Conditions: Metastatic Cancer Melanoma Gastric Cancer Gastroesophageal Junction Adenocarcinoma Colorectal Cancer
Keywords: Metastatic Cancer VE800 Nivolumab Opdivo Melanoma Gastric Cancer Gastroesophageal Junction Adenocarcinoma GEJ Adenocarcinoma Colorectal Cancer CRC-MSS Vedanta BMS
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 56
Healthy volunteers: no

Brief summary:
This study evaluated the safety and efficacy of VE800 in combination with nivolumab in patients with selected types of advanced or metastatic cancer

Detailed description:
CONSORTIUM-IO was the first-in-human multicenter, open-label study; the main objectives were to evaluate:

* Safety and tolerability of VE800 in combination with nivolumab
* Efficacy as measured by objective response rate

The study planned to enroll approximately 111 patients with melanoma, gastric/gastroesophageal junction (GEJ) adenocarcinoma, or microsatellite-stable (MSS) colorectal cancer (CRC).

Nivolumab is already approved by the U.S. Food and Drug Administration (FDA), however, it is not approved for the study cancer indications. VE800 was the investigational product, which was designed to enhance the immune response to the tumor.

Arms:
arm 1: Subjects received 5 days of oral vancomycin, followed by daily VE800 in combination with nivolumab every 4 weeks.

Interventions: intervention 1: VE800 intervention 2: Nivolumab intervention 3: Vancomycin Oral Capsule
Intervention descriptions: intervention 1: VE800 is an orally administered (PO) live biotherapeutic product (LBP) consisting of 11 distinct nonpathogenic, nontoxigenic, commensal bacterial strains manufactured under Good Manufacturing Practice (GMP) conditions. These strains were selected for their ability to induce an immune response. intervention 2: Nivolumab is an approved medication that blocks antibodies for certain types of cancer. intervention 3: Vancomycin is an antibiotic used to treat or prevent infection.

Protocol document:
SAP_002.pdf: 
Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 1 of 23 
 
 
 
 
 
 
 
 
 
 
Phase 1 Study of VE800 and Nivolumab in Patients with Selected Types of Advanced or 
Metastatic Cancer 
 
 
NCT04208958 
 
 
Submitter: John Caccaviello, MS – Clinical Trial Associate at Vedanta Biosciences 
 
 
Included in this submission:  
 
Redacted Statistical Analysis Plan (Version 1.2. 03MAR21) 
 
 
Document Date: 29AUG22 
 
 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 1 of 23 
 
 
Statistical Analysis Plan (SAP) 
 
Protocol Title: 
Phase 1 Study of VE800 and Nivolumab in Patients with Selected 
Types of Advanced or Metastatic Cancer 
Protocol Version No./Date: 
2.0 / 11-DEC-2019 
CRF Version No./Date: 
1.1 / 11-FEB-2020 
SAP Version No./Date: 
1.2 / 03-MAR-2021 
 
Approvals 
Sponsor 
Sponsor Name: 
Vedanta Biosciences, Inc. 
Representative / Title: 
Signature / Date: 
Biostatistician / Title: 
Signature / Date: 
(NOTE: Electronic Signatures should only be used if all parties have the ability to eSign.) 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 2 of 23 
. 
 
 
Change History 
 
Version/Date 
Change Log 
V1.0 / 12-Mar-2020 
Created as new 
V0.2 / 22-Apr-2020 
Update 1 
V0.3 / 12-May-2020 
Update 2 
V0.4 / 13-May-2020 
Update 3 with changes discussed at SAP meeting with Vedanta 
V1.0 / 30-Jun-2020 
Final Version for Approval 
V1.0 / 23-July-2020 
Final Version for Approval after revisions requested from 30-Jun-20 version 
V1.1 / 15-Nov-2020 
V2.0/ 03-Mar-2021 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 3 of 24 
 
