Safety Follow-up visits may be collected as a single Safety Follow-up Visit. 
6.4 
Safety Follow-up Visit 
For all subjects, a Safety Follow-up Visit will be scheduled 30 days (+5 days) after the last dose 
of study drug. If the subject begins another anticancer therapy before the Safety Follow-up Visit, 
every effort will be made to complete all of the Safety Follow-up Visit assessments prior to 
commencing the new therapy. If a CT scan was collected within 9 weeks (±7 days) of the Safety 
Follow-up Visit, then a CT scan at the Safety Follow-up Visit will not be mandatory. Once new 
anticancer therapy has been initiated, the subject will move into the survival follow-up period. 
If there is an adverse event in need of monitoring beyond the Safety Follow-up Visit, the subject 
will be followed until resolution or confirmed stability of the adverse event. Adverse events and 
SAEs must be reported up until at least 30 days after the last dose of study drug, the date of the 
Safety Follow-up Visit, or until study drug-related toxicities resolve, return to baseline, or are 
deemed irreversible, whichever is longer. If a new anticancer therapy has been initiated, the subject 
will move into the survival follow-up phase. 
6.5 
Disease Follow-up 
Subjects who discontinue study treatment for a reason other than radiographically confirmed PD 
will move into the disease follow-up phase and should be assessed every 9 weeks (±7 days) by 
radiologic imaging and CA-125, to monitor disease status. Every effort should be made to collect 
information regarding disease status until the start of new anticancer therapy, documented PD, 
death, withdrawal of consent, or the end of the study, whichever occurs first. Information regarding 
post-study anticancer treatment will be collected if new treatment is initiated. 
6.6 
Survival Follow-up and CRS-207 Surveillance 
Once a subject has radiographically confirmed PD and discontinues study treatment, the subject 
moves into the Survival Follow-up phase. Subjects will be followed every 12 weeks (±7 days) by 
telephone or optional clinic visit to assess for survival status and subsequent cancer-related 
therapies. Blood for culture will also be collected for CRS-207 surveillance at 
 
. Survival follow-
up will continue until death, withdrawal of consent, or the end of the study, whichever occurs first. 
At the conclusion of the study, all remaining subjects who have received at least 1 dose of study 
treatment will be offered enrollment in a long-term follow-up study and continue to be followed 
for survival. 


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6.7 
Unscheduled Visit 
Unscheduled study visits may occur at any time if medically warranted. Additional assessments or 
blood draws may be necessary if clinically indicated. Any assessments performed at those visits 
should be recorded in the eCRFs. 


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7 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
7.1 
Study Enrollment 
For Phase 1, an enrollment form will be completed and sent to the Sponsor (or designee) for 
treatment assignment upon determining that the subject is eligible for study entry. This will occur 
prior to the Cycle 1 Day 1 visit.  
For Phase 2 (including Safety Run-in), upon determining that the subject is eligible for study entry, 
sites will contact the Interactive Response Technology (IRT) to obtain study Arm assignment.  
Further instructions for subject treatment assignment (Phase 1) and treatment randomization 
(Phase 2) are provided in the Study Reference and IRT Manuals. 
7.2 
Demographics and Medical History 
Demographic data and a disease-targeted medical and medication history will be collected at 
screening by the Investigator or qualified designee and will include date of birth, race, ethnicity 
(where allowed by local regulations), medical and surgical history, and concurrent illnesses 
assessed using the NCI CTCAE v4.64 Medical history should include all active conditions and any 
condition considered to be clinically significant by the Investigator. Details regarding the disease 
for which the subject has enrolled in this study (e.g. date of diagnosis, primary tumor histology, 
prior systemic therapies, surgeries, radiation therapy, and stage of cancer) will be recorded 
separately and not listed in medical history. 
7.3 
Distribution of Subject Dosing Diary and Reminder Cards 
Subjects may be provided with reminder cards at each visit. The subject reminder card will indicate 
the date/time of the next visit, and will also remind the subject when they should not take their 
morning dose of study drug (if they are receiving epacadostat).  
Subject daily dosing diaries will be provided to subjects taking epacadostat in order to track date 
and time of all doses taken between clinic visits. Subjects will be instructed to return any unused 
study drug at each visit. All returned study drug must be held in quarantine until the Sponsor or 
representative (Clinical Research Associate [CRA]) completes drug accountability. Dosing diaries 
will be reviewed against unused study drug and any discrepancies will be noted and reviewed with 
the subject (Section 5.5.3). 
Subjects receiving epacadostat will also be given an SS information sheet prior to their first dose 
of epacadostat. The information sheet describes signs and symptoms of SS and also instructs 
subjects to seek immediate medical care if any of these symptoms are observed. 
7.4 
Blood Cultures for CRS-207 Surveillance 
Blood samples from subject’s peripheral vein will be obtained at EOT and at all visits indicated 
after EOT to monitor for presence of CRS-207. For subjects with a central line port, a blood sample 
will also be taken through the port at time points indicated for CRS-207 testing. Subjects with 
samples positive for the presence of CRS-207 will initiate IV antibiotics per Section 5.6.3.2 and 
be re-tested until negative cultures are confirmed. 


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7.5 
Tumor Biopsy 
Detailed instructions for fresh tissue collection, processing, and shipment, as well as details for 
processing and shipping the archived tumor tissue samples, are provided in the Laboratory Manual. 
Biopsies are to be performed in accordance with standard techniques. Biopsies may be from an 
area of primary or metastatic disease. The area biopsied should be recorded. The same area should 
be biopsied for post-treatment biopsy.  
Paired tumor biopsies (pre-dose and on Cycle 2 Day 15 [+7 days]) are mandatory during the study. 
Biopsies should not be collected within 1 day of CRS-207 or pembrolizumab administration. If 
additional biopsies or relevant samples (e.g. pleural fluid) are collected for routine care during the 
course of study, a sample should be retained if possible for Sponsor research evaluation. 
The tissue sample should have proper size to enable IHC analysis. Fine needle aspiration will not 
be acceptable. If a subject provides a baseline biopsy and then subsequently a second biopsy at 
Cycle 2 Day 15 cannot be obtained due to safety or accessibility issues then the subject may remain 
on study treatment if they do not otherwise meet the criteria for withdrawal. 
Tumor samples will be used to determine change in CD8/Treg (FoxP3) ratio before and post-
treatment. Tumor IDO1, PD-L1 and mesothelin protein expression, degree and type of immune 
cell infiltration by IHC or another related method will be performed. Other exploratory biomarkers, 
including analysis of RNA based transcriptional profiles and somatic mutations, may be performed 
to evaluate genomic associations with response or resistance. Depending on emerging data and the 
availability of sufficient sample, the immune response to treatment may also be evaluated by T 
cell receptor (TCR) repertoire analysis to determine the modulation of T cell response in the tumor 
microenvironment. Biopsy specimens to evaluate toxicities may also be collected to evaluate 
target-related expression. 
7.6 
Exploratory Laboratory Evaluations 
7.6.1 
Immune Monitoring, Pharmacokinetic, and Pharmacodynamic Assessments 
Samples will be collected according to the Schedule of Events. All analyses will be conducted by 
the Sponsor or Sponsor’s designee. 
Serum and plasma will be collected from on all subjects at baseline and on-treatment to perform 
immune analyses, including quantifying analytes such as cytokines, chemokines, antibodies, 
relevant tumor markers, and other markers of immune function. Peripheral blood mononuclear 
cells (PBMCs) will be collected from all subjects prior to and during treatment to be analyzed for 
changes in immune cell subsets and functions, protein composition, and transcriptional changes. 
Assays characterizing the T cell functional responses to tumor antigens or CRS-207 may be 
conducted in PBMCs. 
. 
In order to explore whether a diverse T cell repertoire is predictive of and/or T cell repertoire 
changes occur in response to therapy, sequencing of their TCR genes may be performed on DNA 
isolated from peripheral blood and tumor to quantify antigen-specific T cell. A similar analysis 
may be conducted examining B-cell diversity. Genetic markers associated with response or 
resistance may also be measured using peripheral blood DNA, and peripheral blood DNA may be 
used as a germline control to compare with tumor cell DNA.  


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Plasma and whole blood samples for pharmacodynamic analysis will be analyzed for changes in 
protein analytes such as antibodies, relevant tumor markers and markers of immune function by 
enzyme-linked immunosorbent assay, or other relevant methods including peptide or protein 
arrays for antibody profiling. Plasma levels of Trp and Kyn will be evaluated by liquid 
chromatography with tandem mass spectrometry to monitor systemic activity in modulating the 
IDO1 enzyme.  
The whole blood samples for pharmacodynamic analysis will be analyzed for changes in markers 
of immune cell populations, including, but not limited to, markers for immune cell subsets, B cells, 
NK cells, and T cells.  
Additional pharmacodynamic analyses may be evaluated at the discretion of the sponsor using 
excess samples. 
7.6.2 
Unused Research Samples 
Following the trial, any remaining samples not used for analysis per protocol parameters may be 
banked for additional investigations by the Sponsor or designee. The use of such samples will be 
in compliance with guidelines defined by the Guidance on Informed Consent for In Vitro 
Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually 
Identifiable65 and the European Medicines Agency (EMA) Reflection Paper on Pharmacogenomic 
Samples, Testing and Data Handling.66.  
 


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8 
EFFICACY ASSESSMENTS 
8.1 
Tumor Imaging and Assessment 
8.1.1 
Initial Tumor Imaging 
Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 28 days before the first dose of study 
treatment. The same imaging technique should be used on a subject throughout the study. 
Baseline scan must be a contrast CT or MRI, except in circumstances where there is a contrast 
allergy or with Study Medical Monitor approval. When the CT component of a positron emission 
tomography (PET)/CT uses higher energy and thinner slices, it may be acceptable (with Study 
Medical Monitor approval). A standard, full assessment for lesions should be conducted at 
baseline, including CT or MRI scans of chest, abdomen, and pelvis. The same modality (CT or 
MRI) should be used for follow-up assessments every 9 weeks, including radiological assessments 
of all sites of disease present at baseline. In addition to radiological monitoring, all other lesions 
observed at the screening visit should be followed. 
For selection of target lesions, RECIST v1.1 should be followed. For example, RECIST 
discourages selection of target lesions inside the field of prior irradiation. Lesions situated in a 
previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not 
considered measurable unless it is the solitary site of measurable disease AND there has been 
demonstrated progression in the lesion. Also, if a subject has only 1 measurable lesion, this lesion 
should not be biopsied (Exception: in Phase 1 as long as the subject has evaluable disease, i.e. can 
be followed by CA-125, biopsying the only measurable disease is acceptable). 
8.1.2 
Tumor Imaging During the Study 
Tumor imaging should be continued on study treatment and the same imaging technique 
should be used in a subject throughout the study. Imaging should be performed every 9 weeks 
(±7 days) from the first dose of study treatment or more frequently if clinically indicated. Imaging 
should not be delayed for delays in cycle starts or extension of combination treatment cycle 
intervals. 
Imaging should continue to be performed until documented PD, the start of new anticancer 
treatment, withdrawal of consent, death, or the end of the study, whichever occurs first. PD should 
be confirmed at least 4 weeks after the first scan indicating PD in clinically stable subjects. 


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Table 12 Imaging and Treatment After First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD  
Repeat imaging at 
≥ 4 weeks to confirm 
PD 
Should continue 
study treatment 
while awaiting 
confirmatory scan 
Repeat imaging at 
≥ 4 weeks to confirm 
PD if possible 
Discontinue 
treatment 
Repeat scan 
confirms PD  
No additional 
imaging required 
Discontinue 
treatment 
No additional 
imaging required 
N/A 
Repeat scan shows 
SD*, PR*, or CR*  
Continue regularly 
scheduled imaging 
assessments every 
9 weeks  
Continue study 
treatment  
Continue regularly 
scheduled imaging 
assessments every 
9 weeks  
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
investigator's 
discretion** 
* SD, PR, CR is based on new baseline from first evidence of PD 
**If treatment is delayed contact the Medical Monitor to review treatment plans (Section 5.4.1) 
In determining whether or not the tumor burden has increased or decreased, site study team 
should consider all target lesions as well as non-target lesions. 
Scenarios where PD is confirmed at repeat imaging: 
• 
Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to prior scan 
• 
Non-target disease resulting in initial PD is worse (qualitative) 
• 
New lesion resulting in initial PD is worse (qualitative) 
• 
Additional new lesion(s) since last evaluation 
8.1.3 
Tumor Response 
RECIST v1.1 will be used by the local site to determine eligibility however treatment decisions 
will be based on modified RECIST v1.1 (mRECIST) criteria because immunotherapeutic agents 
may produce antitumor effects by potentiating endogenous cancer-specific immune responses 
which may take weeks to emerge. The response patterns seen with such an approach may extend 
beyond the typical time course of responses seen with cytotoxic agents, and can manifest a clinical 
response after an initial increase in tumor burden or even the appearance of new lesions. Standard 
RECIST criteria may not provide a comprehensive response assessment of immunotherapeutic 
agents. Therefore, mRECIST will be used with the following adaptation: 
If radiologic imaging shows initial PD, tumor assessment should be repeated ≥ 4 weeks later in 
order to confirm PD while continuing study treatment while awaiting radiologic confirmation of 
progression. If repeat imaging shows a stability or reduction in the tumor burden compared to the 
initial scan demonstrating PD, treatment may be continued /resumed. If repeat imaging confirms 
progressive PD, subjects will be discontinued from study therapy. In determining whether or not 
the tumor burden has increased or decreased, investigators should consider all target lesions as 
well as non-target lesions. 
In subjects who have initial radiological evidence of PD, it is at the discretion of the treating 
physician whether to continue a subject on study treatment until repeat imaging is obtained a 


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minimum of 4 weeks later. This clinical judgment decision should be based on the subject's overall 
clinical condition, including performance status, clinical symptoms, and laboratory data. Subjects 
may receive treatment while waiting for confirmation of PD if they are clinically stable as defined 
by the following criteria: 
• Absence of new or worsening signs and symptoms indicating PD; 
• No decline in ECOG performance status; 
• Absence of rapid progression of disease; and 
• Absence of progressive tumor at critical anatomical sites (e.g. cord compression) requiring 
urgent alternative medical intervention.  
When feasible, subjects should not be discontinued until progression is confirmed. Subjects who 
are deemed clinically unstable are not required to have repeat imaging for confirmation of PD. 
In all other instances, treatment decisions will be made based on investigator review of the clinical 
and radiographic data. 
Response will additionally be assessed using RECIST v1.1 and GCIG CA-125 criteria (see 
Appendix B and Appendix C, respectively). After confirmation of PD, survival data will be 
collected at least every 12 weeks (±7 days) after the Safety Follow-up Visit until death, withdrawal 
of consent, or the end of the study, whichever occurs first. 
8.2 
Tumor Biomarker CA-125 
Tumor biomarker CA-125 will be monitored before, during, and after the treatment course as 
indicated in the Schedule of Events. Subjects who discontinue treatment for reasons other than PD 
should continue to have CA-125 assessed every 9 weeks (±7 days) until the start of a new 
anticancer therapy, documented PD, death, or the end of the study, whichever occurs first. Tumor 
biomarker CA-125 analysis will be performed by the site’s local laboratory. Additional CA-125 
time points collected per institutional standard should also be entered into the eCRF. Subjects 
considered CA-125 evaluable should have CA-125 repeated no earlier than 28 days if a CA-125 
is reduced by 50% from baseline. See Appendix C for more details. 
8.3 
Pharmacokinetics, Pharmacodynamics, and Tumor Biomarker Analysis 
Samples will be used to perform the following immunological and tumor biomarker analyses: 
Plasma epacadostat pharmacodynamics (kyn/trp ratio), plasma pharmacokinetics for epacadostat, 
number of tumor infiltrating lymphocytes, and CD8/Treg (FoxP3) ratio. 
Plasma pharmacodynamic and epacadostat pharmacokinetics parameters will be assessed at 
multiple time points.  


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9 
SAFETY ASSESSMENTS 
Safety will be assessed during each cycle and within 30 days following final dose of study drug. 
Safety parameters will include SAEs, TEAEs, ECOG performance status, vital sign measurements, 
standard clinical laboratory parameters (serum chemistry, hematology, and urinalysis), shedding 
of CRS-207 (urine, oral swab, and rectal swab), clearance of CRS-207 (blood), ECG parameters, 
and physical examination findings.  
9.1 
Adverse Events 
All pre-existing medical conditions will be recorded on the medical history eCRF. Starting with 
the first administration of study drug, any new event or experience that was not present at 
screening, or worsening of an event present at screening, is considered to be an adverse event. 
Unchanged, chronic conditions are not adverse events and should not be recorded on the adverse 
event page of the eCRF. 
An adverse event is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product.  
PD is a study endpoint and consequently, should not be reported as an adverse event/SAE. 
However, when a subject dies from PD with no other immediate causes, “disease progression” 
should be reported as an SAE if within the safety reporting period as described in Section 9.3. All 
adverse events, including observed or volunteered problems, complaints, or symptoms, are to be 
recorded on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the start of study treatment until 30 days after treatment is discontinued. Subjects 
should be instructed to report any adverse event that they experience to the Investigator or study 
staff. Beginning with Cycle 1 Day 1, Investigators should make an assessment for adverse events 
at each visit and record the event on the appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (e.g. surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure.  
Any medical condition already present at screening or present prior to treatment assignment 
(Phase 1) or randomization (Phase 2) should not be reported as an adverse event unless the medical 
condition or signs or symptoms present at baseline change in severity or seriousness at any time 
during the study. In this case, it should be reported as an adverse event. 
Clinically significant abnormal laboratory or other examination (e.g. ECG) findings that are 
detected during the study or are present at treatment assignment (Phase 1) or randomization (Phase 
2) and significantly worsen during the study should be reported as adverse events. The Investigator 
will exercise his or her medical and scientific judgment in deciding whether an abnormal 


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laboratory finding or other abnormal assessment is clinically significant. Clinically significant 
abnormal laboratory values occurring during the clinical study will be followed until repeat tests 
return to normal, stabilize, or are no longer clinically significant. Any abnormal test that is 
determined to be an error does not require reporting as an adverse event. 
9.1.1 
Assessment of Adverse Events by the Investigator 
The severity of all adverse events should be graded according to the NCI CTCAE v4. These criteria 
can be found at http://ctep.cancer.gov/reporting/ctc.html. Any adverse event that changes in grade 
during its course will be recorded in the eCRF at the highest level experienced by the subject. For 
those adverse events not listed in the NCI CTCAE, the following grading system should be used: 
• Mild (NCI CTCAE Grade 1): Transient symptoms, awareness of sign/symptom, but easily 
tolerated and no interference with subject’s daily activities. 
• Moderate (NCI CTCAE Grade 2): Marked signs/symptoms that interfere with subject’s usual 
activities, but still acceptable. 
• Severe (NCI CTCAE Grade 3): Incapacitating signs/symptoms which cause considerable 
interference with the subject’s daily activities, unacceptable. 
• Life-threatening (NCI CTCAE Grade 4): Life threatening or disabling adverse event. 
• Death (NCI CTCAE Grade 5): Death-related adverse event. 
Causality Assessment: 
For the purposes of Investigational New Drug reporting "reasonable possibility" means there is 
evidence to suggest a causal relationship between the drug and the adverse event. The Investigator 
is obligated to estimate the relationship between the investigational products and the occurrence 
of each adverse event or SAE by using his or her best clinical judgment. Other causes, such as the 
underlying disease, concomitant therapy, other risk factors and the temporal relationship of the 
event to the investigational products will be considered and investigated. The Investigator will also 
consult the IB or product labeling information for marketed products in the determination of the 
assessment. The Investigator should consider all possible etiologies for the adverse event and 
render a causality assessment based on the most likely contributing factor to the adverse event. 
There may be situations when an SAE has occurred and the Investigator has minimal information 
to include in the initial report. However, it is very important that the Investigator always assess 
causality for every event before the transmission of the SAE. The Investigator may change his or 
her opinion of the causality in light of follow-up information, amending the SAE report. The 
causality assessment (see below) is one of the criteria used to determine regulatory reporting 
requirements and should not be left blank. 
• No (unrelated, not related, no relation) – The time course between the administration of study 
drug and the occurrence or worsening of the adverse event is not consistent with a causal 
relationship to study drug and another cause (concomitant drugs, therapies, intercurrent 
illnesses, underlying disease, etc.) is the most likely etiology. 
• Yes (related) – The time course between the administration of study drug and the occurrence 
or worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) appears to be more likely. 