 
Table of Contents 
Approvals ................................................................................................................................................. 1 
Change History ........................................................................................................................................ 2 
Table of Contents .................................................................................................................................... 3 
Purpose ................................................................................................................................................... 5 
Scope ...................................................................................................................................................... 5 
Introduction .............................................................................................................................................. 5 
. ...................................................................................................................... 5 
Study Objectives ...................................................................................................................................... 5 
Study Design ........................................................................................................................................... 5 
8.1 Sample Size Considerations ................................................................................................................. 7 
8.2 Randomization ..................................................................................................................................... 7 
Study Endpoints ...................................................................................................................................... 7 
Conventions and Derivations ................................................................................................................. 8 
10.1 Baseline, change from baseline ......................................................................................................... 8 
10.2 Study Day Definition .......................................................................................................................... 8 
10.3 Treatment-Emergent Adverse Events Definition ............................................................................... 8 
10.4 Imputation of Partial Dates ................................................................................................................ 8 
10.5 Imputation of Laboratory Values with Character Symbol .................................................................. 9 
10.6 Imputation of Missing Treatment Emergent Adverse Event Causality .............................................. 9 
Analysis Sets ....................................................................................................................................... 10 
11.1 Full Analysis Set .............................................................................................................................. 10 
11.2 Safety Analysis set .......................................................................................................................... 10 
11.3 DLT-Evaluable population ............................................................................................................... 10 
11.4 Efficacy Population ........................................................................................................................... 10 
11.5 Screened Population ....................................................................................................................... 10 
Interim Analyses .................................................................................................................................. 10 
Statistical Methods ............................................................................................................................... 10 
13.1 Subject Disposition ........................................................................................................................... 11 
13.2 Important Protocol Deviations ......................................................................................................... 11 
13.3 Treatments ...................................................................................................................................... 11 
13.3.1 Extent of Study Drug Exposure ................................................................................................. 11 
13.3.2 Prior and Concomitant Medications ........................................................................................... 12 
13.3.3 Systemic Anti-Cancer Therapy Regimen and Radiation Procedures ....................................... 12 
13.4 Demographic and Baseline Characteristics ..................................................................................... 12 
13.5 Disease History and Characteristics ................................................................................................. 13 
13.6 Medical History ................................................................................................................................. 13 
13.7 Efficacy Analyses ............................................................................................................................ 13 
13.7.2 Primary Endpoint ...................................................................................................................... 14 
13.7.3 Secondary Endpoints ............................................................................................................... 14 
13.8 Safety Analyses ............................................................................................................................... 15 
13.8.1 Adverse Events ........................................................................................................................ 15 
13.8.2 Deaths and Serious Adverse Events ........................................................................................ 16 
13.8.5 Laboratory Data ........................................................................................................................ 17 
13.8.6 Vital Signs and ECOG Performance Status ............................................................................. 19 
13.8.5 Physical Examinations .............................................................................................................. 19 
13.8.6 ECGs ........................................................................................................................................ 20 
13.8.7 Important Protocol Deviation Identification Listings .................................................................. 20 
13.8.8 Long Term Follow-up................................................................................................................ 20 
13.8.9 Death Report ............................................................................................................................ 20 
References .......................................................................................................................................... 21 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 4 of 24 
 
 
Glossary of Abbreviations .................................................................................................................... 22 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 5 of 24 
 
 
Purpose 
The Statistical Analysis Plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Vedanta Biosciences Protocol VE800-001. 
 
Scope 
The Statistical Analysis Plan outlines the study design and objectives, analysis endpoints and subject sets, 
applicable study definitions, and statistical methods. 
 
Introduction 
This SAP should be read in conjunction with the study protocol and case report form (CRF) versions noted 
on the title page. Any further changes to the protocol or CRF may necessitate updates to the SAP. Final 
approval of the SAP by the Sponsor 
will occur prior to the database lock. 
 
 
Study Objectives 
Primary objectives: 
• 
To evaluate the safety and tolerability of VE800 in combination with nivolumab in terms of adverse 
events (AE) rates using Common Terminology Criteria for Adverse Events (CTCAE, v. 5.0) 
• 
To evaluate clinical activity as measured by objective response rate (ORR) of the study drug 
combination using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Secondary objectives: 
• 
To evaluate additional measures of clinical benefit, including: 
o 
Duration of response (DOR) according to RECIST 1.1 
o 
Best overall response (BOR) according to RECIST 1.1 
o 
Disease control rate (DCR) according to RECIST 1.1 
o 
Progression-free survival (PFS) according to RECIST 1.1 
o 
Overall survival (OS) 
Exploratory objectives: 
• 
 
 
Study Design 
This is a first-in-human multicenter, open-label study evaluating the safety and clinical activity of VE800 in 
combination with nivolumab in patients with selected types of advanced or metastatic cancer, where 
efficacy of an anti-PD-1 antibody is expected to be modest to null. Safety, clinical activity, PK, and 
pharmacodynamics (stool, blood and/or tumor biomarker changes) will be evaluated. 
The following cohorts of patients with advanced/metastatic cancer will be enrolled: 
• 
Melanoma 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 6 of 24 
 
 
• 
Gastric/gastroesophageal junction (GEJ) adenocarcinoma 
• 
Colorectal cancer microsatellite-stable (CRC-MSS) 
 
 
 
All patients will continue study treatment until progression, unacceptable 
toxicity, withdrawal of consent, study discontinuation criteria are met, completion of 2 years of treatment, or 
the study ends, whichever occurs first. Patients benefiting from study treatment, as judged by the 
Investigator, may continue study treatment for up to 2 years. 
 
In each disease-specific expansion cohort, a Simon two-stage design will be used to provide an initial 
assessment of the clinical activity at Stage 1. ORR will be evaluated using RECIST 1.1. 
 
Figure 1 Flow Diagram of Study VE800-001—Simon Two-Stage Design 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 7 of 24 
 
 
A total of up to approximately 111 patients will be enrolled at up to 45 centers in the United States (US). 
 
8.1 Sample Size Considerations 
The study will use a Simon two-stage design. In each disease-specific expansion cohort, a Simon two- 
stage design will be used to provide an initial assessment of the clinical activity at Stage 1 for continuation 
to Stage 2. ORR will be evaluated using RECIST 1.1. 
In the melanoma and the gastric/GEJ adenocarcinoma cohorts, with an undesirable ORR of 10% or less, 
a desirable ORR of 25% or more, and Type 1 error rate of 10%, 42 patients give 85% power to detect the 
minimal desirable or indecision ORR of 25%. After the first stage (enrollment of 14 patients), enrollment (of 
another 28 patients) maybe discontinued to the second stage if less than 2 patients achieve objective 
response. The cohort will be declared a success at the end of the second stage if more than 6 patients 
achieve objective response. 
Similarly, in the CRC-MSS cohort, with an undesirable ORR of 2% or less, a desirable ORR of 15% or 
more, and Type 1 error rate of 10%, 27 patients give 85% power to detect the minimal desirable or 
indecision ORR of 15%. After the first stage (enrollment of 13 patients), enrollment (of another 14 patients) 
maybe discontinued to the second stage if no patients achieve objective response. The cohort will be 
declared a success at the end of the second stage if more than 1 patient achieves objective response. 
 
8.2 Randomization 
This is an open-label, non-randomized study. Patients will be enrolled in cohorts based on cancer type. 
 
Study Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety and tolerability of VE800 in 
combination with nivolumab in terms of AE rates using 
Common Terminology Criteria for Adverse Events, v. 5.0 
• 
Number of subjects with 
adverse events by type, grade, 
seriousness and causality 
• 
Incidence of DLTs 
• 
Number of subjects 
discontinuing study treatment 
due to an adverse event 
• 
To evaluate clinical activity as measured by objective 
response rate (ORR) of the study drug combination using 
RECIST 1.1 
• 
ORR according to RECIST 1.1 
Secondary 
• 
To evaluate additional measures of clinical benefit, 
including: 
− 
Duration of response according to RECIST 1.1 
− 
Best overall response according to RECIST 1.1 
− 
Disease control rate according to RECIST 1.1 
− 
Progression-free survival according to RECIST 1.1 
− 
Overall survival 
• 
DOR according to RECIST 1.1 
• 
Best overall response 
according to RECIST 1.1 
• 
DCR according to RECIST 1.1 
• 
PFS according to RECIST 1.1 
• 
OS 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 8 of 24 
. 
 