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9.1.2 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) must be recorded as such in the eCRF as an AESI. 
AESIs must be reported within 24 hours of knowledge of the occurrence including a detailed 
narrative of the AESI. AESIs will be collected from the time of first dose of study drug until 30 
days following the last dose of study drug, or the subject initiates alternative antineoplastic therapy 
that is not permitted during this study, and must be reported regardless of causality. All AESIs that 
the Investigator considers related to study drug occurring after the 30-day follow-up period must 
be reported to the Sponsor (including ALL suspected infections with CRS-207 and/or Listeria). 
For this study AESIs include: 
• Suspected infection with CRS-207 and/or Listeria  
• The development of Serotonin Syndrome 
• The development of autoimmune diseases  
• The development of any of the followings: 
o ≥ Grade 3 diarrhea 
o ≥ Grade 3 colitis 
o ≥ Grade 2 pneumonitis 
o ≥ Grade 3 hypo- or hyperthyroidism 
 
9.1.2.1 
Adverse Events of Special Interest Related to Serotonin Syndrome 
As noted in Section 1.3.4, there is a theoretical chance that epacadostat could cause an increase in 
serotonin levels in the brain that might trigger SS when administered in combination with other 
serotonergic agents.60 This syndrome has been most closely associated with use of MAOIs, 
Demerol®, linezolid, or methylene blue; all of these agents are prohibited during the study. SSRIs 
and SNRIs are permitted in the study. Procedures listed in Section 5.4.6 will be implemented if 
subjects exhibit the signs and symptoms of SS described in Table 10, including tremor; 
hyperreflexia; and spontaneous, ocular, or inducible clonus together with agitation, fever, 
diaphoresis, or muscle rigidity. 
9.1.2.2 
Adverse Events of Special Interest Related to Persistent Infection with CRS-207  
Suspected infection with CRS-207 and/or Listeria should be reported irrespective of temporal 
relationship to study drug administration. This includes scheduled blood cultures during post-
treatment surveillance monitoring that are positive for CRS-207 or if a subject presents with 
symptoms suspicious for a Listeria-like infection and/or has tested positive for Listeria at a local 
hospital/clinic. Any occurrence of suspected infection with CRS-207 and/or Listeria, regardless of 
when the last CRS-207 infusion was administered, should be reported to the Sponsor.  
9.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 


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• Death; 
• A life-threatening adverse event; 
o NOTE: An adverse event or adverse reaction is considered “life-threatening” if, in view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death. 
• Requires hospitalization or prolongation of existing hospitalizations; 
o NOTE: Any hospital admission with at least one overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will not be 
recorded as an SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent. However, unexpected complications and/or 
prolongation of hospitalization that occur during elective surgery should be recorded as 
adverse events and assessed for seriousness. Admission to the hospital for social or 
situational reasons (i.e. no place to stay, live too far away to come for hospital visits) will 
not be considered inpatient hospitalizations.  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• A congenital anomaly/birth defect; or 
• An important medical event. 
o NOTE: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above. 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 hospitalizations, or the 
development of drug dependency. 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time of treatment assignment (Phase 1) or randomization (Phase 2) 
until 30 days following the last administration of study drug, or the subject initiates alternative 
antineoplastic therapy that is not permitted during this study, must be reported to Medpace Clinical 
Safety within 24 hours of the knowledge of the occurrence (this refers to any adverse event that 
meets any of the aforementioned serious criteria). All SAEs that the Investigator considers related 
to study drug occurring after the 30-day follow-up period must be reported to the Sponsor. The 
Principal Investigator must notify the IRB and IBC of the SAE in writing (electronic transmissions 
acceptable), in accordance with IRB and IBC requirements.  
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically and will retrieve the form. If the event meets serious criteria and it is not possible to 
access the EDC, send an email to Medpace Safety at Medpace-safetynotification@medpace.com 


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or call the Medpace SAE hotline (phone number listed below), and fax the completed paper SAE 
form to Medpace (fax number listed below) within 24 hours of awareness. When the EDC system 
becomes available, the SAE information must be entered within 24 hours of the system becoming 
available. 
Safety Contact Information: Medpace Clinical Safety 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, ext. 2999 or +1-513-579-9911, ext. 2999 
Facsimile: +1-866-336-5320 or +1-513-579-0444 
e-mail: medpace-safetynotification@medpace.com 
Follow-up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the subject 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, subject discharge summary or autopsy reports) to Medpace Clinical Safety via fax or e-mail. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs. 
9.4 
Pregnancy Reporting 
If the subject becomes pregnant during the study or within 30 days of discontinuing study drug, 
the Investigator should report the pregnancy to Medpace Clinical Safety within 24 hours of being 
notified. Medpace Clinical Safety will then forward the Exposure In Utero form to the Investigator 
for completion.  
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed. 
The subject should be followed by the Investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the Investigator should notify Medpace 
Clinical Safety. At the completion of the pregnancy, the Investigator will document the outcome 
of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification 
as an SAE (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
9.5 
Expedited Reporting 
The Sponsor will report all relevant information about suspected unexpected serious adverse 
reactions that are fatal or life-threatening as soon as possible to the FDA and other applicable 
regulatory authorities as applicable, and in any case no later than 7 days after knowledge by the 
Sponsor of such a case, and that relevant follow-up information will subsequently be 
communicated within an additional 8 days.  
All other suspected unexpected serious adverse reactions will be reported to the FDA and other 
applicable regulatory authorities as soon as possible but within a maximum of 15 days of first 
knowledge by the Sponsor.  


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The Sponsor will also inform all Investigators as required.  
9.6 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor 
For purposes of this study, an overdose is defined as the accidental or intentional administration 
of any dose of a product that is considered both excessive and medically important. All occurrences 
of overdose must be reported as an SAE (see Section 9.3 for reporting details). 
There has been no clinical experience with overdosage of CRS-207, epacadostat, or 
pembrolizumab. Treatment of overdosage should consist of general supportive measures. 
9.7 
Clinical Laboratory Evaluations 
The Investigator may use clinical judgment when determining the clinical significance of 
laboratory parameter findings throughout the study. The Study Medical Monitor may, depending 
on study criteria, be consulted before enrollment about a potential subject with abnormal 
laboratory values that are not considered clinically significant. Additional tests may be performed 
or repeated as clinically indicated. 
9.7.1 
Chemistry and Hematology 
A comprehensive serum chemistry and hematology panel will be performed as indicated in the 
Schedule of Events; required analytes for this panel are listed in Appendix A, Clinical Laboratory 
Analytes. The chemistry and hematology panel will be performed by the site’s local laboratory. 
Fasting is not required unless clinically indicated. 
9.7.2 
Liver Function Tests 
LFTs will be performed as indicated in the Schedule of Events; required analytes for this panel are 
listed in Appendix A, Clinical Laboratory Analytes. If LFTs are found to be abnormal, frequency 
of monitoring should be increased to once per week until LFTs have resolved to baseline or 
corticosteroid treatment has begun, at which time chemistry test monitoring will be performed 
according to institutional standards or approximately weekly, whichever is shorter. Liver function 
does not need to be monitored once per week indefinitely for persistent low-grade abnormalities. 
Appropriate liver function monitoring intervals should be discussed with the Study Medical 
Monitor. LFTs will be performed by the site’s local laboratory. 
9.7.2.1 
Potential Drug-Induced Liver Injury (Hy’s Law)  
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (DILI) event (also known as 
Hy's Law). All occurrences of potential DILIs, meeting the defined criteria, must be reported as 
SAEs (see Section 9.3 for reporting details). 
Potential DILI is defined as meeting all of the following criteria: 
• Aminotransferase (ALT or AST) elevation >3 × ULN 
• Total bilirubin >2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
• ALP < 2 ULN 


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• No other immediately apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drugs known to be hepatotoxic. 
9.7.3 
Urinalysis 
Urinalysis will be performed as indicated in the Schedule of Events; required analytes for this 
panel are listed in Appendix A, Clinical Laboratory Analytes. Urinalysis will be analyzed by the 
site’s local laboratory. 
9.7.4 
Coagulation 
A coagulation panel will be performed as indicated in the Schedule of Events; required analytes 
for this panel are listed in Appendix A, Clinical Laboratory Analytes. If a coumarin-based 
anticoagulant is given, INR should be monitored as described in the Schedule of Events. 
Coagulation panel will be analyzed by the site’s local laboratory. 
9.7.5 
Endocrine and Thyroid Function Testing 
Endocrine and thyroid function testing will be performed as indicated in the Schedule of Events; 
required analytes for this panel are listed in Appendix A, Clinical Laboratory Analytes. Endocrine 
function testing will not be collected for CRS-207 monotherapy dosed subjects. The endocrine and 
thyroid function testing will be performed by the site’s local laboratory. 
9.7.6 
Pregnancy Testing 
Pregnancy testing will be performed as indicated in the Schedule of Events. A serum pregnancy 
test is required for women of childbearing potential only and must be performed and confirmed 
negative prior to the first dose of study drug. Urine pregnancy tests for women of childbearing 
potential should be repeated and confirmed negative on Day 1 of each cycle and at the Safety 
Follow-up Visit. Serum testing may be conducted if urine pregnancy testing in unavailable. Serum 
and/or urine pregnancy test may be conducted up to 3 days before each dosing cycle where 
indicated. Pregnancy testing will be performed by the site’s local laboratory.  
If the serum pregnancy test is negative after a urine test was positive, the Investigator will assess 
the potential benefit/risk to the subject and determine whether it is in the subject's best interest to 
resume study drug and continue participation in the study. 
9.7.7 
Additional Laboratory Assessments 
CD4 count, HLA-typing (low resolution), and a virology screen (Appendix A) will be performed 
once during the study as indicated in the Schedule of Events. 
9.7.8 
Shedding and Clearance of CRS-207 
During Phase 1 and the Safety Run-in of Phase 2 at select US centers only, urine, rectal swab, oral 
swab, and whole blood will be collected from subjects pre-dose, and at 6 hours, 18 to 24 hours, 
and Day 7 post-CRS-207 infusion on Cycle 1 and Cycle 2. The central line MAY NOT be used 
for obtaining blood samples. Additional assessments will be performed if results are positive for 
CRS-207 at the Day 7 time point. Samples will be sent to the central laboratory. Additional details 
on sample collection, processing, and shipping are provided in the Laboratory Manual. 


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9.7.9 
Blood Cultures for CRS-207 Surveillance 
Blood samples will be obtained from subject’s peripheral vein and from the central line port, if 
applicable, at the EOT visit 
 
 
 
 
9.8 
Vital Signs, Weight, and Height 
Vital signs, including seated BP, pulse rate, respiratory rate, and temperature, will be performed 
for all Treatment Arms as indicated in the Schedule of Events. Pulse oximetry will be measured if 
clinically indicated. Vital signs will additionally be monitored during infusion, per the CRS-207 
infusion guidelines (Section 5.5.2.1).  
Weight will be taken on Day 1 of each cycle. Height is required at screening only. 
9.9 
Physical Examinations 
9.9.1 
Comprehensive Physical Examination 
Physical examinations must be performed by a medically qualified individual such as a licensed 
Physician, Physician's Assistant, or an advanced Registered Nurse Practitioner, as local law 
permits. The comprehensive physical examination will include the following organ or body system 
assessments: skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular system; 
abdomen (liver and spleen); extremities; lymph nodes; and a brief neurological examination. 
Before the first dose of study drug, clinically significant abnormal findings should be recorded as 
medical history. After the first dose of study treatment, new clinically significant abnormal 
findings should be recorded as adverse events. 
9.9.2 
Symptom-Directed Physical Examination 
For visits that do not require a full physical examination per the Schedule of Events, the 
Investigator or medically qualified designee will perform a symptom-directed evaluation as 
clinically indicated. The targeted physical examination will include assessment(s) of the body 
systems or organs, as indicated by subject symptoms, adverse events, or other findings. New 
clinically significant abnormal findings should be recorded as adverse events. 
9.10 
ECOG Performance Status 
The ECOG Scale of Performance Status is recognized as a standard tool to measure disease impact 
on daily living activities. The ECOG scale will be used by site personnel to determine eligibility 
and characterize a subject’s level of functioning (self-care, daily activity, and basic physical 
ability) as indicated in the Schedule of Events. 
9.11 
Electrocardiograms 
ECG assessments will be conducted as indicated in the Schedule of Events. All 12-lead ECGs will 
be performed in triplicate with the subject in a recumbent or semi-recumbent position after 5 
minutes of rest. In order not to confound interpretation of the ECG, if anti-emetics or other 
prophylactic agents are given then these should be given after the pre-dose ECG rather than before. 


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Clinically significant abnormal findings after signing informed consent should be recorded as an 
adverse event. The 12-lead ECGs will be interpreted by the Investigator at the site and will be used 
for immediate subject management. The decision to include or exclude a subject or withdraw a 
subject from the study based on an ECG flagged as "Abnormal, Clinically Significant" is the 
responsibility of the Investigator, in consultation with the Study Medical Monitor, as appropriate. 


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10 
STATISTICS 
10.1 
Analysis Populations 
The Full Analysis Set (FAS) includes all subjects who received at least 1 dose of study drug. FAS 
analyses will be conducted on the basis of the randomized treatment. All efficacy analyses will be 
assessed using the FAS. 
A Per-Protocol Set (PPS) will also be used to analyze efficacy endpoints and will be based on 
study drug exposure (compliance and/or time on study drug) and major protocol deviations. The 
criteria for inclusion in the PPS will be finalized and documented in the statistical analysis plan 
(SAP) prior to database lock. 
The Safety Set (SAF) includes all randomized subjects who received at least 1 dose of study drug. 
The SAF will be conducted on the basis of the actual treatment received. All safety analyses will 
be assessed using the SAF. 
10.2 
Statistical Methods 
All statistical analyses will be performed using SAS® version 9 or higher. 
Phase 1 and Phase 2 will be analyzed separately. Data will be summarized descriptively for Phase 
1 by cohort and overall and Phase 2 by Arm and overall. Descriptive summaries for categorical 
variables will include counts and percentages. Descriptive summaries for continuous variables will 
include means, medians, standard deviations and minimum and maximum values. Descriptive 
summaries of time to event data will include median, 25th and 75th percentiles and standard error. 
Graphical summaries of the data may be presented. All data will be listed for all subjects. 
The effects of noncompliance, time to first dose, treatment discontinuations, premature withdrawal 
from study and covariates will be assessed to determine the impact on the general applicability of 
results from this study. Further details of the analysis, including the handling of missing data, 
transformations and other data handling procedures will be provided in the SAP. Exploratory 
analyses of the data will be conducted as deemed appropriate. 
10.2.1 
Analysis of Efficacy 
All efficacy analyses will be conducted on both the FAS and PPS. 
10.2.1.1 
Objective Response Rate 
Objective response rate (ORR) is defined as the proportion of subjects with PR or CR according 
to mRECIST. Subjects who discontinue prior to post-baseline tumor assessments will be 
considered as non-responders.  
The primary definition for objective disease response is based on mRECIST. Analyses will be 
performed separately using objective disease responses definitions based on the mRECIST, 
RECIST v1.1, and GCIG CA-125 criteria. Analysis repeated for RECIST v1.1 and GCIG CA-125 
are considered supportive.  
Progressive serial elevation of serum CA-125 will be used to determine CA-125 response. 
Guidelines for using CA-125 response have been developed. Refer to Appendix C for 
Gynecological Cancer Intergroup Definitions for Response and Progression Based on CA-125 
Quick Reference. Subjects should have a pre-treatment CA-125 of at least twice the ULN in order 


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to be considered for CA-125 response. Subjects are not evaluable by CA-125 if they have received 
mouse antibodies or if there has been medical and/or surgical interference with their peritoneum 
or pleura during the previous 28 days. In those subjects considered evaluable by CA-125, a CA-
125 response would be obtained the moment the CA-125 is reduced by 50% and this should be 
confirmed with a consecutive CA-125 assessment not earlier than 28 days after the previous one, 
with however the date of the first 50% reduction to be the reference date for the CA-125 response. 
For each cohort in Phase 1 and each Arm in Phase 2, objective disease responses will be 
summarized by response at each visit and best objective response. The number of subjects with 
disease control, defined as subjects with best objective response of CR, PR or SD, will also be 
summarized. 
For expansion to the second stage in Phase 2, ORR and PFS will be assessed using mRECIST as 
the primary measure for assessment.  
10.2.1.2 
Progression-Free Survival 
PFS is defined as the time from the date of first dose to PD or death due to any cause. Subjects 
who do not experience PD and do not die on or before the data cut-off date will be censored at the 
time of last tumor assessment or data cut-off date, whichever is earlier. Subjects who do not 
experience PD and start new systemic therapy will be censored at the time the new systemic 
therapy was begun or the data cut-off date, whichever is earlier. Subjects with no assessments of 
PD will be censored at the time of first dose. Subjects who are lost to follow up for assessment of 
PD will be censored at their last tumor assessment or data cut-off date whichever is earlier. 
Kaplan-Meier methodology will be used to estimate median PFS for each cohort in Phase 1 and in 
each Arm in Phase 2.  
The primary definition of PD for PFS is based on mRECIST. Analyses will be performed 
separately using objective disease responses definitions based on the mRECIST, RECIST v1.1, 
and GCIG CA-125 criteria. Analysis repeated for RECIST v1.1 and GCIG CA-125 are considered 
supportive.  
10.2.1.3 
Overall Survival 
Duration of survival is defined as the time from first dose until date of death due to any cause. 
Subjects without documentation of death at the time of analysis will be censored as of the date the 
subject was last known to be alive. Kaplan-Meier methodology will be used to estimate the survival 
probabilities and median survival time for each cohort in Phase 1 and in each Arm in Phase 2. 
10.2.1.4 
Immune Biomarker Parameters 
Changes in immune response parameters will be summarized using descriptive statistics by each 
cohort in Phase 1 and each Arm in Phase 2. 
Tumor samples will be analyzed by multiplexed IHC to enumerate CD8/Treg (FoxP3) ratio, 
biomarker expression, immune checkpoint expression including IDO, PD-L1 and tumor 
infiltrating lymphocytes. Plasma Kyn-Trp ratio, circulating tumor biomarkers, circulating 
cytokines and chemokines, circulating immune cell subsets and their activation status, listeriolysin 
(LLO) and mesothelin-specific T cells, and humoral responses against LLO, mesothelin, and other 
tumor antigens will be assessed. 


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10.2.2 
Analysis of Safety 
Safety assessments will occur on all subjects who received any study medication. All safety 
analyses will be performed for each cohort and overall in Phase 1 and each Arm and overall in 
Phase 2.  
Terminations/premature withdrawals, adverse events, DLTs, vital signs, and laboratory data will 
be tabulated. 
Terminations and premature withdrawals will be summarized by frequency counts and 
percentages. 
Adverse events will be coded to a standard set of terms using the most current version of the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary and graded according to NCI 
CTCAE v4. Adverse events will be listed individually and incidence of adverse events summarized 
by system organ class and preferred terms within a system organ class. Analysis of toxicity will 
focus on SAEs and adverse events ≥ Grade 3 and attribution to assigned therapy. 
Administration-site reactions will be listed and tabulated separately from the adverse events. 
Changes in vital signs, hematology and clinical chemistry parameters from baseline to the end of 
the study will be examined. Treatment-emergent changes from normal to abnormal values in key 
laboratory parameters will be identified. Laboratory data will be summarized for each time point 
that specimens are collected. Changes in NCI toxicity grading of laboratory data will be presented 
using shift tables and listings of clinically significant values. 
10.2.3 
Interim Analysis 
Safety data will be reviewed on an ongoing basis by the SRC.  
For Phase 2 of the study, after 13 treated subjects are enrolled in an Arm (Stage 1), an additional 
14 treated subjects will be enrolled in the Arm (Stage 2) if 1 or more subjects respond (objective 
disease response of CR or PR) or if the median PFS is at least 4.8 months. Objective response rate 
and PFS are based on mRECIST. If neither of the criteria for response and PFS is met, the 
preliminary anti-tumor activity in the Arm will be rejected and no further subjects will be 
randomized to the Arm. 
10.2.4 
Sample Size Determination 
During Phase 1, dose escalation will be based on traditional escalation guidelines (3+3) to 
determine the RP2D and evaluate safety data (including DLTs and adverse events) of each planned 
treatment.  
Phase 2 will be an open-label, randomized study design conducted in 2 stages to achieve up to 
27 treated subjects per Arm. After 13 subjects in an Arm are randomized at the confirmed dose 
following the Safety Run-in (stage 1), an additional 14 subjects will be enrolled in that Arm (stage 
2) if 1 or more subjects respond or if the median PFS is at least 4.8 months. If the criteria for either 
ORR or PFS are not met, the preliminary anti-tumor activity in the Arm will be rejected and no 
further subjects will be randomized to the Arm. If the Arm goes on to stage 2, a total of 27 
treated subjects will be studied in that Arm. The Arm will be considered successful if 4 or more 
subjects respond or the median PFS is at least 4.8 months. If the criteria for either ORR or PFS are 
not met, the Arm will be rejected. This design is applied to each Arm independently. There are no 
formal comparisons planned between Arms.  


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This is an exploratory study of each Arm where the sample size and ORR and PFS criteria for each 
stage are based on clinical judgement; each Arm is assumed to be evaluated separately. Type 1 
error will not be controlled over both Arms. The ORR criteria and number of subjects for each 
stage within Arm are based on a Simon minimax 2-stage design (null hypothesis that ORR ≤ 0.05 
versus the alternative that ORR≥ 0.20 with alpha = 0.05 and power = 0.80). The PFS criteria are 
based on the lower limit of the 95% CI determined based on meta-analysis in the 3rd relapse patient 
population where the median PFS is 5.6 months, (95% CI: 4.8 to 6.2 months).67 The one-sided test 
for PFS (i.e. observing median PFS≥ 4.8 months) has a Type I error rate of 0.0744 when the null 
hypothesis is that the median PFS=3.6 months, PFS is exponentially distributed, accrual is 
uniform, and total study duration is 30 months for 27 subjects enrolled over 24 months. For a one-
sided test of observing PFS≥ 4.8 months, there is approximately 77% power to detect a median 
PFS of 5.6 months and 50% power to detect a median PFS of 4.8 months. 
Assuming a non-negative correlation between the one-sided tests for ORR and PFS, the overall 
Type I error for either test criteria being met is at most 0.1203. There is at least 70% power to meet 
at least one of the test criteria if ORR=0.25 and median PFS=4.8 and at least 79% power if 
ORR=0.25 and median PFS=5.6. 
 
 
. 
 
 


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11 
DATA MANAGEMENT AND RECORD KEEPING 
11.1 
Data Management 
11.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. The 
CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data will be appropriately tracked in an audit trail in the EDC system. 
For those who fail screening, only demographics and reason for screen failure will be documented 
on the eCRF. If a subject withdraws from the study, the reason must be noted on the eCRF. If a 
subject is withdrawn from the study because of a treatment-limiting AE, thorough efforts should 
be made to clearly document the outcome.  
An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data has 
been accounted for and electronically signed by the Investigator. 
11.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
11.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user-name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
11.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Latest version of MedDRA for medical history and adverse events, and 
• World Health Organization Drug Dictionary for prior and concomitant medications. 
11.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator in order to be 
considered complete. 


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11.2 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Trial Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


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12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
12.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study subjects 
are protected, consistent with the principles that have their origin in the Declaration of Helsinki, 
and that the clinical study data are credible. 
12.2 
Institutional Review Board and Institutional Biosafety Committee 
Participating sites will be responsible for reporting to their IRB and IBC. The IRB and IBC will 
review all appropriate study documentation in order to safeguard the rights, safety, and well-being 
of subjects. The study will only be conducted at sites where IRB and IBC approval has been 
obtained. The protocol, IB, ICF, advertisements (if applicable), written information given to the 
subjects, safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB and IBC by the Investigator. 
Federal regulations and International Conference on Harmonisation (ICH) require that approval 
be obtained from an IRB and IBC prior to participation of subjects in research studies. Prior to 
study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for subject 
recruitment, and any other written information regarding this study to be provided to a subject or 
subject’s legal guardian must be approved by the IRB and IBC. 
No study drug will be released to the site for dosing until written IRB authorization has been 
received by the Sponsor. 
12.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB and IBC prior to its use and must be in compliance with all ICH 
GCP, local regulatory requirements, and legal requirements. 
The Investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
subject has been informed of his/her rights to privacy. The Investigator will obtain written 
informed consent from each subject before any study-specific activity is performed and should 
document in the source documentation that consent was obtained prior to enrollment in the study. 
The original signed copy of the ICF must be maintained by the Investigator and is subject to 
inspection by a representative of the Sponsor, their representatives, auditors, the IRB and/or 
regulatory agencies. A copy of the signed ICF will be given to the subject. 
12.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory requirements, and that 
valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized, and easily retrievable data. 
Before the enrollment of any subject in this study, the Sponsor or their designee will review with 


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the Investigator and site personnel the following documents: protocol, IB, eCRFs and procedures 
for their completion, informed consent process, study drug accountability, and the procedure for 
reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
12.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Subjects or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Subject medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 
12.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to link 
records, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor. 
12.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 


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12.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR §54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 


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13 
STUDY ADMINISTRATIVE INFORMATION 
13.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for subject safety. In this case, 
the situation must be documented and reported to the IRB within 5 working days. 
13.2 
Address List 
13.2.1 
Sponsor 
Aduro Biotech, Inc. 
740 Heinz Avenue  
Berkeley, CA 94710-2224  USA 
Telephone: +1 510-848-4400 
Facsimile: +1 510-848-5614 
13.2.2 
Contract Research Organization 
Medpace, Inc. 
5375 Medpace Way 
Cincinnati, OH 45227  USA 
Telephone: +1 513-579-9911 
Facsimile: +1 513-579-0444 
13.2.3 
Drug Safety 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, ext. 2999 or +1-513-579-9911, ext. 2999 
Facsimile: +1-866-336-5320 or +1-513-579-0444 
e-mail: medpace-safetynotification@medpace.com 
13.2.4 
Biological Specimens 
Refer to the Laboratory Manual for shipment instructions and addresses. 
 


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14 
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18. 
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Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 
2011;480:480-9. 
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mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci U S A 
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Scholler N, Fu N, Yang Y, et al. Soluble member(s) of the mesothelin/megakaryocyte 
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Le Page C, Ouellet V, Madore J, et al. Gene expression profiling of primary cultures of 
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T-cell memory by vaccination with recombinant Listeria monocytogenes. J Virol 
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Bahjat KS, Liu W, Lemmens EE, et al. Cytosolic entry controls CD8+-T-cell potency 
during bacterial infection. Infect Immun 2006;74:6387-97. 
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segregate immunogenicity from toxicity. Proc Natl Acad Sci U S A 2004;101:13832-7. 
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Le DT, Brockstedt DG, Nir-Paz R, et al. A live-attenuated Listeria vaccine (ANZ-100) 
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expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res 
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Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin 
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Mellor AL, Baban B, Chandler P, et al. Cutting edge: induced indoleamine 2,3 
dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J 
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and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a 
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38. 
Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 
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Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic fetal rejection by 
tryptophan catabolism. Science 1998;281:1191-3. 
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Uyttenhove C, Pilotte L, Theate I, et al. Evidence for a tumoral immune resistance 
mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 
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indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene 
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dioxygenase and acquired immune privilege. Int Rev Immunol 2010;29:133-55. 
43. 
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concentration predicts poor prognosis in malignant melanoma patients. Dermatology 
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plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 2004;114:280-
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of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin Cancer 
Res 2005;11:6030-9. 
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Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3-
dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin 
Cancer Res 2006;12:1144-51. 
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Ino K, Yoshida N, Kajiyama H, et al. Indoleamine 2,3-dioxygenase is a novel prognostic 
indicator for endometrial cancer. Br J Cancer 2006;95:1555-61. 
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Nakamura T, Shima T, Saeki A, et al. Expression of indoleamine 2, 3-dioxygenase and 
the recruitment of Foxp3-expressing regulatory T cells in the development and 
progression of uterine cervical cancer. Cancer Sci 2007;98:874-81. 
49. 
Witkiewicz A, Williams TK, Cozzitorto J, et al. Expression of indoleamine 2,3-
dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to 
avoid immune detection. J Am Coll Surg 2008;206:849-54; discussion 54-6. 
50. 
Hamid O, Chasalow SD, Tsuchihashi Z, Alaparthy S, Galbraith S, Berman D. 
Association of baseline and on-study tumor biopsy markers with clinical activity in 
patients (pts) with advanced melanoma treated with ipilimumab. J Clin Oncol 
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De Felice F, Marchetti C, Palaia I, et al. Immunotherapy of Ovarian Cancer: The Role of 
Checkpoint Inhibitors. J Immunol Res 2015;2015:191832. 
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Badoual C, Hans S, Fridman WH, Brasnu D, Erdman S, Tartour E. Revisiting the 
prognostic value of regulatory T cells in patients with cancer. J Clin Oncol 2009;27:e5-6; 
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approaches: a current perspective. Cancer Res 2012;72:3439-44. 
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Gattinoni L, Ranganathan A, Surman DR, et al. CTLA-4 dysregulation of self/tumor-
reactive CD8+ T-cell function is CD4+ T-cell dependent. Blood 2006;108:3818-23. 
56. 
Pamer EG. Immune responses to Listeria monocytogenes. Nat Rev Immunol 2004;4:812-
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57. 
Portnoy DA. Manipulation of innate immunity by bacterial pathogens. Curr Opin 
Immunol 2005;17:25-8. 
58. 
Serbina NV, Kuziel W, Flavell R, Akira S, Rollins B, Pamer EG. Sequential MyD88-
independent and -dependent activation of innate immune responses to intracellular 
bacterial infection. Immunity 2003;19:891-901. 
59. 
Torres D, Barrier M, Bihl F, et al. Toll-like receptor 2 is required for optimal control of 
Listeria monocytogenes infection. Infect Immun 2004;72:2131-9. 
60. 
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20. 
61. 
Gangadhar TC, Hamid O, Smith DC, et al. Epacadostat plus pembrolizumab in patients 
with advanced melanoma and select solid tumors: Updated phase 1 results from ECHO-
202/KEYNOTE-037.  ESMO; 2016 Oct 10. p. 379-400. 
62. 
Opinion of CCBS for classifying Listeria monocytogenes strains with deletions in the 
genes prfA, hly, actA, and plcB. 1999. at 
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63. 
Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical 
Oncology clinical practice guideline update. J Clin Oncol 2011;29:4189-98. 
64. 
Common terminology criteria for adverse events (CTCAE) Version 4.0. National 
Institutes of Health, National Cancer Institute, 2010. (Accessed Apr 26, 2016, at 
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65. 
Food and Drug Administration. Guidance on informed consent for in vitro diagnostic 
device studies using leftover human specimens that are not individually identifiable. 
2006. 
66. 
EMA. Reflection paper on pharmacogenomic samples, testing and data handling. In: 
(CHMP) CfHMP, ed. London, UK2007. 
67. 
Hanker LC, Loibl S, Burchardi N, et al. The impact of second to sixth line therapy on 
survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann 
Oncol 2012;23:2605-12. 
 


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APPENDIX A: 
CLINICAL LABORATORY ANALYTES 
Serum Chemistry 
Hematology 
Other 
Albumin 
Amylase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
Iron 
Lactate dehydrogenase 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
Uric acid 
CRP (standard sensitivity) 
 
Complete blood count, including: 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
Reticulocyte count 
White blood cell count 
 
 
Differential count, including: 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils (ANC) 
 
CD4 Count (Screening Only) 
Pregnancy test: 
Female subjects of childbearing 
potential only require a serum test at 
screening.  
Pregnancy tests (urine or serum if 
required) should be repeated as 
required per schedule of events.  
 
Coagulation: 
PT  
aPTT 
INR 
D-dimer 
Fibrinogen 
 
HLA-typing 
Low resolution (Screening only) 
Liver Function (LFT) Monitoring 
Alkaline phosphatase 
ALT 
AST 
Total bilirubin 
Direct bilirubin (only if total bilirubin 
is elevated above ULN at screening) 
Urinalysis  
Virology Screening 
Endocrine/Thyroid Monitoring  
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
Hepatitis B (HBsAg)  
Hepatitis antibody (HCV-RNA, 
Qualitative) 
HIV 
 
 
Adrenocorticotropic hormone 
Serum cortisol (9 AM) 
Luteinizing hormone 
Prolactin 
Thyroid stimulating hormone (TSH) 
Free thyroxine (FT4) 
Total triiodothyronine (T3) or Free 
Triiodothyronine (FT3) 
 
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; ANC= absolute neutrophil count; AST = 
aspartate aminotransferase; INR = international normalized ratio; HBsAg = Hepatitis B surface antigen; HCV-RNA = 
Hepatitis C virus ribonucleic acid; HIV = human immunodeficiency virus; LFT = liver function test; PT = prothrombin time. 


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APPENDIX B: 
RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS VERSION 1.1 QUICK REFERENCE 
Apply RECIST v1.1 criteria to tumor assessment and record on the eCRF. 
RECIST v1.1 Criteria 
 
RECIST v1.1 
Measurable tumor 
burden 
A maximum of 5 target lesions in total (and up to 2 per organ) can be identified at 
baseline and measured through the course of therapy. 
Minimum size of 
measurable lesions 
≥10 mm in LD and 2 times the slice thickness for extranodal lesions; 
≥15 mm in SAD for nodal lesions; 
≥10 mm in LD for clinical lesions (must be measured electronic calipers); 
≥20 mm in LD for chest X-ray (if clearly defined & surrounded by aerated lung); 
CT is preferable; and 
Ultrasound cannot be used to measure lesions. 
Lymph nodes 
Lymph nodes are considered pathologically enlarged if >10 mm in SAD. To be 
measurable, nodal lesions must be ≥15 mm in SAD. Nodal lesions with SAD >10 mm 
and <15 mm are nonmeasurable. The sum of the diameters (LD for extranodal target 
lesions, SAD for nodal lesions) is followed through the course of therapy. 
Bone lesions 
A lytic or mixed lytic-blastic bone lesion with a soft tissue component assessed on 
CT/MRI can be measurable if the minimum size criteria are met. Blastic bone lesions 
and bone lesions assessed on bone scan, PET, or plain films are non-measurable. 
Cystic lesions 
Lesions that meet the criteria for radiographically defined simple cysts are not 
malignant. Cystic lesions thought to be metastases can be measurable if they meet the 
minimum size criteria. Noncystic lesions are preferable. 
Lesions with prior 
local treatment 
Lesions in previously irradiated areas (or areas treated with local therapy) are not 
measurable unless the lesion has progressed since therapy. Conditions should be 
defined in study protocols. 
Too small to measure 
If a target lesion becomes too small to measure, a default value of 5 mm is assigned. If 
the lesion disappears, the measurement is recorded as 0 mm. 
Lesions which split or 
coalesce 
If extranodal target lesions fragment, the LDs of the fragmented portions are added to 
the sum. If target lesions coalesce and cannot be distinguished, the LD of the 
coalesced lesion is added to the sum. 
Definition of CR 
Complete response requires the disappearance of all extranodal lesions, the regression 
of all nodal lesions to <10 mm SAD, and the normalization of tumor marker level. 
Definition of PD 
Progressive disease is assessed if the sum of the diameters has increased by ≥20% and 
≥5 mm from nadir (including baseline if it is the smallest sum). Patients with 
measurable disease: for "unequivocal progression" based on non-target disease, there 
must be an overall level of substantial worsening that merits discontinuation of therapy 
(if target disease is SD/PR). Patients without measurable disease: for "unequivocal 
progression" of non-target disease, the increase in overall tumor burden must be 
comparable to the increase required for PD of measurable disease. 
Assessment of new 
lesions 
New lesions should be unequivocal and not attributable to differences in scanning 
technique or findings which may not be tumor (ie, 'new' bone lesions may be healing 
or flare of preexisting lesions). If one is equivocal, repeat scans are needed to confirm. 
If confirmed, PD is assessed at the date of the initial scan. Lesions identified in 
anatomic locations not scanned at baseline are considered new. New lesions on 
ultrasound should be confirmed on CT/MRI. 
CR = complete response; CT = computed tomography; FDG-PET = positron emission tomography with fluorodeoxyglucose; 
LD = longest diameter; MRI = magnetic resonance imaging; PD = progressive disease; PET = positron emission tomography; 
PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SAD = short axis diameter; SD = stable 
disease. 