 
 
 
 
Conventions and Derivations 
10.1 Baseline, Change from Baseline 
Unless otherwise stated, baseline refers to the last assessment prior to the first dose of nivolumab and 
VE800. Unscheduled assessments preceding Study Day 1 (i.e., Cycle 1/Day 1 [C1/D1]) will be considered 
for baseline. If the assessment time is missing and there is no way to determine if the assessment occurred 
before or after the study drug administration, assessments on Study Day 1 will be considered for baseline. 
 
10.2 Study Day Definition 
Study day is defined as (study date – C1/D1 date + 1). C1/D1 is the planned start date for the first dose of 
nivolumab and VE800. 
 
10.3 Treatment-Emergent Adverse Events Definition 
A TEAE is an undesirable event not present prior to medical treatment, or an already present event that 
worsens either in intensity or frequency following study treatment. AEs that begin after the first dose of any 
study treatment (vancomycin, nivolumab, or VE800) and prior to 28 days after the last dose of any study 
treatment and prior to the initiation of follow up systemic anti-cancer therapy are considered as TEAEs. 
Baseline signs and symptoms that change attribution or severity during the on-study period are TEAEs. 
 
10.4 Missing Data Imputation 
10.4.1 Imputation of Partial Dates 
Below are rules for imputing missing or partial dates for analyses of AEs, prior/concomitant medications, 
and systemic anti-cancer therapy regimen, and radiation procedures. Though imputed for analyses, actual 
dates (missing or partial) will be reflected in listings. Otherwise, there will be no imputation of missing data 
values. Data on subjects who withdraw early will be summarized up until the time of withdrawal. 
Stop date imputation will not be applied to ongoing AEs or concomitant medications. Missing or partial 
dates for AEs, prior/concomitant medications, systemic anti-cancer therapy, and radiation procedures will 
be imputed as follows: 
• 
Start Date for AEs 
o 
If only the day is missing and the month and year are the same as the month and year of 
the first dose date of any study treatment (including vancomycin), then the day will be 
imputed with the day of the first dose date. Otherwise the day will be imputed with the first 
day of the event month. 
o 
If both the day and month are missing and the year is the same as the year of the first dose 
date of any study treatment (including vancomycin), then they will be imputed with the 
month and day of the first dose date. Otherwise they will be imputed as January 1st of the 
event year. 
o 
If the start date is completely missing, the date will be imputed with the first dose date of 
any study treatment (including vancomycin). 
o 
If the stop date is complete and the imputed start date is after the stop date, then the 
imputed start date will be set to the stop date. 
• 
Start Date for Concomitant Medications, Systemic Anti-Cancer Therapy, and Radiation Procedures 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 9 of 24 
 
 
o 
If only the day is missing and the month and year are the same as the month and year of 
the first dose date of any study treatment (excluding vancomycin), then the day will be 
imputed with the day of the first dose date. Otherwise the day will be imputed with the first 
day of the event month. 
o 
If both the day and month are missing and the year is the same as the year of the first dose 
date of any study treatment (excluding vancomycin), then they will be imputed with the 
month and day of the first dose date. Otherwise they will be imputed as January 1st of the 
event year. 
o 
If the start date is completely missing, the date will be imputed with the first dose date of 
any study treatment (excluding vancomycin). 
o 
If the stop date is complete and the imputed start date is after the stop date, then the 
imputed start date will be set to the stop date. 
• 
Stop Date 
o 
If only the day is missing and the month and year are the same as the month and year of 
the study discontinuation date, then the day will be imputed with the day of the study 
discontinuation date. Otherwise the day will be imputed with the last day of the event 
month. 
o 
If both the day and month are missing and the year is the same as the year of the study 
discontinuation then they will be imputed with the month and day of the study 
discontinuation date. Otherwise they will be imputed as December 31st of the event year. 
o 
If the stop date is completely missing, then it will be imputed with the study discontinuation 
date. 
o 
If the imputed stop date is greater than the last contact date, then the imputed stop date 
will be set to last contact date. 
• 
Diagnosis date 
o 
If only the day is missing, day 1 of the diagnosis month will be imputed. 
o 
If day and month are missing, January 1 will be imputed. 
10.4.2 Imputation of Laboratory Values with Character Symbol 
Missing laboratory data will not be imputed. However, laboratory values of the form of “< x” (i.e., below the 
lower limit of quantification) or “> x” (i.e., above the upper limit of quantification) will be imputed as “x” for 
calculation of summary statistics and comparing to normal ranges. These values will still be displayed as 
“< x” or “> x” in the listings. 
 