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RECIST v1.1 
FDG-PET 
New lesions can be assessed using FDG-PET: (-) PET at baseline and (+) PET at 
follow-up is PD based on a new lesion. No PET at baseline and (+) PET at follow-up 
is PD if the new lesion is confirmed on CT. If a subsequent CT confirms the new 
lesion, the date of the PD is the date of the initial PET scan. No PET at baseline and 
(+) PET at follow-up corresponding to pre-existing lesion on CT that is not 
progressing; not PD. 
Recurrence of lesions 
For a patient with SD/PR, a lesion which disappears and then reappears will continue 
to be measured and added to the sum. Response will depend upon the status of the 
other lesions. For a patient with CR, reappearance of a lesion would be considered PD. 
Overall response 
One overall response table integrates target, non-target and new lesions and another 
table integrates non-target and new lesions for the assessment of subjects without 
measurable disease. 
Confirmation of 
response 
Confirmation of PR/CR is ONLY required for non-randomized trials where response 
is the primary endpoint. In these trials, subsequent confirmation of PR with 1 interim 
timepoint of SD is acceptable. 
CR = complete response; CT = computed tomography; FDG-PET = positron emission tomography with fluorodeoxyglucose; 
LD = longest diameter; MRI = magnetic resonance imaging; PD = progressive disease; PET = positron emission tomography; 
PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SAD = short axis diameter; SD = stable 
disease. 
 
 
 


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APPENDIX C: 
GYNECOLOGICAL CANCER INTERGROUP 
DEFINITIONS FOR RESPONSE AND PROGRESSION BASED ON CA-125 
QUICK REFERENCE 
Based on “Definitions for Response and Progression in Ovarian Cancer Clinical Trials 
Incorporating RECIST 1.1 and CA-125,” a set of agreements by the Gynecological Cancer 
Intergroup (GCIG), the following definitions will be used in this study: 
Definition of Response 
“A CA-125 response is defined as at least a 50% reduction in CA-125 levels from a pretreatment 
sample. The response must be confirmed and maintained for at least 28 days. Patients can be 
evaluated according to CA-125 only if they have a pretreatment sample that is at least twice the 
upper limit of the reference range and within 2 weeks before starting the treatment. 
“To calculate CA-125 responses accurately, the following rules apply: 
• Intervening samples and the 28-day confirmatory sample must be less than or equal to (within 
an assay variability of 10%) the previous sample. 
• Variations within the reference range of CA-125 levels will not interfere with the response 
definition.  
• For each patient, the same assay method must be used, and the assay must be tested in a quality 
control scheme. 
• Patients are not evaluable by CA-125 if they have received mouse antibodies (unless the assay 
used has been shown not to be influenced by human antimouse antibody) or if there has been 
medical and/or surgical interference with their peritoneum or pleura during the previous 
28 days (eg, paracentesis). If assessing therapy that includes 2 treatment modalities for relapse 
(eg, surgery and chemotherapy), any CA-125 response results from both treatment modalities. 
CA-125 cannot distinguish between the effects of the 2 treatments. 
“The date when the CA-125 level is first reduced by 50% is the date of the CA-125 response. To 
calculate response, an intent-to-treat analysis should be used that includes all patients with an 
initial CA-125 level of at least twice the upper limit of the reference range as eligible and evaluable. 
In addition, as a separate analysis, those patients who have a CA-125 response and whose CA-125 
level falls to within the reference range can be classified as CA-125 complete responders. In Tables 
2 and 3 [per Rustin et al] where CA-125 is stated as normalised or normal, means within the 
reference range. Patients who have a fall of CA-125 to within the reference range but whose initial 
CA-125 was less than twice the upper limit of the reference range have not had a CA-125 response 
and cannot therefore be classified as a CA-125 complete responder. 
Definition of Progression on Therapy and Recurrence After Therapy According to CA-125 
“Progression is conventionally defined according to RECIST 1.1 but can also be based on serum 
CA-125 [defined in Rustin et al]. However, in assigning the date of progression, PD by objective 
change in tumor size should always take precedence over CA-125 should it occur first. If 
measurable disease is reducing in size during treatment but the CA-125 results suggest progression 
[defined in Rustin et al], the patient should continue to receive protocol treatment. If measurable 
disease is stable but CA-125 indicates confirmed progression over at least 4 weeks, some protocols 


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may advise changing protocol treatment, unless there is the possibility that the therapy could be 
slowing the rate of rise of CA-125. If patients are having routine CA125 measurements as part of 
follow-up, the date of progression is likely to be several months earlier than symptoms or signs of 
progression develop. Therefore, when categorizing patients according to time to progression, it is 
necessary to specify how the date of progression was defined (CA-125 alone, CA125 and 
symptoms, and RECIST). Protocols will need to specify that these data have to be collected.” 
Source: Rustin GJS, Vergote I, Eisenhauer E, et al. Definitions for Response and Progression in Ovarian Cancer Clinical Trials 
Incorporating RECIST 1.1 and CA 125 Agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 
2011;21:419-423. 
 


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APPENDIX D: 
PROHIBITED MONOAMINE OXIDASE INHIBITORS 
AND DRUGS ASSOCIATED WITH SIGNIFICANT MONOAMINE 
OXIDASE INHIBITORY ACTIVITY 
Monoamine Oxidase Inhibitors  
Drugs Associated With Significant Monoamine 
Oxidase Inhibitory Activity 
Hydrazines (example phenelzine) 
Meperidine 
Caroxazone 
Linezolid 
Echinopsidine 
Methylene blue 
Furazolidone 
 
Tranylcypromine 
 
Brofaromine 
 
Metralindole 
 
Minaprine 
 
Moclobemide 
 
Pirlindole 
 
Toloxatone 
 
Lazbemide 
 
Pargyline 
 
Rasagiline 
 
Selegiline 
 
 
 
 


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APPENDIX E: 
INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating in the Study: 
The following methods that can achieve a failure rate of <1% per year when used consistently and 
correctly are considered as highly effective birth control methods.  
Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation1 
o Oral, 
o Intravaginal, and 
o Transdermal, 
• Progestogen-only hormonal contraception associated with inhibition of ovulation,1 
o Oral, 
o Injectable, and 
o Implantable,2 
• Intrauterine device (IUD), 2 
• Intrauterine hormone-releasing system (IUS),2 
• Bilateral tubal occlusion,2 
• Vasectomized partner,2,3 and 
• Sexual abstinence.4 
4. 
Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the contraception 
method. 
5. 
Contraception methods that in the context of this guidance are considered to have low user dependency. 
6. 
Vasectomized partner is a highly effective method provided of avoiding pregnancy that partner is the sole sexual partner of 
the woman of child bearing potential trial participant and that the vasectomized partner has received medical assessment of 
the surgical success.  
7. 
In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
subject. 
Source: CTFG 2014.


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APPENDIX F: 
SCHEDULE OF EVENTS (PHASE 1 ONLY) 
Study Phase 
Screening  
Treatment Period 
Follow-up Period 
Screening 
Cycle 1  
Cycle 2  
Cycle 3 and 
Beyond 1 
EOT 2 
Safety 
Follow-up3 
Survival 
Follow-
up  
Week 1 
Week 2 
Week 3 
Week 1 
Week 2 
Week 3 
Week 1 
Week 2 
Study Day 
-28 to -1 
1 
2 
8 
15 
1 
2 
8 
15 
1 
8 
ASAP 
After 
Last 
Dose 
30 Days 
After Last 
Dose 
Every 12 
Weeks 
Visit Window (Days) 
- 
- 
- 
±1 
±1 
- 
- 
±1 
±1 
- 
±1 
 
+5 
±7 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assignment/Randomization to 
Treatment Arm 4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs, Height, Weight 5 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
Physical Examination 6 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
ECOG Performance Status 
X 
X 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
Electrocardiogram 7 
X 
X 
 
 
X 7 
 
 
 
 
X  
 
 
X  
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior and Concomitant 
Medications and Therapies 8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival and Additional 
Treatment Status 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory/Sample 
Collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virology Screen 10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CD4 Count 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 11 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Clinical Hematology, Serum 
Chemistry, Liver Function 12 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
Coagulation Panel 13 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
CA-125 Assessment 14 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Serum/Plasma for Immune 
Monitoring 15 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
HLA-Typing 16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Phase 
Screening  
Treatment Period 
Follow-up Period 
Screening 
Cycle 1  
Cycle 2  
Cycle 3 and 
Beyond 1 
EOT 2 
Safety 
Follow-up3 
Survival 
Follow-
up  
Week 1 
Week 2 
Week 3 
Week 1 
Week 2 
Week 3 
Week 1 
Week 2 
Study Day 
-28 to -1 
1 
2 
8 
15 
1 
2 
8 
15 
1 
8 
ASAP 
After 
Last 
Dose 
30 Days 
After Last 
Dose 
Every 12 
Weeks 
Visit Window (Days) 
- 
- 
- 
±1 
±1 
- 
- 
±1 
±1 
- 
±1 
 
+5 
±7 
Endocrine Testing 17 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
PBMC 18 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
Serum for Epacadostat (PK) 19 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
Shedding and Clearance 20 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
Blood sample for CRS-207 
testing28 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Archived Tumor Specimen  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma/Whole Blood for 
Pharmacodynamic Analysis 21 
 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
 
 
Tumor Biopsy 22 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Tumor Evaluation 23 
X 
Every 9 weeks (± 7 days) 
 
X 
X 9 
Blood for CRS-207 
Surveillance 28 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Investigational Product 
Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer CRS-207 24 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Epacadostat 25 
 
X 25 
 BID  
 
 
 
Epacadostat Compliance & 
Accountability 26 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Other Concomitant 
Medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antibiotics 27 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Footnotes 
1. 
Treatment will continue for 6 cycles as long as there is potential for clinical benefit. After 6 cycles, treatment may continue if there is continued potential benefit and upon 
approval from the Study Medical Monitor. After Cycle 3 Day 8, visits between administrations of CRS-207 will be conducted based on Investigator’s discretion. After Cycle 
3 Day 1, initiation of a new cycle may be delayed up to 3 days due to subject scheduling. Epacadostat should continue uninterrupted during the treatment period.  
2. 
An EOT Visit will occur as soon as determined that the subject will permanently discontinue study treatment, and at least 7 days after the last dose of CRS-207. If the EOT 
visit coincides with a regular study visit, the EOT evaluations will supersede those of that scheduled visit, and the data should be entered in the EOT page in the eCRF. If the 
EOT Visit occurs >21 days after the last administration of study drug, procedures from the EOT and Safety Follow-up visits may be collected as a single Safety Follow-up 
Visit.  
3. 
A Safety Follow-up Visit will be scheduled 30 days (+5 days) post last dose of study treatment. If the subject begins another anticancer therapy before the Safety Follow-up 
Visit, every effort will be made to complete all of the Safety Follow-up Visit assessments prior to commencing the new therapy. If there is an adverse event in need of 


Aduro Biotech, Inc. 
Clinical Study Protocol ADU-CL-11 
 
Confidential & Proprietary 
125 
Amendment 3, 18 Feb 2017 
monitoring beyond the Safety Follow-up Visit, the subject will be followed until resolution or confirmed stability of the adverse event. If a CT scan was collected within 
9 weeks (±7 days) of the Safety Follow-up Visit, then a CT scan at the Safety Follow-up Visit will not be mandatory. 
4. 
For Phase 1, enrollment form will be completed and sent to Medpace for treatment assignment. As an added safety measure during Phase 1, Dose Cohort 1 will have a 
staggered enrollment of no more than 1 new subject treated per week during the dose escalation phase. Thereafter, a decision to further stagger combination enrollment will be 
made by the SRC and will be based on emergent safety data.  
5. 
Vital sign measurements consist of seated BP, pulse, respiratory rate, and temperature. Pulse oximetry will be measured if clinically indicated. Weight will be taken on Day 1 
of each cycle. Height is required at screening only. 
6. 
Complete physical examinations will be conducted at screening and Safety Follow-up Visits; symptom-directed physical examinations will be conducted on Day 1 of all other 
cycles and at the EOT visit. Physical exams may be conducted up to 3 days before dosing with CRS-207. 
7. 
12-lead ECG assessments will be conducted on all subjects at screening, Cycle 1 (Day 1 and Day 15), and on Day 1 of every odd numbered cycle (Cycle 3, Cycle 5, etc.) 
while on treatment. Serial ECGs will be collected pre-dose and approximately 60 to 90 minutes after the first dose of epacadostat at Cycle 1 Day 2. For Subject receiving 
CRS-207 monotherapy, ECG will be collected pre-dose and approximately 60-90 minutes after their CRS-207 infusion has begun. In order not to confound interpretation of 
the ECG, if anti-emetics or other prophylactic agents are given then these should be given after the pre-dose ECG rather than before. ECGs will be performed with the subject 
in recumbent or semi-recumbent position after 5 minutes rest. Subsequent ECGs will be obtained as clinically indicated, and at the Safety Follow-up Visit.  
8. 
All concomitant medications and cancer-related therapies and procedures will be recorded within 28 days before study treatment begins and 30 days after the last dose of 
study drug, or until the subject completes the Safety Follow-up Visit. In addition, all prior and post-study treatment anticancer therapy will be recorded in the eCRFs. 
9. 
Once a subject has radiographic confirmed PD, discontinues study treatment or starts a new anticancer therapy, the subject moves into the Survival Follow-up phase. Subject 
will be contacted every 12 weeks (by phone/email is permissible if no recent (with 14 days) medical charting is available) to collect data on survival and any additional 
cancer-related therapies that may have been administered. Follow-up will continue until death, withdrawal of consent, or the end of the study, whichever occurs first. 
10. Virology screen will include the following: HIV antibody, hepatitis B (HBsAg), and hepatitis C (HCV-RNA, Qualitative); additional virology may also be evaluated. 
Virology screen will be performed by the site’s local laboratory. 
11. Serum pregnancy test is required for women of childbearing potential only and must be performed and confirmed negative prior to the first dose of study treatment. Urine 
pregnancy test for women of childbearing potential should be repeated and confirmed negative on Day 1 of each cycle and at the Safety Follow-up Visit. Serum testing may 
be conducted if urine pregnancy testing in unavailable. Serum and/or urine pregnancy test may be conducted up to 3 days before dosing with CRS-207. Pregnancy testing will 
be performed by the site’s local laboratory. 
12. Refer to Appendix A for complete list of clinical hematology, chemistry and liver function analytes. Day 1 blood draws may be taken up to 3 days before dosing with CRS-
207. Blood draws required on Day 2 after CRS-207 dosing for Cycle 1 and Cycle 2; additional timepoints may be obtained if clinically indicated. For subject in Arm 3 at 
Cycle 3, chemistry, hematology and liver function should be collected on Day 2 after their first infusion of CRS-207. To avoid inadvertent contamination of a central line 
(eg, infusion ports, PICC lines), blood draws MUST NOT be collected from a central line for at least 4 days after infusion of CRS-207 has started. If LFTs are found 
to be abnormal (>Grade 2), frequency of monitoring should be increased to once per week until LFTs have resolved to baseline at which time chemistry test monitoring will 
be performed according to institutional standards or approximately weekly, whichever is shorter. Liver function does not need to be monitored once per week indefinitely for 
persistent low-grade abnormalities. Appropriate liver function monitoring intervals should be discussed with the Study Medical Monitor. Hematology, chemistry and liver 
panel will be performed by the site’s local laboratory. 
13. Coagulation panel will include the following: D-dimer, fibrinogen, INR of PT, and aPTT; INR should be monitored weekly for the first 4 weeks after initiation of coumarin-
based anticoagulants (see Section 5.6.2 for anticoagulant restrictions) and upon discontinuation of epacadostat. Coagulation testing will be performed by the site’s local 
laboratory. 
14. CA-125 will be assessed at screening as close to but no more than 14 days before the first study treatment, then on Day 1 of each cycle while on treatment (or every 3 weeks if 
subject dosing is delayed). Subjects who discontinue treatment for reasons other than PD should continue to have CA-125 assessed every 9 weeks until the start of a new 
anticancer therapy, documented PD, death, or the end of the study, whichever occurs first. Additional CA-125 timepoints collected per institutional standard should also be 
entered into the eCRF. Subjects considered CA-125 evaluable should have CA-125 repeated no earlier than 28 days if a CA-125 is reduced by 50% from baseline. See section 
Appendix C for more details. 
15. Approximately 7.5 mL of whole blood for immune monitoring will be drawn as indicated. After Cycle 3, serum and plasma for immune response analysis will be collected at 
odd numbered Cycles (eg, Cycle 5, Cycle 7, etc.) Plasma will not be collected for Day 8 time points. Samples will be sent to the central laboratory. 
16. The HLA-typing should include type A and B of class I antigens, low resolution. HLA will be performed by the site’s local laboratory. 


Aduro Biotech, Inc. 
Clinical Study Protocol ADU-CL-11 
 
Confidential & Proprietary 
126 
Amendment 3, 18 Feb 2017 
17. Endocrine testing will include: adrenocorticotropic hormone, serum cortisol (9 AM), luteinizing hormone prolactin, thyroid stimulating hormone, free thyroxine (T4), total 
triiodothyronine (T3). After Cycle 3, endocrine testing will be completed every 12 weeks (at Cycle 7, Cycle 11, etc.) Endocrine testing will not be collected for CRS-207 
monotherapy dosed subjects.  
18. Approximately 70 mL of whole blood to be processed as described in the Laboratory Manual. After Cycle 3, PBMCs will be collected on Day 1 for odd numbered Cycles 
only (eg, Cycle 5, Cycle 7, etc.).  
19. Serum PK sample (3.5 mL) for epacadostat will be taken on Cycle 2 Day 1 at pre-dose, 2 (+/- 5 minutes), 4 (+/-10 minutes), and 6 (+/-15 minutes) hours after the morning 
dose of epacadostat. A pre-dose PK sample will be collected on Cycle 2 Day 2. Samples will be sent to the Central Laboratory. Epacadostat will be administered in clinic on 
Cycle 2 Day 1 and Day 2 in order to collect pre-dose blood sample for PK. PK samples will not be collected for those on CRS-207 monotherapy . 
20. In Phase 1 US sites only: urine, rectal swab, oral swab, and whole blood will be collected from subjects treated with CRS-207 pre-dose, and at 6 hours, 18 to 24 hours, and 
Day 8 post-infusion on Cycle 1 and Cycle 2. DO NOT use the central line for blood sample collection. Additional assessments will be performed if results are positive for 
CRS-207 at the Day 8 time point. Samples will be sent to the central laboratory. 
21. Plasma and whole blood (7 mL) for pharmacodynamic analysis will be collected only for those who receive epacadostat) at the following timepoints: Cycle 1 Day 1 and 
Cycle 2 Day 1 pre-dose, 2, and 6 hours post-dose; Cycle 1 Day 2 and Cycle 2 Day 2 prior to epacadostat dose; and Cycle 3 Day 1 and every odd numbered Cycle Day 1 
thereafter) prior to epacadostat dose. 
22.  Paired tumor biopsies collected during the screening period (pre-dose) and on Cycle 2 Day 15 (+7 days). Paired biopsies are mandatory during Phase 1. Fine needle 
aspiration will not be acceptable. Samples will be sent to the Central Laboratory.  
23. Tumor evaluations will be performed using CT with contrast of the abdomen and pelvis (or MRI in case of contrast dye allergy) within 28 days prior to treatment, and 
repeated every 9 weeks (±7 days) after initiation of study drug using the same assessment technique. Subjects who discontinue treatment for reasons other than PD should 
continue to have their disease assessed by CT every 9 weeks (±7 days) until the start of a new anticancer therapy, documented PD, death, withdrawal of consent, or the end of 
study, whichever occurs first. Data from any standard of care CT scans may also be collected for tumor evaluation. 
24. CRS-207 will be administered on Day 1 of each cycle via IV infusion over approximately 1 hour. Before each CRS-207 infusion, subjects will be pre-medicated with 
acetaminophen and saline will be given immediately before and after infusion with CRS-207 (Section 5.5.2.1). Vital signs (BP, pulse, respiratory rate, temperature) will be 
obtained every 30 minutes (+/- 5 minutes) during CRS-207 infusion and every hour (+/- 5 minutes) during post-infusion follow-up. Subjects will be observed for at least 4 
hours after each infusion. Subjects who are not stable enough to be released at 4 hours after infusion should continue to be monitored until stable. Presence of fever alone does 
not indicate subject is not clinically stable. Document the time subject becomes stable in the medical records. To avoid inadvertent contamination of a central line (eg, 
infusion ports, PICC lines), DO NOT administer CRS-207 or saline through a central line during infusion or for 4 days following infusion. DO NOT flush the 
central line for any reason during and for 4 days after CRS-207 infusion.  
25. Enough epacadostat will be dispensed to last one cycle. Phase Arm 1: Epacadostat will be administered orally starting on Day 2 and BID thereafter. Tablets will be taken at 
the assigned dose in the morning and evening, approximately 12 hours apart. Epacadostat will be administered in clinic on Cycle 2 Day 1 and Day 2 in order to collect pre-
dose blood sample for PK. Epacadostat dosing does not apply to CRS-207 monotherapy (Phase 1, Arm 2). 
26. At each visit, provide a dosing diary and instructions on recording each dose of epacadostat. Collect unused epacadostat and review competed dosing diary with subject at 
following visit.  
27. A 7-day course of antibiotics will be administered at the EOT visit after blood has been collected for CRS-207 culture to ensure clearance of CRS-207. Antibiotic regimen 
must be completed prior to initiation of any other cancer-related therapy. Subjects with a central line port will receive 1 dose of IV antibiotics followed by 6 days of oral 
antibiotics; all other subjects will receive 7 days of oral antibiotics (refer to Section 5.6.3). Site personal will contact the subject by to confirm compliance with the antibiotic 
treatment and document in source and CRFs. 
28. At EOT, blood for culture will be collected prior to initiation of antibiotics (if applicable, blood must also be collected through the central line port) to assess CRS-207 
clearance. After EOT, blood for culture will be collected for CRS-207 surveillance at 
 
aPTT = activated partial thromboplastin time; ASAP = as soon as possible; BID = twice daily; BP = blood pressure; CA-125 = cancer antigen 125; CT = computed tomography; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EOT = End-of-Treatment; HIV = human immunodeficiency virus; 
HLA = human leukocyte antigen; INR = international normalized ratio; IRT = Interactive Response Technology; IV = intravenous; LFT = liver function test; MRI = magnetic 
resonance imaging; PBMC = peripheral blood mononuclear cells; PD = disease progression; PICC = peripherally inserted central catheter; PK = pharmacokinetic; 
PT = prothrombin; SRC = Safety Review Committee.  

SAP_001.pdf: 
 
 
ADU-CL-11 
 
 A PHASE 1/2, OPEN-LABEL SAFETY AND EFFICACY 
EVALUATION OF CRS-207 IN COMBINATION WITH 
EPACADOSTAT IN ADULTS WITH PLATINUM-RESISTANT 
OVARIAN, FALLOPIAN, OR PERITONEAL CANCER 
 
 
Abbreviated Statistical Analysis Plan (ASAP) 
 
 
 
ASAP VERSION 1.0 
DATE OF PLAN: 
03MAY2018 
 
 
STUDY DRUG:  
CRS-207, epacadostat, and pembrolizumab 
 
PREPARED FOR: 
Aduro Biotech, Inc. 
740 Heinz Avenue 
Berkeley, CA 94710 USA 
Telephone: +1 510-848-440 
 


-
-
-
-- - - -------------~-- --------
Sponsor: Aduro Biotech. Inc. 
Protocol N umber: ADU-CL-I I 
Version and Date: Version 1.0. OJM/\ Y20 l 8 
Approval Signature Page: Array Biostatistics, LLC 
I confirm that I have reviewed this document and agree on the content. 
Document Author: Vanessa Beddo. Ph.D. 
Senior Director. Biostatistics 
\~ 
Dme· 
01 MA-Y 201'b 
Document Reviewer: Anna Burkhardt. \/1.S. 
Senior Biostatistician 
Date 


Sponsor: Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MA Y2018 
Approval Signature Page: Aduro Biotech, Inc. 
I confirm that I have reviewed this document and agree on the content. 
Document Reviewer: Hamid Namini, PhD 
Senior Director of Biometrics 
Aduro Biotech 
0 7J1Jff 2-C/8 
Date 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
 
Contents 
1. 
Introduction ............................................................................................................................. 7 
2. 
Study Objectives and Endpoints .............................................................................................. 7 
3. 
Study Design............................................................................................................................ 9 
3.1. 
Study Design and Population ........................................................................................... 9 
3.2. 
Randomization and Blinding .......................................................................................... 13 
3.3. 
Sample Size Considerations ........................................................................................... 13 
3.4. 
Interim Analysis ............................................................................................................. 14 
3.5. 
Timing of Analyses ........................................................................................................ 14 
4. 
Data Analysis Considerations ................................................................................................ 14 
4.1. 
Stratification and Covariates .......................................................................................... 15 
4.2. 
Evaluation of Subgroups ................................................................................................ 15 
4.3. 
Multiple Comparisons and Multiplicity ......................................................................... 15 
5. 
General Data Handling Conventions ..................................................................................... 15 
5.1. 
Assigned and Actual Treatment ..................................................................................... 15 
5.2. 
Reference Dates .............................................................................................................. 16 
5.3. 
Study Day and Duration Variables ................................................................................. 17 
5.4. 
Study Time Periods ........................................................................................................ 17 
5.5. 
Baseline, Post-Baseline Changes, and Endpoint ............................................................ 17 
5.6. 
Imputation of Partial Dates ............................................................................................ 18 
5.7. 
Lost to Follow Up or Lapse of Adequate Assessments ................................................. 19 
6. 
Study Subject Data ................................................................................................................ 19 
6.1. 
Analysis Populations/Sets .............................................................................................. 19 
6.2. 
Subject Disposition ........................................................................................................ 19 
6.3. 
Protocol Deviations ........................................................................................................ 20 
6.4. 
Demographic and Baseline Characteristics .................................................................... 20 
6.5. 
Medical History .............................................................................................................. 21 
6.6. 
Prior and Concomitant Medication ................................................................................ 21 
6.7. 
Anticancer Therapies ...................................................................................................... 21 
6.8. 
Study Drug Exposure and Compliance .......................................................................... 21 
7. 
Efficacy .................................................................................................................................. 22 
7.1. 
Efficacy Endpoints and Analyses ................................................................................... 25 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
8. 
Safety ..................................................................................................................................... 27 
8.1. 
Adverse Events ............................................................................................................... 27 
8.2. 
Clinical Laboratory Evaluations ..................................................................................... 29 
8.3. 
Other Safety Evaluations ................................................................................................ 29 
9. 
Changes to the planned analysis ............................................................................................ 30 
10. 
References .......................................................................................................................... 31 
11. 
APPENDICES ................................................................................................................... 33 
11.1. 
Table of Contents for Tables ...................................................................................... 33 
11.2. 
Table of Contents for Listings .................................................................................... 35 
11.3. 
Table of Contents for Figures ..................................................................................... 36 
 
 
 
 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
ABBREVIATIONS 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Class 
CA-125 
Cancer antigen-125 
CTCAE 
Common Terminology Criteria for Adverse Events 
CFU 
Colony-forming units 
CR 
Complete Response 
CSR 
Clinical study report 
ECG  
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of treatment  
FAS 
Full analysis set 
GCIG 
Gynecological Cancer Intergroup  
IDO 
Epacadostat 
LLN 
Lower limit of normal 
MedDRA 
Medical Dictionary for Medical Affairs 
mRECIST 
Modified Response Evaluation Criteria in Solid Tumors 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell(s) 
Pembro 
Pembrolizumab 
PR 
Partial response 
PPS 
Per protocol set 
PD 
Progressive disease or Pharmacodynamics 
PT 
Preferred Term 
PFS 
Progression-free survival 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse events 
SAP  
Statistical analysis plan 
SD 
Stable disease or Standard deviation 
SOC 
System Organ Class 
SRT 
Safety review team 
Treg 
Regulatory T Cells 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
1. INTRODUCTION 
 
This is an abbreviated statistical analysis plan (ASAP) designed to outline the planned analysis 
required to satisfy the Clinical Study Report (CSR) synopsis of study number ADU-CL-11:  A 
Phase 1/2, Open-Label Safety and Efficacy Evaluation of CRS-207 in Combination with 
Epacadostat in Adults with Platinum-Resistant Ovarian, Fallopian, or Peritoneal Cancer.  The 
derivation and analysis of selected immunological/ biomarker endpoints and PK parameters will 
be discussed in another standalone document(s). The statistical analyses and summary 
tabulations described in this ASAP will provide the basis for the CSR synopsis reporting of the 
final analysis results from this trial.  Population, data handling rules, statistical methods, changes 
from the study protocol, and formats for data presentation are provided. The content of this SAP 
is based on the protocol Amendment 3 18FEB2017.  Protocol revision history appears as 
follows: 
V1.0 
28OCT2015 
Original 
V2.0 
22APR2016 
Amendment 1 
V3.0 
15NOV2016 
Amendment 2 
V4.0 
18FEB2017 
Amendment 3 
 
2. STUDY OBJECTIVES AND ENDPOINTS 
 
Phase 1: Dose Evaluation, Assigned Arms: 
Objectives 
Endpoints 
Primary 
• Determine the RP2D of epacadostat 
administered with CRS-207 in subjects with 
platinum-resistant ovarian, fallopian or 
peritoneal cancer 
• Assess safety and tolerability of CRS-207 
alone and CRS-207 in combination with 
epacadostat in subjects with platinum-
resistant ovarian, fallopian or peritoneal 
cancer 
• Hematologic and non-hematologic DLTs; 
• Adverse events by CTCAE grade; vital 
signs, physical exam findings, changes in 
ECG readings and changes in chemistry and 
hematology and coagulation parameters 
Secondary 
• *Characterize the PK of epacadostat 
• Evaluate the preliminary anti-tumor activity 
of each study drug regimen 
• *Characterize pharmacological effects on 
immune biomarkers in peripheral blood and 
tumor tissue 
 
• Plasma concentration of epacadostat and 
derived PK parameters; 
• ORR, defined as CR or PR as determined by 
mRECIST, RECIST v1.1, and GCIG CA-125 
criteria; 
• PFS, defined as the time from the date of 
first dose to PD or death due to any cause. 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
• *Characterize shedding and clearance of 
CRS-207 when given alone or with 
epacadostat 
PFS is measured through the last tumor 
assessment or commencement of a new 
systemic therapy. PD is determined by 
mRECIST, RECIST v1.1 and GCIG CA-125 
criteria; 
• Disease control rate, defined as CR+PR+SD 
as determined by mRECIST, RECIST v1.1, 
and GCIG CA-125 criteria; 
• Duration of response, defined as the time 
from first CR or PR until PD as determined 
by mRECIST, RECIST v1.1, and GCIG CA-
125 criteria; 
• OS, defined as the time from first dose until 
date of death due to any cause; 
• Ratio of tumor infiltrating lymphocytes 
CD8/Treg (FoxP3); 
• Plasma kynurenine/tryptophan ratio; 
• Other immunological and tumor biomarker 
endpoints: 
 o Cytokine/chemokine responses 
 o Antibody responses 
 o Modulation of immune cell 
populations and functions in PBMCs 
and tumor, and 
 o CA-125, mesothelin, IDO-1, PD-L1 
and additional tumor biomarkers; and 
• Detection of CRS-207 in urine, saliva, feces, 
and blood 
 
Phase 2: Randomized, 2-stage: 
Objectives 
Endpoints 
Primary 
• Assess safety of CRS-207/pembrolizumab 
administered with or without epacadostat 
• Assess tumor response and PFS 
• Adverse events, vital signs, physical exam 
findings, changes in ECG readings, and 
changes in chemistry, hematology, and 
coagulation parameters 
• ORR, defined as CR or PR as determined by 
mRECIST 
• PFS, defined as the time from the date of 
first dose to PD or death due to any cause. 
PFS is measured through the last tumor 
assessment or commencement of a new 
systemic therapy. PD is determined by 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
mRECIST. 
Secondary 
• Assess disease control rate and duration of 
response 
• Assess OS 
• Disease control rate, defined as CR+PR+SD 
as determined by mRECIST, RECIST v1.1, 
and GCIG CA-125 criteria 
• Duration of response, defined as the time 
from first CR or PR until PD as determined 
by mRECIST, RECIST v1.1, and GCIG CA-
125 criteria 
• ORR as determined by RECIST v1.1 and 
GCIG CA-125 criteria 
• OS, defined as the time from first dose until 
date of death due to any cause 
• PFS where PD is determined by RECIST 
v1.1 and GCIG CA-125 criteria 
Additional 
• *Assess the association of clinical efficacy 
(ORR, PFS, and OS) with immunologic and 
tumor biomarkers 
• *Characterize the PK of epacadostat 
• *Characterize shedding and clearance of 
CRS-207/pembrolizumab administered with 
or without epacadostat 
Immunological and tumor biomarker 
endpoints: 
• Cytokine/chemokine and antibody responses 
• Modulation of immune cell populations and 
functions in PBMCs and tumor 
• Mesothelin, IDO-1 and PD-L1 expression 
• CA-125 and additional candidate tumor 
biomarkers 
Pharmacokinetic endpoints: 
• Plasma concentration of epacadostat and 
derived PK parameters 
• Detection of CRS-207 in urine, saliva, feces, 
and blood 
 This ASAP provided derivation and listing of the efficacy endpoint, however no summary tables 
will be produced for these endpoints.  The derivation and analysis of selected immunological/ 
biomarker endpoints and PK parameters will be discussed in another standalone document(s).  
3. STUDY DESIGN 
3.1. Study Design and Population 
 
The study is designed to assess the safety and efficacy of the following investigational treatment 
regimens in adult females with epithelial ovarian, fallopian, or primary peritoneal cancer that is 
platinum-resistant (i.e. has progressed within 6 months after completing platinum-based 
chemotherapy): 
• CRS-207/epacadostat/pembrolizumab (CRS-207/IDO/pembro) 
• CRS-207/pembrolizumab (CRS-207/pembro) 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
The study will be conducted in 2 phases as depicted in Figure 1.  Phase 1 seeks to evaluate safety 
and tolerability and is aimed at determining the recommended Phase 2 dose (RP2D) of 
epacadostat administered with CRS-207 for further evaluation in Phase 2. The randomized Phase 
2 portion of the study will begin with a safety-run in to evaluate the addition of pembrolizumab, 
followed by a 2-stage design to evaluate safety and efficacy in subjects who have received no 
more than 3 prior chemotherapy regimens for locally advanced or metastatic disease. 
 