10.4.3 Imputation of Missing Treatment Emergent Adverse Event Causality 
If causality is missing for any TEAE, it will be imputed as related to treatment. 
 
10.4.4 Imputation of Missed VE800 Doses 
When computing the cumulative VE800 exposure, if the number of returned capsules is missing, "were 
there any missed doses" is missing or "N", and the number of sequential days missed is missing or "0", 
then assume all doses dispensed were taken. 
When computing the cumulative VE800 exposure, if "Were there any missed doses" is checked on the CRF 
page but the number of missed doses is missing: 
• 
If the number of sequential days missed has been entered, use the number of sequential days 
missed as the number of missed doses. 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 10 of 24 
 
 
• 
If both number of missed doses and number of sequential days missed are missing, then assume 
the patient did not get any doses during that period. 
 
Analysis Sets 
11.1 Full Analysis Set 
All patients who were enrolled and received any dose of any study drug (vancomycin, VE800, or 
nivolumab). The Full Analysis Set will be the default analysis set for all analyses, unless otherwise specified. 
 
11.2 Safety Set 
All patients who were enrolled and received at least 1 dose of any study drug (VE800 or nivolumab). The 
Safety Analysis Set will be the primary set for the analysis of safety data. 
 
11.3 DLT-Evaluable Population 
The first 12 patients to complete the first 28 days of combination treatment of VE800 and nivolumab 
administration or experience a DLT. DLT-evaluable population will be used for DLT analysis. 
 
11.4 Efficacy Population 
All patients who receive one dose of the combination treatment of VE800 and nivolumab and have at least 
one tumor assessment (target) at baseline and at least one post-baseline overall RECIST response based 
on the Disease Response CRF. An overall disease response of "NE" shall be considered a valid post- 
baseline response for this purpose. Death or clinical progression without imaging documented in the End 
of Study form may also be considered a valid post-baseline response. The Efficacy Population will be used 
for all efficacy analyses. 
 
11.5 Screened Population 
The Screened Population is defined as all patients who sign an informed consent for the study. Screen 
failure patients and disposition summaries will be displayed using the Screened Population. 
 
Interim Analyses 
No interim analyses are planned for this study. 
 
Statistical Methods 
Unless otherwise stated, data from 3 cohorts will be analyzed and reported separately by cohort. 
Categorical variables will be summarized using counts and percentages. Percentages will be rounded to 
one decimal place, except 100% will be displayed without any decimal places and percentages will not be 
displayed for zero counts. Continuous variables will be summarized using the number of observations (n), 
mean, standard deviation (SD), median, minimum and maximum. The minimum and maximum values will 
be displayed to the same level of precision as the raw data, the mean, median, Q1, and Q3 to a further 
decimal place and the SD to two additional decimal places. 
Missing data will not be imputed other than the circumstances mentioned in Section 10.4. 
For summary tables of efficacy endpoints where point estimates cannot be computed, the value "NA" will 
be reported. For summary tables of efficacy endpoints where confidence intervals cannot be computed, the 
value "(NA, NA)" will be reported. 
All analyses will use SAS version 9.4 or higher. 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 11 of 24 
 