Figure 1: Study Schematic 
In Phase 1, the epacadostat dose will be evaluated based on a 3+3 design utilizing protocol 
defined DLT criteria as follows in Table 1. 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
Table 1: Dose-limiting Toxicity Criteria 
Cohort3 
0/3 subjects have 
DLT1 
1/3 subjects have 
DLT1 
<2/6 subjects have 
DLT1 
>2 in a cohort have 
DLT1,2 
Dose Cohort 1 4 
CRS-207 + 100 mg 
BID IDO 
Escalate to Dose 
Cohort 2 
Expand Dose 
Cohort 1 to 
6 subjects 
Escalate to Dose 
Cohort 2 
De-escalate to Dose 
Cohort -1 (CRS-207 
+ 50 mg BID IDO)3 
Dose Cohort 2 
CRS-207 + 300 mg 
BID IDO 
Expand cohort to 12 
subjects with paired 
biopsies 
Expand Dose 
Cohort 2 to 
6 subjects 
Expand cohort to 12 
subjects with paired 
biopsies 
Dose expand with 
100 mg BID IDO 
1. 
DLT period is 21 days after first dose of CRS-207. 
2. 
In the case that a cohort is closed to enrollment, subjects who are ongoing at that dose level without DLTs may continue 
treatment at the assigned dose level at the discretion of the Investigator. 
3. 
Evaluation of Dose Cohort -1 will enable the same 3+3 rules for dose cohort expansion or de-escalation to 25 mg (Dose 
Cohort -2). Evaluation of Dose Cohort -2 will enable the same 3+3 rules for dose cohort expansion. If Dose Cohort -2 is not 
tolerated, the Arm will be terminated. 
4. 
As an added safety measure, Dose Cohort 1 will have a staggered enrollment of no more than 1 new subject treated per 
week during the dose escalation phase. Thereafter, a decision to further stagger combination enrollment will be made by the 
Safety Review Committee (SRC) and will be based on emergent safety data. 
BID = twice daily; DLT = dose-limiting toxicity 
 
A Safety Review Committee (SRC) will be convened for the study, consisting of the 
Investigators who enrolled subjects in the study, the Lead Investigator, Study Medical Monitor, 
and Sponsor representatives. Adverse events, DLTs and safety data for all subjects will be 
reviewed on an ongoing basis by the SRC. Dose escalation and reduction decisions, 
determination of the recommended dose for expansion, and R2PD will be made by the SRC. 
Additionally, up to 12 subjects will be enrolled in in the CRS-207 alone arm to assess the safety 
and tolerability of CRS-207 in subjects with platinum-resistant ovarian, fallopian or peritoneal 
cancer. 
Phase 2 will begin by assessing safety of the addition of pembrolizumab to CRS-207 and CRS-
207/epacadostat; pembrolizumab will be administered at the 200 mg fixed dose level (as 
approved in other cancer indications). Phase 2 will initiate after the RP2D of CRS-
207/epacadostat is determined in Phase 1 and approximately 12 subjects with paired biopsies 
have been dosed at that level. 
A Safety Run-in will be completed since there are no precedent data on the addition of 
pembrolizumab to the planned drug combinations. Treatment of the first 6 randomized subjects 
in each treatment arm will be staggered, with no more than 1 subject treated per week, per arm. 
Subjects will be monitored during the Safety Run-in Period [the first 21 days] using the protocol 
defined DLT criteria. In the event ≥2 subjects in up to 6 (per arm) experience DLTs, the SRC 
will convene to determine if subsequent subjects enrolled will require a different dose level (per 
Table 2), or if additional subjects should be enrolled at a specified dose level to further assess 
safety and tolerability. In the event >2 subjects in the next 6 subjects (per arm) treated experience 
DLTs, the SRC will reconvene to determine if the dose will be further modified for the 
remaining subjects to be enrolled. The SRC may convene at any time during the Safety Run-in 
Period to review and evaluate available safety data as warranted by emerging safety data. 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
Table 2: Safety Run-in Dose Levels and Dose Reduction Table 
Dose level 
pembrolizumab  
 
epacadostat 
CRS-207 
  
1 
200 mg 
300 mg BID 
1 × 109 CFU 
-1 
200 mg 
100 mg BID 
1 × 109 CFU 
-2 
Further dose reductions will be discussed and confirmed by the SRC 
based on emergent safety data. 
 
Phase 2 will utilize a 2-stage design. Subjects will be randomized 1:1 into 2 treatment arms. In 
the first stage, once the final dose is confirmed in the Safety Run-in, a total of 13 subjects will be 
randomized into each arm (total 26 subjects). If the phase 2 dose is modified, at least 13 subjects 
will be enrolled and treated at the final dose level in each arm. If the pre-specified objective 
response-rate (ORR) and progression-free survival (PFS) criteria for advancement in the 2-stage 
design are met (≥1 response or median PFS ≥ 4.8 months) for an arm, an additional 14 subjects 
will be enrolled in that arm, for a potential total of 27 subjects per arm (up to 54 subjects total if 
both arms advance to stage 2). 
In the event that during the safety run in there are 2 DLTs in 6 patients in the CRS-
207/pembrolizumab arm but the CRS-207/pembrolizumab/epacadostat has 0 or 1 DLTs in 6 
patients using the same dose levels as in the 2 arm combination, the SRC will review the data 
and may allow enrollment of another 3 subjects in each run-in to better define the toxicities. 
The Schedules of Events for Phases 1 and 2 are provided in Protocol Appendix F and Table 1, 
respectively. The study consists of a 28-day screening period, followed by administration of 
study drug(s) in 3-week cycles. Treatment will continue for as long as there is adequate safety 
and potential for clinical benefit with the exception that pembrolizumab may be given for up to 
24 months to subjects without disease progression. After 6 cycles, CRS-207 will be administered 
every 6 weeks (Q6W); all other assigned treatments remain the same. 
Archived tumor tissue and paired tumor biopsies (collected at Screening and Cycle 2 Day 15) 
will be used to explore the association of programmed death receptor ligand-1 (PD-L1) 
expression, mesothelin expression, and tumor-infiltrating lymphocyte (TIL) characteristics with 
clinical responses. Tumor evaluation by radiographic imaging will be performed within 28 days 
blood will be collected to assess immune responses directed against L. monocytogenes, 
mesothelin, and other tumor-associated antigens. Circulating levels of Cancer antigen 125 (CA-
125) will be assessed at Screening and on Day 1 of each 3 week cycle while on treatment, and 
every 9 weeks thereafter until disease progression is confirmed. CRS-207 shedding and 
clearance will be assessed during Phase 1 and during the Safety Run-in of Phase 2 at US sites 
only. Urine, rectal swab, oral swab, and whole blood will be collected from subjects treated with 
CRS-207. Additional assessments will be performed if results are positive for CRS-207 at the 
Day 8 time point. 
An End-of-Treatment (EOT) Visit will be scheduled once treatment has been discontinued. 
Blood will be collected at EOT to assess clearance of CRS-207 and at 
 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
. To eliminate any 
potentially residual CRS-207, subjects will be administered antibiotics at the EOT Visit; the 
antibiotic regimen should be completed prior to receiving any subsequent cancer-related therapy. 
An additional Safety Follow-up Visit will occur 30 days after the last dose of study drug. If the 
subject begins another anticancer therapy before the end of the 30-day period, the subject should 
complete all of the Safety Follow-up Visit assessments prior to commencing the new therapy. 
After the Safety Follow-up Visit, subjects will return to the clinic every 9 weeks for tumor 
evaluation and CA-125 until radiographic disease progression is confirmed, at which time 
subjects will be followed every 12 weeks by phone/email (if no recent medical charting 
available) to collect data on survival and any subsequent anti-cancer treatment that may have 
been administered. Follow-up will continue until death, withdrawal of consent, or the end of the 
study, whichever occurs first. At the conclusion of the study, all remaining subjects who have 
received at least 1 dose of study treatment will be offered enrollment in a long-term follow-up 
study and continue to be followed for survival. 
3.2. Randomization and Blinding 
 
In Phase 2 of the study, subjects will be randomized into dose levels identified in Figure 1 in a 
1:1 ratio.  The study is open-label and knowledge of treatment assignments is not restricted. 
3.3. Sample Size Considerations 
 
During Phase 1, dose escalation will be based on traditional escalation guidelines (3+3) to 
determine the RP2D and evaluate safety data (including DLTs and adverse events) of each 
planned treatment. 
Phase 2 will be an open-label, randomized study design conducted in 2 stages to achieve up to 27 
treated subjects per Arm. After 13 subjects in an Arm are randomized at the confirmed dose 
following the Safety Run-in (Stage 1), an additional 14 subjects will be enrolled in that Arm 
(Stage 2) if 1 or more subjects respond or if the median PFS is at least 4.8 months. If the criteria 
for either ORR or PFS are not met, the preliminary anti-tumor activity in the Arm will be 
rejected and no further subjects will be randomized to the Arm. If the Arm goes on to stage 2, a 
total of 27 treated subjects will be studied in that Arm. The Arm will be considered successful if 
4 or more subjects respond or the median PFS is at least 4.8 months. If the criteria for either 
ORR or PFS are not met, the Arm will be rejected. This design is applied to each Arm 
independently. There are no formal comparisons planned between Arms. 
This is an exploratory study of each Arm where the sample size and ORR and PFS criteria for 
each stage are based on clinical judgement; each Arm is assumed to be evaluated separately. 
Type 1 error will not be controlled over both Arms. The ORR criteria and number of subjects for 
each stage within Arm are based on a Simon minimax 2-stage design (null hypothesis that ORR 
≤ 0.05 versus the alternative that ORR≥ 0.20 with alpha = 0.05 and power = 0.80). The PFS 
criteria are based on the lower limit of the 95% CI determined based on meta-analysis in the 3rd 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
relapse patient population where the median PFS is 5.6 months, (95% CI: 4.8 to 6.2 months) 
(Hanker, 2012). The one-sided test for PFS (i.e. observing median PFS≥ 4.8 months) has a Type 
I error rate of 0.0744 when the null hypothesis is that the median PFS=3.6 months, PFS is 
exponentially distributed, accrual is uniform, and total study duration is 30 months for 27 
subjects enrolled over 24 months. For a one-sided test of observing PFS≥ 4.8 months, there is 
approximately 77% power to detect a median PFS of 5.6 months and 50% power to detect a 
median PFS of 4.8 months. 
Assuming a non-negative correlation between the one-sided tests for ORR and PFS, the overall 
Type I error for either test criteria being met is at most 0.1203. There is at least 70% power to 
meet at least one of the test criteria if ORR=0.25 and median PFS=4.8 and at least 79% power if 
ORR=0.25 and median PFS=5.6. 
3.4. Interim Analysis 
 
Safety data will be reviewed on an ongoing basis by the SRC. 
For Phase 2 of the study, after 13 subjects have been treated with the CRS-207 dose identified at 
the end of the Safety run-in period within an Arm (Stage 1), an additional 14 treated subjects will 
be enrolled in the Arm (Stage 2) if 1 or more subjects respond (objective disease response of CR 
or PR) or if the median PFS is at least 4.8 months. Objective response rate and PFS are based on 
mRECIST. If neither of the criteria for response and PFS is met, preliminary antitumor activity 
in the Arm has not been identified and no further subjects will be randomized to the Arm. 
3.5. Timing of Analyses 
 
On 12 December 2017, Aduro decided to cease development activities of CRS-207 and close out 
ongoing studies. As of 12 January 2018 every subject had completed their end of treatment visit 
except for 2 subjects who will have the option to continue treatment based on agreement between 
the Investigator and patient.  All data through 12 January 2018 will be cleaned and soft-locked 
for CSR synopsis reporting. Additional data collection will be ongoing for these 2 subjects 
through to the date of database soft-lock.  Additional data following database lock will be 
captured in an amendment to the final CSR synopsis once the 2 subjects have completed their 
end of study follow-up.  This ASAP details the analysis plans for the CSR synopsis. 
4. DATA ANALYSIS CONSIDERATIONS 
 
All analyses will be conducted based on SAS 9.3 or higher. 
All data in the database will be presented in by-subject data listings. 
Unless otherwise stated, all listings will be sorted by subject number and assessment date (and 
time, if available). 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
Unless stated otherwise, continuous data will be summarized by Arm and overall within each 
Phase based on n, mean, median, standard deviation (SD), first quartile (Q1), third quartile (Q3), 
minimum value, and maximum value. 
Unless stated otherwise, categorical data will be summarized by treatment group using n and 
percentage based on the number of nonmissing values. 
• The number of missing values will be presented as a separate category with no 
percentage, but only if one or more subjects are missing data. 
• Counts of zero will be presented without percentages. 
Precision 
• Mean, Median, Q1, and Q3: one additional decimal place to that reported for 
Minimum and Maximum 
• SD: two additional decimal places than the Minimum and Maximum  
• Percentages: reported to one decimal place 
No statistical significance test will be performed. 
With the exception of missing data handling noted in Section 5.6, data will not be imputed for 
analysis purposes.   
  
4.1. Stratification and Covariates 
 
Not Applicable. 
4.2. Evaluation of Subgroups 
 
No subgroup analyses are planned. 
4.3. Multiple Comparisons and Multiplicity 
 
Not applicable. 
5. GENERAL DATA HANDLING CONVENTIONS 
 
5.1. Assigned and Actual Treatment 
 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
All subjects enrolled in the study are assigned to a therapy Arm based on the information in 
Table 3: 
Table 3: ADU-CL-11 Treatment Cycles by Arm 
 
Phase 
 
Arm 
Dose 1 / Route 
Treatment Cycle 
 
 
1 
CRS-207/ 
IDO 
CRS-207:  1 × 109 CFU by IV infusion 
over ~ 1 hour 
IDO:         100 mg or 300 mg BID Oral 
CRS-207:  Day 1 of each cycle (Cycles 1-6); 
Q6W thereafter 
IDO:          BID starting Cycle 1 Day 2 
CRS-207 
CRS-207: 1 × 109 CFU by IV infusion 
over ~ 1 hour  
CRS-207:  Day 1 of each cycle (Cycles 1-6); 
Q6W thereafter 
 
 
 
 
 
 
2 
CRS-207/ 
Pembro/ 
IDO 
Pembro:    200 mg by IV infusion over 30 
min 
CRS-207:  1 × 109 CFU by IV infusion 
over ~ 1 hour 
IDO:         300 mg Oral BID 1 
Pembro:    Day 1 of each cycle 
CRS-207:  Day 2 of each cycle (Cycles 1-6); 
Q6W thereafter 
IDO:          BID starting Cycle 1 Day 3 
CRS-207/ 
Pembro 
Pembro:   200 mg by IV infusion over 30 
min 
CRS-207: 1 × 109 CFU by IV infusion 
over ~ 1 hour 
Pembro:    Day 1 of each cycle 
CRS-207:  Day 2 of each cycle (Cycles 1-6); 
Q6W thereafter 
 
BID = twice daily; CFU = colony-forming units; IDO = epacadostat; IV = intravenous; pembro = pembrolizumab; Q6W = once 
every 6 weeks 
1 RP2D of epacadostat based on Phase 1 dose-evaluation parameters and determined by the SRC; the phase 2 dose 
may be further adjusted during Phase 2 Safety Run-in 
 
Phase 2 is a randomized assignment. 
Subject data will appear in the column representing the treatment they were assigned during 
enrollment/randomization, regardless of the treatment actually received. 
5.2. Reference Dates 
 
• Age and time from diagnosis uses the enrollment date as its reference date. 
• Safety data, such as AEs and laboratory assessments will use the first treatment date as a 
reference date. 
• Efficacy data will use the first date of study treatment as a reference date.  
• Study day will be based on the date of first study treatment as a reference date. 
The date of first study treatment will be based on the first date on which any therapy component 
was taken. 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
5.3. Study Day and Duration Variables 
 
Reference date calculations will be defined as the following:  
• date of interest – reference date + 1 when the date of interest >= reference date; 
• otherwise, date of interest – reference date. 
 
For instance, study day will be based on the date of first study treatment as the reference would 
either have a negative value if collected before dosing or a positive value if collected after drug 
dosing; there will be no study day zero.  
Duration of time is dependent on reference dates and will be calculated in a manner similar to 
that of the reference date calculation, assuming that dates of interest will strictly follow reference 
dates (e.g. no negative values).  For example, duration on study treatment is defined as the end of 
study date – first dose date + 1.  Duration of treatment is defined as the last date of treatment – 
first dose date + 1.  Duration of the safety observation period is defined as (the last date of 
treatment + 30 days) – first dose date + 1. Subjects still receiving ongoing treatment or 
participating in study follow up at the time of analysis will use imputed treatment end and end of 
study dates as described in Section 5.6. 
Survival, or time-to-event, endpoints such as progression-free survival (PFS) or overall survival 
(OS) are followed until first event or censoring.  As a result, survival time will be calculated as: 
event or censoring date – reference date + 1.  These are further described in Section 7. 
When reporting survival or duration outcomes, the results (in days) above will be converted to an 
appropriate unit.  When reporting in months it will be divided by 30.4375; for reporting in weeks 
it will be divided by 7; and for reporting in years it will be divided by 365.25. 
5.4. Study Time Periods 
 
Safety reporting will be classified by the following study periods for analysis: 
Pre-therapy is defined as the period prior to a subject’s first dose of study treatment. 
On therapy is defined as the period between first dose of study treatment and within 30 days 
following the last dose of study treatment.   
Post-therapy is defined as the period of time following the on therapy period. 
5.5. Baseline, Post-Baseline Changes, and Endpoint 
 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
Baseline will be based on the last nonmissing value collected prior to or on the date [and time, if 
applicable] of first study treatment.  Post-baseline values will be those collected after first dose 
of study drug.   
Change from baseline is defined as: value – baseline value.  
Percentage change from baseline is defined as: (value – baseline value)/baseline value X 100%.  
Most extreme change:  The maximum most extreme change will be the maximum post-baseline 
value; the minimum most extreme change will be the smallest post-baseline value. This 
calculation will consider all assessments collected within the on therapy period, scheduled or 
unscheduled. 
5.6. Imputation of Partial Dates 
 
Adverse Events and Concomitant Medications 
• If the AE start date is completely missing, no imputation will be conducted. 
• If the AE start date is missing day and month, do the following: 
o If the treatment start date is missing or the AE year does not fall in the same as 
that of first treatment or if the AE contains information to indicate that the event 
ended before the date of first study treatment (e.g. AE end date month and year 
are earlier than the treatment start date or the full date is known and occurs earlier 
than the date of first treatment), then set the start month and day to January 1st 
o Otherwise, set the start date to the date of first study treatment  
• If only the day is missing, do the following: 
o If the study treatment start date is missing or the month and year does not fall in 
the same as that of first treatment or if the AE contains information to indicate 
that the event ended before the date of first study treatment, then set the start 
month and day to the 1st of the stated month 
o Otherwise, set the start date to the date of first study treatment 
• End dates will not be imputed  
Subsequent Anticancer Therapy, Radiotherapy or Anticancer Surgical Procedures  
Partial dates for subsequent therapies will not typically be imputed, but may be needed to support 
efficacy outcome derivations (e.g. PFS censoring dates).  In this case, the following will be 
applied for imputation of new anti-cancer therapies taken after first study treatment: 
• If the start date is completely missing, no imputation will be conducted 
• If the start date is missing day and month, do the following: 
o If progressive disease (PD) has been identified in the year noted, new anti-cancer 
therapy date will be assigned to begin one day after the date of PD.   
o Otherwise the new anti-cancer therapy date will be assigned to January 1st. 
• If only the day is missing, do the following: 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
o If PD has been identified in the year noted, new anti-cancer therapy date will be 
assigned to begin one day after the date of PD.   
o Otherwise the new anti-cancer therapy date will be assigned to the 1st of the stated 
month. 
Overall Response Date  
For each visit-specific disease assessment, the date of overall response will need to be 
established.  For complete response (CR) and partial response (PR), set the date of overall 
response to the latest of all tumor assessments for the specified visit.  Otherwise, set to the 
earliest date of all assessments made during the specified visit.  
Treatment End Date  
Missing treatment end dates will not necessarily be imputed at the end of the study.  However, 
due to ongoing reporting needs, treatment end date will be imputed as the earliest of the data 
cutoff date, date of death, or date of treatment study withdrawal. 
End of Study Date  
Missing study end dates will not necessarily be imputed at the end of the study.  However, due to 
ongoing reporting needs, end of study dates will be imputed as the earliest of the data cutoff date 
or date of death. 
5.7. Lost to Follow Up or Lapse of Adequate Assessments  
 