 
13.1 Subject Disposition 
The number and percentage of subjects screened, enrolled, and treated in the study will be presented, 
together with the number and percentage of subjects who discontinue VE800, Nivolumab or leave the study 
prematurely and a breakdown of the corresponding reason for discontinuation. 
Tabulations of the number and percentage of subjects included in each analysis set, together with a 
breakdown of the reason for exclusion for non-evaluable subjects will be provided. 
A tabulation of the number and percentage of subjects, enrolled, and treated with VE800 and nivolumab at 
each center will be presented. 
Patient eligibility, and enrollment status will be listed. Subjects who discontinued VE800, Nivolumab or 
withdrew from the study will be listed. 
 
13.2 Important Protocol Deviations 
The study specific Protocol Deviation Guidance Document defines all important protocol deviations. 
 
13.3 Treatments 
13.3.1 Extent of Study Drug Exposure 
Exposure to VE800 and nivolumab will be summarized in the safety analysis set. Vancomycin compliance 
(yes or no) will be summarized in the baseline characteristics table. 
 
For VE800, the summary will include the duration of exposure (weeks), cumulative dose administered 
(capsules), subjects with at least 1 dose not administered, and absolute and relative dose intensities. 
 
For nivolumab, the summary will include the duration of exposure (cycles), total number of actual 
infusions administered, cumulative dose administered (mg), subjects with at least 1 dose not 
administered, subjects with at least 1 dose interruption, and relative dose intensity. 
Exposure to VE800 and nivolumab will also be listed. 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
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13.3.2 Prior and Concomitant Medications 
All medications and supplements administered within 14 days prior to screening through the last follow-up 
visit will be recorded in a log electronic case report form (eCRF) page. All antibiotics used within the 60 
days prior to Screening will be recorded in the eCRF. Medications are considered prior medications if they 
have a start date prior to the date of first dose of study medication (VE800 or nivolumab). Concomitant 
medications are defined as medications administered to study participants on or after the first dose of study 
treatment (VE800 or nivolumab). A medication can be considered both prior and concomitant. 
Prior and concomitant medications will be coded using the World Health Organization (WHO) medical 
dictionary (September 2019 or higher). For the purpose of categorizing prior versus concomitant 
medications, partially or completely missing start dates and end dates will be imputed via the rules in 
Section 10.4. 
Prior and concomitant medications will be coded using World Health Organization (WHO) Drug Dictionary. 
Prior and concomitant medications will be summarized in two separate tables and categorized by 
Anatomical Therapeutic Chemical (ATC) Classification. Listings will be created for prior and concomitant 
medications. 
 
13.3.3 Systemic Anti-Cancer Therapy Regimen and Radiation Procedures 
Prior and concomitant systemic anti-cancer therapy regimen will be coded using WHO Drug Dictionary 
(September 2019 or higher). Concomitant systemic anti-cancer therapies and radiotherapy will be 
summarized and listed, including regimen number, ATC medication name/PT/verbatim term, start date 
(day)/stop date (day), type of therapy, therapy setting, best response and date of best response, best 
response and date of best response for immune checkpoint inhibitor (iCPI) therapy (for melanoma only), 
and date of progressive disease. 
 
13.4 Demographic and Baseline Characteristics 
Baseline demographic characteristics variables will be summarized in the full analysis set. 
The summary will include age (years), sex, ethnicity, race, weight (kg), height (cm), Eastern Cooperative 
Oncology Group (ECOG) status, temperature, systolic blood pressure, diastolic blood pressure, pulse and 
vancomycin compliance (yes or no). 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
Sponsor: Vedanta Biosciences, Inc. 
Protocol no: VE800-001 
Page 13 of 24 
 
 
Listing of the demographic and baseline characteristics will also be presented. 
 
13.5 Disease History and Characteristics 
The history and characteristics of the disease under study at first diagnosis and at screening will be 
summarized and listed by cohort. The variables include time from first diagnosis to screening (months), 
stage, metastatic status and histological classification at first diagnosis, grade, stage, metastatic status and 
histological classification at screening, microsatellite stability status, and PD-L1 expression. Time from 
diagnosis to screening (months) is defined as (date of screening – date of initial diagnosis + 1) / 30.4375. 
 