If a subject has missed two or more scheduled disease assessments, a censoring date will be 
required in support of relevant survival endpoint derivations.  For example, PFS will be censored 
at the last adequate disease assessment prior to the lost to follow up window.  However, this 
survival outcome would be considered censored after an extended amount of time without 
additional assessment (after two have been missed).  Based on a protocol specified disease 
assessment schedule of every 9 weeks, a window of 140 days [18 weeks + 14 days] would be 
used as the censoring date (assuming a protocol window period of 7 days for each assessment). 
6. STUDY SUBJECT DATA  
6.1. Analysis Populations/Sets 
 
The Safety Analysis Set (SAF) includes all randomized subjects who received at least 1 dose of 
any study drug. The SAF will be conducted on the basis of the treatment assigned and is the 
basis of analysis summary tables unless otherwise indicated. 
6.2. Subject Disposition 
 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
Summaries of analysis population membership; final study status (ongoing or terminated), 
including reasons for study termination; treatment status (ongoing or discontinued), including 
reasons for treatment discontinuation will be produced based on all subjects enrolled in the 
study.   Time on study and duration of treatment will also be summarized.   
Screen failures and final subject disposition status will be listed. 
6.3. Protocol Deviations 
 
Protocol deviations will be identified and classified as major (violations) before the database is 
locked. Major protocol deviations may include but are not limited to: 
• Violation of Inclusion/Exclusion Criteria 
• Dose not properly administered, including 
o Administrations in which protocol-required pre-medication were not administered 
• Use of prohibited medications 
Protocol deviations will be listed. 
6.4. Demographic and Baseline Characteristics 
 
Subject demographics will be summarized for age (years), sex, ethnicity, race, baseline height 
(cm), baseline weight (kg), BMI (kg/m2), and BSA (m2).  Age will also be categorized as a 
categorical variable (age < 65, ≥ 65 years) for reporting.    
 
The following conversions and equations will be used as applicable: 
• Height (in cm) = height (in inches) * 2.54 
• Weight (in kg) = weight (in lbs) * 0.4536 
• BMI (kg/m2) = weight(kg)/[height(m)2]  
• BSA(m2) = √[(height(cm)*weight(kg))/3600] 
Duration of time from initial diagnosis to screening (in months); cancer type; histology; genetic 
mutations; TNM staging at diagnosis; TNM staging at study entry; stage at diagnosis; stage at 
study entry; disease specific genetic mutations; prior systemic therapy, prior radiation and prior 
surgery (Yes/No); sum of target lesions per RECIST 1.1 at baseline (mm); baseline CA-125 (and 
response evaluability per GCIG as Yes/No as identified in Section 7); and baseline ECOG will 
be summarized.  Histology and genetic mutations for phase 1 patients will be provided by Aduro 
outside of the clinical database. 
 
Subject demographics and baseline characteristics, including cancer related surgeries, systemic 
therapies, and prior radiotherapy, will be listed. 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
6.5. Medical History 
 
Medical history will be listed. 
6.6. Prior and Concomitant Medication  
 
Concomitant medications will be coded to ATC and preferred name based on the WHO Drug 
Dictionary (WHO-DDE B2, March 2016).  Prior medications are those which have been 
identified to have been discontinued prior to first study treatment (e.g. taken exclusively during 
the pre-therapy period). Concomitant medications are those which have been identified to have 
been taken at any point during the on therapy period.   
Prior, concomitant, and post-therapy medications will be presented in data listings; medications 
which do not occur during the on therapy period will be identified.  
6.7. Anticancer Therapies 
 
Anticancer therapies will be coded to ATC and preferred name based on the WHO Drug 
Dictionary (WHO-DDE B2, March 2016).  It is assumed that these therapies will be collected on 
the associated CRF have been taken following study drug discontinuation in compliance with the 
protocol.   Anticancer therapies will be presented in a data listing. 
6.8. Study Drug Exposure and Compliance 
 
The number of cycles of administration (of any dose amount) of pembrolizumab and epacadostat 
will be reported as a continuous and categorical outcome; categories for reporting will include:  
< 5 Cycles; 5 - 15 Cycles; > 15 to 25 Cycles; and > 25 Cycles.   
The number of infusions of CRS-207 will also be reported as both a continuous and categorical 
outcome; categories for reporting will be < 5 infusions; 5 – 10 infusions; > 10 to 15 infusions; 
and > 15 infusions. 
For CRS-207, the average volume administered for each infusion (or cycle) will be summarized 
by therapy.  This will be calculated for each subject in (mL / infusion or mL / Cycle): 
(Sum of Total Volume Administered [mL]) / (Total Number of Administrations) 
The average dose intensity for each pembrolizumab cycle will be summarized.  This will be 
calculated for each subject in (mg / Cycle): 
(Sum of Total Dose Received [mg]) / (Total Number of Administrations) 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
The incidence of infusion interruptions, as well as the total number of interruptions will be 
displayed for CRS-207 and pembrolizumab separately.  Reasons for infusion interruption will 
also be summarized.  
The incidence and number of epacadostat dose reductions will be summarized.   
For epacadostat, the mean daily dose will be summarized.  This will be calculated for each 
subject in (mg / Day): 
(Sum of Total Doses Received [mg]) / (Duration of epacadostat therapy) 
Duration of treatment for each drug, based on similar definitions provided in 5.3, will also be 
summarized.   
Epacadostat dosing, CRS-207 and pembrolizumab administrations, infusion interruptions, and 
dose reduction information, as well as derived drug exposure metrics, will be listed. 
7. EFFICACY  
 
All efficacy variables derived from tumor imaging and response assessments will be determined 
by the local Investigator using modified RECIST 1.1 (mRECIST) guidelines.  Based on the study 
protocol, evaluations of overall response are identified as complete response (CR), partial 
response (PR), stable disease (SD), progressive disease (PD), or Not Evaluable (NE) by 
investigators in the CRF based on RECIST 1.1.  mRECIST is taken into consideration for cases 
in which PD have been identified; this is of impact to study discontinuation considerations as 
noted below. 
If radiologic imaging shows initial PD, tumor assessment should be repeated ≥ 4 weeks later in 
order to confirm PD while continuing study treatment and awaiting radiologic confirmation of 
progression. If repeat imaging shows a stability or reduction in the tumor burden compared to the 
initial scan demonstrating PD, treatment may be continued /resumed. If repeat imaging confirms 
progressive PD, subjects will be discontinued from study therapy and their initial PD evaluation 
date will be considered as their date of progression. In determining whether or not the tumor 
burden has increased or decreased, investigators should consider all target lesions as well as non-
target lesions. 
In subjects who have initial radiological evidence of PD, it is at the discretion of the treating 
minimum of 4 weeks later. This clinical judgment decision should be based on the subject's 
overall clinical condition, including performance status, clinical symptoms, and laboratory data. 
Subjects may receive treatment while waiting for confirmation of PD if they are clinically stable 
as defined by the following criteria: 
• Absence of new or worsening signs and symptoms indicating PD; 
• No decline in ECOG performance status; 
• Absence of rapid progression of disease; and 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
• Absence of progressive tumor at critical anatomical sites (e.g. cord compression) 
requiring urgent alternative medical intervention. 
When feasible, subjects should not be discontinued until progression is confirmed. Subjects who 
are deemed clinically unstable are not required to have repeat imaging for confirmation of PD. 
In all other instances, treatment decisions will be made based on investigator review of the 
clinical and radiographic data.  
Progressive serial elevation of serum CA-125 will be used to determine CA-125 response. 
Guidelines for using CA-125 response have been developed and are based on the Gynecological 
Cancer Intergroup (GCIG) Definitions for Response and Progression. Subjects should have a 
pre-treatment CA-125 of at least twice the ULN in order to be considered for CA-125 response 
assessment. Subjects are not evaluable by CA-125 if they have received mouse antibodies or if 
there has been medical and/or surgical interference with their peritoneum or pleura during the 
previous 28 days. In those subjects considered evaluable by CA-125, a CA-125 response would 
be obtained the moment the CA-125 is reduced by 50% and this should be confirmed with a 
consecutive CA-125 assessment not earlier than 28 days after the previous one; the date of the 
first 50% reduction to be the reference date for the CA-125 response.  
Progression is conventionally defined according to RECIST 1.1 but can also be based on serum 
CA-125. In assigning the date of progression, PD by objective change in tumor size should 
always take precedence over CA-125 should it occur first. If measurable disease is reducing in 
size during treatment but the CA-125 results suggest progression, the patient should continue to 
receive protocol treatment. If measurable disease is stable but CA-125 indicates confirmed 
progression over at least 4 weeks, may advise changing protocol treatment, unless there is the 
possibility that the therapy could be slowing the rate of rise of CA-125. CA-125 progression is 
defined as: 
• Elevated CA-125 pretreatment and normalisation of CA-125 must show evidence of CA-
125 greater than, or equal to, two times the upper normal limit on two occasions at least 
one week apart or 
• Patients with elevated CA-125 pretreatment, which never normalises must show evidence 
of CA-125 greater than, or equal to, two times the nadir value on two occasions at least 
one week apart or 
• Patients with CA-125 in the normal range pretreatment must show evidence of CA-125 
greater than, or equal to, two times the upper normal limit on two occasions at least one 
week apart. 
• Elevated values must be confirmed by two separate measurements obtained at least one 
week apart. CA 125 progression will be assigned the date of the first measurement that 
meets the criteria as noted.  
A patient may be declared to have progressive disease on the basis of either the objective 
RECIST criteria or the CA-125 criteria. The date of PD will be the date of the earlier of the two 
events if both are documented. 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
The use of GCIG CA-125 in tandem with RECIST 1.1 in the evaluation of overall response at 
each visit is identified in  
Table 4. 
Table 4: Overall Response in Patients with Initial Measurable Disease and Evaluable by CA-125, 
Combining Both Criteria 
Target Lesion 
Non-target Lesion 
New Lesion 
CA-125 
Overall Response 
CR 
CR 
No 
Normal 
CR 
CR 
Non-CR 
Non-PD 
No 
Not PD 
PR 
CR 
CR 
No 
PR not normal 
PR 
PR 
Non-PD 
No 
Not PD 
PR 
NE 
Non-PD 
No 
PR 
PR 
PD or New > 28 Days from CA-125 PR* 
PR 
PR 
SD 
Non-PD 
No 
PR 
PR 
SD 
Non-PD 
No 
Not PR or PD 
SD 
PD or New <= 28 Days from CA-125 PR* 
PR 
PD 
PD 
Any 
Yes or No 
Any 
PD 
NE 
PD 
Yes or No 
Any 
PD 
NE 
Any 
Yes 
Any 
PD 
NE 
Any 
Yes or No 
PD 
PD 
* patients who have a CA-125 response that occurs more than 28 days from PD according to RECIST are considered a PR 
according to best response, but PD if the RECIST PD is within 28 days of CA-125 response 
For subjects with non-measurable disease, GCIG CA-125 based overall response derivations will 
be conducted according to Table 5. 
Table 5: Overall Response in Subjects without Initial Measurable Disease and Evaluable by CA-125 
CA-125 
Non-target 
Lesion# 
New Lesion 
Overall 
Serological 
Response 
Response and 
normalized 
CR 
No 
CR 
Response 
Non-PD 
No 
PR 
Normalized but 
not response 
Non-CR 
Non-PD 
No 
SD 
Non-PR 
Non-PD 
Non-PD 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD* 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
#Non-target lesions include ascites and peritoneal thickening, which are not measurable according to RECIST. 
*Unequivocal progression in non-target lesions may be accepted as disease progression. 
 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
Subjects which do not have measurable disease at study entry will be evaluated based on GCIG 
criteria and will not be included in mRECIST and RECIST 1.1 analyses; endpoint derivations 
will be considered not evaluable (NE).  Subjects which are not evaluable per GCIG CA-125 
criteria will be handled similarly. 
7.1. Efficacy Endpoints and Analyses 
 
Refer to Section 2 for further details on Phase 1 and Phase 2 efficacy endpoint hierarchy. 
Objective Response Rate  
For purposes of mRECIST based derivations, a subject’s best overall response (BOR) is 
determined by the highest qualitative value assessed during the study given a hierarchy of overall 
response results: CR > PR > SD > PD > NE.  In order for a valid value of SD to be assigned, 
there must be evidence of stable disease for at least 8 weeks.  If the minimum time for SD has 
not been met on the first assessment, the assignment of BOR will depend on subsequent response 
assessments.  Subjects which do not have follow up data after a first assessment of SD prior to 
the minimum time requirement will be considered as not evaluable.  BOR will be based on 
assessments collected after the first dose of study until confirmed disease progression; 
assessments collected after the start of new cancer treatment will not be considered.   
The objective response rate (ORR) is defined as the number of subjects who exhibit a BOR 
response of CR or PR divided by the number of evaluable subjects. Subjects who discontinue 
prior to any evaluation of post-baseline tumor assessments will be considered as non-responders 
regardless of discontinuation reason. ORR will not be reported in the CSR synopsis. 
BOR will be listed for each subject.  
Progression-Free Survival  
PFS is defined as the number of weeks from the date of first dose of study treatment to the first 
date of objectively determined progressive disease or death from any cause and is computed as 
described in Section 5.3.  The primary analysis of PFS will include tumor assessments collected 
after the end of study treatment and will be based on mRECIST criteria for progressive disease 
confirmation. Tumor assessments taken after switch to another anti-cancer therapy will be 
excluded from consideration. 
The first date of objectively determined progressive disease would be the earliest date of any 
post-baseline overall response finding of progressive disease is confirmed as part of the tumor 
lesion assessment data or death, unless a subject is censored at an earlier date.  If an assessment 
occurs over several days, the method described in Section 5.6 will be used.  If there are no 
adequate assessments for a subject, they will be censored on their first dose date unless they died 
prior to having their first assessment (in which case they will be considered to have had a PFS 
event of death).  If a subject receives subsequent anticancer therapy prior to documentation of 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
progressive disease, PFS will be censored at the latest adequate assessment prior to therapy 
initiation.   
Subjects who progress or die following an extended period of follow up will also be censored at 
a latest adequate assessment prior to the end of a predefined lapse window, even if information is 
available regarding progression or death after this extended period.  Should a subject die after the 
end of this lapse window they will be censored at their first dose date.  The lapse window after 
which PFS events will not be considered is defined in Section 5.7.   
If a subject does not receive confirmation of radiologically identified PD, and there are no further 
assessments prior to censoring, the subject will be considered to have progressed based on their 
last valid assessment. 
Otherwise, if a subject does not have documented progression, the subject will be censored at the 
latest adequate assessment. 
PFS will be listed for each subject. 
Disease Control Rate 
Disease control rate (DCR) is defined as the number of subjects who exhibit a BOR response of 
CR, PR or SD divided by the number of evaluable subjects. 
The derivation analysis of DCR will be produced based on mRECIST, RECIST 1.1, and GCIG 
CA-125 criteria.  A description of BOR derivations for RECIST 1.1 and GCIG CA-125 can be 
found in a previous section.   
DCR will not be reported in the CSR synopsis.  BOR will be listed for each subject. 
Duration of Response 
Duration of response (DOR) will be computed for subjects who have been identified as a 
responder (achieved an overall response of CR or PR during the PFS observation period); it will 
be computed as described in Section 5.3, where the reference date will be the first date where a 
subject has been documented to have achieved a responder designation.  Censoring algorithms 
similar to those identified for PFS will be used for DOR. 
The derivation of DOR will be conducted based on RECIST 1.1 and GCIG CA-125 criteria. 
DOR will not be derived if there are no responders on the study. 
Objective Response Rate Based on RECIST 1.1 and GCIG CA-125 
For purposes of RECIST v1.1 derivation, the BOR will be based on methods described in 
Section 7.1 but with alternate assumptions around study treatment discontinuation; assessments 
following an initial, radiologically identified overall response of PD will not be considered 
regardless of confirmation status.  


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
For purposes of GCIG CA-125 derivation, BOR will be evaluated over the course of the study based on the method described in 
7.1, using overall responses as defined in  
Table 4 (for subjects with measurable disease at baseline) and Table 5 (for subjects who did not 
have measurable disease at baseline).  
For both methods, ORR remains defined as the percentage of subjects identified to have 
responded (CR or PR) for BOR.   
The analyses specified in Section 7.1 for ORR will be repeated for ORR based on RECIST v1.1 
and GCIG CA-125 criteria.   
Overall Survival 
Overall survival (OS) is defined as the number of weeks from the date of first dose of study 
treatment to the date of death from any cause and is computed as described in Section 5.3. 
Subjects still alive as of the data cut-off date will be censored on the last known alive date from 
mortality status follow up. For subjects that are lost to follow up, the last visit in the database or 
last contact date where the subject is documented to be alive will be used to estimate last known 
date alive. 
Progression-Free Survival Based on RECIST 1.1 and GCIG CA-125 
The analyses specified in Section 7.1 for PFS will be repeated for PFS based on RECIST v1.1 
and GCIG CA-125 criteria. 
8. SAFETY  
All safety analysis reporting will be based on the SAF.  
8.1. Adverse Events 
Treatment emergent adverse events (TEAEs) are defined as all events that occur from the time of 
first study drug administration until 30 days following the last dose of study drug or initiation of 
subsequent cancer-related therapy, whichever occurs first.   TEAEs are assessed for severity 
using the NCI-CTCAE v. 4.0, relationship to each therapy, and seriousness.     For Phase 1 data, 
infusion-related reactions (IRRs) are those which: have an onset date on or one day after the date 
of a CRS-207 administration; have been identified as related to CRS-207; and are coded to the 
following specific preferred terms: dyspnoea, chills, decreased appetite, fatigue, headache, hives, 
hypersensitivity, hypotension, hypoxia, influenza like illness, infusion related reaction, myalgia, 
nausea, pain, presyncope, pyrexia, rash, and vomiting.  Phase 2 IRRs are identified by the 
investigator using the appropriate eCRF field. 
A summary of TEAEs will be produced, including counts and percentages of subjects with any 
incidences of:  TEAEs, CTCAE Grade 3 or higher TEAEs, TEAEs related to any study 
treatment, CTCAE Grade 3 or higher TEAEs related to any study treatment, serious adverse 
events (SAEs), SAEs related to any study treatment, TEAEs leading to study drug 
discontinuation, CRS-207 infusion related reactions, and fatal TEAEs. 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
A separate summary of AEs identified as CRS-207 IRRs will include the number of infusions 
received by subjects, the number of subjects having an IRR, total number of IRRs per subject, 
maximum IRR grade, and dose modifications resulting from IRRs. 
Adverse events will be coded based on the Medical Dictionary for Regulatory Affairs 
(MedDRA) version 18.1 or higher, for reporting by system organ class (SOC) and preferred term 
(PT) in descending order of overall incidence for the type of event reported.  Within these 
summaries, TEAEs will be sorted for each subject by PT and severity; subjects will be counted 
once within a PT based on their TEAE having maximum severity.   
Summaries of AEs by SOC and PT will include the following types of events:  
• TEAEs; 
• TEAEs related to any study treatment (Definitely Related, Probably Related, or Possibly 
Related);  
• CTCAE Grade 3 or higher TEAEs; 
• CTCAE Grade 3 or higher TEAEs related to any study treatment; 
• CRS-207 infusion-related reactions; 
• SAEs; 
• SAEs related to any study treatment;  
• TEAEs that lead to discontinuation of study drug; and 
• Fatal TEAEs. 
To account for potential differences in the extent of exposure between the treatment categories, a 
subject-year adjusted rate will also be presented. The rate is calculated as the number of subjects 
with an event divided by the total subject-years of safety observation, where subject-years of 
safety observation for each subject is defined as duration of safety observation (defined in 
Section 5.3) in days divided by 365.25. 
A comprehensive listing of all AEs will be provided in a by-subject data listing; events which do 
not occur during the on therapy period will be identified. In addition, the following listings will 
be provided:  
• SAEs;  
• TEAEs leading to treatment discontinuation; and 
• Fatal TEAEs (with identification of those which occur within the on therapy period). 
• Dose limiting toxicities (DLTs) 
• AEs of special interest (AESIs), as defined in Section 9.1.2 of the study protocol 
Deaths 
The number and percentage of subjects who died along with primary cause of death will be 
summarized overall (including the post-study survival surveillance period) and within 30 days of 
last dose of study drug. All death data will be listed. 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
8.2. Clinical Laboratory Evaluations 
 
Clinical chemistry and hematology parameters will be reported based on the International 
System of Units (SI).  The following laboratory evaluations will were collected, those with 
asterisks (*) indicating those that will be graded using NCI-CTCAE v 4.03: 
Hematology: hematocrit, hemoglobin*, red blood cell (RBC), platelet count*, white blood cell 
(WBC)*, absolute neutrophil count*, absolute lymphocyte count*, monocytes, eosinophils, and 
basophils. 
Clinical chemistry: Electrolytes: bicarbonate, calcium*, chloride, magnesium*, phosphorus*, 
potassium*, sodium*; Hepatic function tests: albumin*, alkaline phosphatase*, bilirubin (total*, 
direct, indirect), total protein, alanine aminotransferase (ALT)*, aspartate aminotransferase 
(AST)*; renal function tests: blood urea nitrogen (BUN), creatinine*; Other chemistry tests: 
glucose*, LDH, amylase*, uric acid*. Note: Uric acid is graded only for Grade 4 as other grades 
require additional, clinical judgement.  It will otherwise be assumed normal (Grade 0). 
Coagulation:  Activated partial thromboplastin time*, international normalized ratio, D-dimer, 
and fibrinogen*. 
Endocrine testing (for subjects treated with epacadostat):  Adrenocorticotropic hormone, serum 
cortisol, luteinizing hormone, prolactin, thyroid stimulating hormone, T3, FT3, FT4. 
Thyroid function testing: Total triiodothyronine (T3), free triiodothyronine (FT3), free thyroxine 
(FT4), thyroid stimulating hormone. 
Shift tables displaying the shift from baseline to the worst value of NCI-CTCAE grades for 
hematology and clinical chemistry parameters will be presented based on the most extreme 
change as it relates to the relevant NCI-CTCAE definition. NCI-CTCAE relating to “high/hyper” 
conditions will depend on the maximum post-baseline value while NCI-CTCAE “low/hypo” will 
be reported based on the minimum post-baseline value.  Shift tables will also include parameters 
with bi-directional toxicity grading. 
All laboratory parameters will be provided in subject data listings.  Laboratory evaluations with a 
CTCAE grade of 3 or higher will also be provided as a separate listing. 
8.3. Other Safety Evaluations 
 
Vital Signs 
Vital signs include: pulse (bpm); respiratory rate (breaths/min); temperature (oC); systolic and 
diastolic blood pressure (mmHg); pulse oximetry (%), and weight (kg).  
Vital sign data will be provided in data listings. 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
Electrocardiogram (ECG) 
Electrocardiogram (ECG) parameters include HR (bpm) and the following intervals (ms): PR, 
QRS, QT, JTc, and QTcF. Observed values for ECG parameters will be listed.  
Shifts in investigator-reported ECG interpretation shifts from screening worst case post-baseline 
will be summarized.  Worst case post-baseline will be based on a subject’s most abnormal 
observed investigator-reported ECG interpretation during the on therapy period. 
ECG data will be provided in data listings. 
ECOG Performance Status 
ECOG data will be provided in data listings. 
Physical Examinations 
Physical examinations will be presented in subject data listings. 
9. CHANGES TO THE PLANNED ANALYSIS 
 
All efficacy endpoints will be derived and listed, but will not be summarized. 
 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
10. REFERENCES 
 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E3 Guideline: Structure and content of clinical study 
reports questions & answers (R1). 2012.            
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_QAs_
R1_Step4.pdf.  Accessed 13 Jan 2016. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH Harmonised Tripartite Guideline: Structure and content of 
clinical study reports E3. Step 4. 1995. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guide
line.pdf. Accessed 13 Jan 2016. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E9: Statistical principles for clinical trials. 1998. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9
_Guideline.pdf . Accessed 15 June 2016. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs. 2005.  
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_G
uideline.pdf. Accessed 17 February 2017. 
Hamilton S, Bernstein AB, Blakey G, Fagan V, Farrow T, Jordan D, Seiler W, Shannon A, 
Gertel A, Budapest Working Group: Developing the Clarity and Openness in Reporting: E3-
based (CORE) Reference user manual for creation of clinical study reports in the era of clinical 
trials transparency. Research Integrity and Peer Review. (2016) 1:4. 
Hanker LC, Loibl S, Burchardi N, et al. The impact of second to sixth line therapy on survival of 
relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol 2012;23:2605-
12. 
PhUSE CSS Development of Standard Scripts for Analysis and Programming Working Group.  
Analyses and Displays Associated with Demographics, Disposition, and Medications in Phase 2-
4 Clinical Trials and Integrated Summary Documents.  2014. 
http://www.phusewiki.org/wiki/images/c/c9/CSS_WhitePaper_DemoDispMed_v1.0.pdf . 
Accessed 03 Jan 2017. 
PhUSE CSS Development of Standard Scripts for Analysis and Programming Working Group.  
Analyses and Displays Associated to NonCompartmental Pharmacokinetics – With a Focus on 
Clinical Trials. 2014. 
http://www.phusewiki.org/wiki/images/e/ed/PhUSE_CSS_WhitePaper_PK_final_25March2014.
pdf . Accessed 31 Dec 2016. 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
PhUSE CSS Development of Standard Scripts for Analysis and Programming Working Group.  
Analyses and Displays Associated with Thorough QT/QTc Studies. 2016. 
http://www.phusewiki.org/docs/CSS%20White%20Papers%202016/230316%20CS_WhitePaper
_TQTStudies_v1.0.pdf .  Accessed 03 Jan 2017. 
National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human 
Services. [Accessed January 2, 2017];Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0. Published May 28, 2009; Revised Version 4.03 June 14, 2010 (Vol. 
Available from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf. 
Eisenhauer E.A., Therasse P, Schwartz LH, et. al. New Response Criteria in Solid Tumors: 
Revised RECIST Guidelines (Version 1.1).  European Journal of Cancer.  (2009) 45: 228-247. 
CDER/CBER. 2007. Guidance for industry: Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics. Silver Spring, MD: Food and Drug Administration.  
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
072109.pdf . Accessed 17 October 2016. 
Rustin GJS, Vergote I, Eisenhauer E, et al. Definitions for Response and Progression in Ovarian 
Cancer Clinical Trials Incorporating RECIST 1.1 and CA 125 Agreed by the Gynecological 
Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011;21:419-423.  
 
 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
11. APPENDICES 
 
11.1. Table of Contents for Tables 
 
Table 14.1.1.1: 
Subject Disposition: Phase 1: Dose Evaluation - Enrolled Subjects 
Table 14.1.1.2: 
Subject Disposition: Phase 2: Randomized - Randomized Subjects 
Table 14.1.1.3: 
Subject Disposition: Phase 1: Dose Evaluation – Safety Analysis Set 
Table 14.1.1.4: 
Subject Disposition: Phase 2: Randomized - Safety Analysis Set 
Table 14.1.2.1: 
Subject Demographics: Phase 1: Dose Evaluation - Safety Analysis Set 
Table 14.1.2.2: 
Subject Demographics: Phase 2: Randomized – Safety Analysis Set 
Table 14.1.3.1: 
Baseline Disease Characteristics: Phase 1: Dose Evaluation – Safety 
Analysis Set 
Table 14.1.3.2: 
Baseline Disease Characteristics: Phase 2: Randomized - Safety Analysis 
Set 
Table 14.1.4.1: 
Summary of Treatment Exposure: Phase 1: Dose Evaluation – Safety 
Analysis Set 
Table 14.1.4.2: 
Summary of Treatment Exposure: Phase 2: Randomized – Safety Analysis 
Set 
Table 14.3.1.1.1.1: Overall Summary of Treatment-Emergent Adverse Events: Phase 1: Dose 
Evaluation – Safety Analysis Set 
Table 14.3.1.1.1.2: Overall Summary of Treatment-Emergent Adverse Events: Phase 2: 
Randomized - Safety Analysis Set 
Table 14.3.1.1.2.1: Summary of Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term: Phase 1: Dose Evaluation – Safety Analysis Set 
Table 14.3.1.1.2.2: Summary of Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term: Phase 2: Randomized – Safety Analysis Set 
Table 14.3.1.1.3.1:  Summary of Treatment-Emergent Adverse Events Related to Study 
Treatment by System Organ Class and Preferred Term: Phase 1: Dose 
Evaluation – Safety Analysis Set 
Table 14.3.1.1.3.2: Summary of Treatment-Emergent Adverse Events Related to Study 
Treatment by System Organ Class and Preferred Term: Phase 2: 
Randomized – Safety Analysis Set 
Table 14.3.1.1.4.1: Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term: Phase 1: Dose Evaluation – Safety 
Analysis Set 
Table 14.3.1.1.4.2: Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term: Phase 2: Randomized – Safety 
Analysis Set 
Table 14.3.1.1.5.1: Summary of Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Treatment by System Organ Class and Preferred Term: 
Phase 1: Dose Evaluation – Safety Analysis Set 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
Table 14.3.1.1.5.2: Summary of Grade 3 or Higher Treatment-Emergent Adverse Events 
Related to Study Treatment by System Organ Class and Preferred Term: 
Phase 2: Randomized – Safety Analysis Set 
Table 14.3.1.2.1.1: Summary of CRS-207 Infusion Related Reactions: Phase 1: Dose 
Evaluation – Safety Analysis Set 
Table 14.3.1.2.1.2: Summary of CRS-207 Infusion Related Reactions: Phase 2: Randomized – 
Safety Analysis Set 
Table 14.3.1.2.2.1: Summary of CRS-207 Infusion Related Reactions by System Organ Class 
and Preferred Term: Phase 1: Dose Evaluation – Safety Analysis Set 
Table 14.3.1.2.2.2: Summary of CRS-207 Infusion Related Reactions by System Organ Class 
and Preferred Term: Phase 2: Randomized – Safety Analysis Set 
Table 14.3.2.1.1: 
Summary of Serious Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term: Phase 1: Dose Evaluation – Safety Analysis Set 
Table 14.3.2.1.2: 
Summary of Serious Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term: Phase 2: Randomized – Safety Analysis Set 
Table 14.3.2.2.2.1: Summary of Serious Treatment-Emergent Adverse Events Related to Study 
Treatment by System Organ Class and Preferred Term: Phase 1: Dose 
Evaluation – Safety Analysis Set 
Table 14.3.2.2.2.2: Summary of Serious Treatment-Emergent Adverse Events Related to Study 
Treatment by System Organ Class and Preferred Term: Phase 2: 
Randomized – Safety Analysis Set 
Table 14.3.2.2.3.1: Summary of Treatment-Emergent Adverse Events Leading to Study 
Treatment Discontinuation by System Organ Class and Preferred Term: 
Phase 1: Dose Evaluation – Safety Analysis Set 
Table 14.3.2.2.3.2: Summary of Treatment-Emergent Adverse Events Leading to Study 
Treatment Discontinuation by System Organ Class and Preferred Term: 
Phase 2: Randomized – Safety Analysis Set  
Table 14.3.2.2.4.1: Summary of Fatal Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term: Phase 1: Dose Evaluation – Safety Analysis Set 
Table 14.3.2.2.4.2: Summary of Fatal Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term: Phase 2: Randomized – Safety Analysis Set 
Table 14.3.2.2.5.1: Summary of Fatal Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term: Phase 1: Dose Evaluation – Safety Analysis Set 
Table 14.3.2.2.5.2: Summary of Fatal Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term: Phase 2: Randomized – Safety Analysis Set 
Table 14.3.2.5.1: 
Summary of Subject Deaths: Phase 1: Dose Evaluation – Safety Analysis 
Set 
Table 14.3.2.5.2: 
Summary of Subject Deaths: Phase 2: Randomized – Safety Analysis Set 
Table 14.3.4.1.1: 
Clinical Chemistry Shifts from Baseline to Maximum on Therapy CTCAE 
Grade: Phase 1: Dose Evaluation – Safety Analysis Set 
Table 14.3.4.1.2: 
Clinical Chemistry Shifts from Baseline to Maximum on Therapy CTCAE 
Grade by Laboratory Parameter: Phase 2: Randomized – Safety Analysis Set 
Table 14.3.4.2.1: 
Hematology Shifts from Baseline to Maximum on Therapy CTCAE Grade 
by Laboratory Parameter: Phase 1: Dose Evaluation – Safety Analysis Set 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
Table 14.3.4.2.2: 
Hematology Shifts from Baseline to Maximum on Therapy CTCAE Grade 
by Laboratory Parameter: Phase 2: Randomized – Safety Analysis Set 
Table 14.3.5.1: 
ECG Shift from Baseline to Worst on Therapy Result: Phase 1: Dose 
Evaluation – Safety Analysis Set 
Table 14.3.5.2: 
ECG Shift from Baseline to Worst on-Therapy Result: Phase 2: Randomized 
– Safety Analysis Set 
 
11.2. Table of Contents for Listings 
 
Listing 16.2.1: 
Subject Disposition 
Listing 16.2.2.1: 
Eligibility 
Listing 16.2.3: 
Subjects Excluded from Analysis Populations 
Listing 16.2.4.1: 
Demographics and Baseline Characteristics 
Listing 16.2.4.2: 
Cancer History 
Listing 16.2.4.3: 
Prior Cancer Related Surgery 
Listing 16.2.4.4:  
Prior Radiotherapy 
Listing 16.2.4.5:  
Prior Cancer Systemic Therapy 
Listing 16.2.4.6:  
Medical History 
Listing 16.2.5.1: 
CRS-207 Administration 
Listing 16.2.5.2:  
Epacadostat Administration 
Listing 16.2.5.3:  
Pembrolizumab Administration 
Listing 16.2.5.4:  
Concomitant Medications 
Listing 16.2.6.2.1:  Response Assessments 
Listing 16.2.6.2.2:  CA-125 Result 
Listing 16.2.6.2.3:  Tumor Assessment – Target Lesions 
Listing 16.2.6.2.4:  Tumor Assessment – Non-Target Lesions 
Listing 16.2.6.2.5:  Tumor Assessment – New Lesions 
Listing 16.2.6.2.6:  Progression-Free Survival 
Listing 16.2.6.2.7:  Duration of Response 
Listing 16.2.6.2.8:  Overall Survival 
Listing 16.2.7.1:  
Adverse Events 
Listing 16.2.7.2:  
Dose Limiting Toxicities 
Listing 16.2.7.3:  
Adverse Events of Special Interest 
Listing 16.2.7.4:  
Serious Adverse Events – Safety Analysis Set 
Listing 16.2.7.5:  
Treatment-Emergent Adverse Events Leading to Study Treatment 
Discontinuation 
Listing 16.2.7.6:  
Fatal Adverse Events 
Listing 16.2.7.7: 
 Deaths 
Listing 16.2.8.1:  
Laboratory Test Results: Clinical Chemistry 
Listing 16.2.8.2: 
Laboratory Test Results: Hematology 
Listing 16.2.8.3:   
Laboratory Test Results: Thyroid Function 
Listing 16.2.8.4:  
Laboratory Test Results: Endocrine Testing 
Listing 16.2.8.5: 
Laboratory Test Results: Coagulation Panel 
Listing 16.2.8.6: 
Laboratory Parameters with a CTCAE Grade 3 or Higher Result 


Sponsor:  Aduro Biotech, Inc. 
Protocol Number: ADU-CL-11 
Version and Date: Version 1.0, 03MAY2018 
 
Listing 16.2.8.7: 
Laboratory Test Results: Urinalysis: Phase 1: Dose Evaluation 
Listing 16.2.8.8: 
Pregnancy Tests 
Listing 16.2.8.9: 
Virology, CD4, HLA 
Listing 16.2.9: 
Vital Signs 
Listing 16.2.10: 
ECG 
Listing 16.2.11: 
Physical Examination 
Listing 16.2.12: 
Subsequent Anti-Cancer Therapy 
Listing 16.2.13: 
ECOG Performance Status 
 
11.3. Table of Contents for Figures 
 
No figures planned.