13.6 Medical History 
Medical history will be tabulated by system organ class and coded using MedDRA version 22.1 or higher 
and preferred term using counts and percentages for the full analysis set. Medical history will be also listed. 
 
13.7 Efficacy Analyses 
The primary efficacy endpoint is the ORR, defined as the proportion of patients achieving a best overall 
response of CR or PR from C1/D1 until disease progression or start of a new anti-cancer therapy, whichever 
comes first. Objective responses will be confirmed no less than 4 weeks after the criteria for response are 
met. 
 
Secondary efficacy endpoints include Antitumor response based on change in measurable tumor burden, 
DOR, BOR, DCR, PFS and OS. All response assessments in this section will follow RECIST 1.1. DCR is 
defined as the percentage of patients who have achieved CR, PR or stable disease (SD). Change in 
measurable tumor burden at will be calculated for each assessment time point. Landmark PFS at 6 and 
12 months will be evaluated. 
 
 
 
 
All efficacy endpoints will be summarized on the data from patients by tumor cohort. The primary efficacy 
analysis is based on the Efficacy Population. All analyses will include summary statistics, including number 
of patients (n) and percentage (%) for categorical variables and number of patients, mean, standard 


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Protocol no: VE800-001 
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deviation, median, minimum, and maximum for continuous variables. Time-to-event analyses will be 
performed using Kaplan-Meier (KM) methods. 
 
The date of response or progression will be the Date of Procedure recorded for the tumor assessment for 
each applicable time point. 
 
 
 
13.7.2 Primary Endpoint 
ORR is defined as the number of patients with ORR divided by the number of patients in the efficacy 
population. ORR will be categorized in accordance with RECIST 1.1 and is defined as having a best overall 
response (BOR) of confirmed complete response (CR) or confirmed partial response (PR). BOR is defined 
as the best response among all overall responses (in the order CR, PR, stable disease [SD], progressive 
disease [PD], and not evaluated [NE]) recorded from C1/D1 until disease progression or start of new anti- 
cancer therapy, whichever comes first. Confirmation of CR or PR should be at least 4 weeks between 
previous tumor assessment/imaging and confirmation. If the status of CR or PR cannot be confirmed by 
repeat tumor assessment, the BOR of unconfirmed CR and PR will be determined per RECIST 1.1. The 
status of BOR of SD requires the SD assessment to be more than 4 weeks from baseline. Patients without 
a valid clinical response assessment will be assigned a BOR of NE. 
The number and percentage of patients with OR, DCR, and each category of BOR (CR, PR, SD, PD, NE) 
and DCR (percentage of patients who have achieved CR, PR, or SD) will be presented by cohort along 
with the 90% CI using the Clopper-Pearson method. Listings of tumor assessments and responses 
assessment will be provided. Spider plots will be produced to depict each patient’s percentage change in 
tumor size as a line over time. Waterfall plots will present each patient’s best percentage change in tumor 
size as a separate bar, with the bars ordered from the largest increase to the largest decrease. 
 
13.7.3 Secondary Endpoints 
13.7.3.1 Best Overall Response and Disease Control Rate 
BOR and DCR will be included in the analysis of ORR (Section 13.7.2) 
 
13.7.3.2 Duration of Response 
DOR (in months) is defined for patients with confirmed CR or confirmed PR, i.e. responders, as the time 
from date of the first documentation of objective tumor response (CR or PR) to the first documentation of 
PD or death due to any cause, whichever is earlier. DOR (in months) is calculated as (event or censor date 
– first objective response date + 1) / 30.4375. Patients who have not progressed or died at the time of 
analysis will be censored at the latest date of response assessment with a CR, PR, or SD. However, if the 
patient progresses or dies after two or more consecutive missed scheduled visits, the patient will be 
censored at the latest date of response assessment with a CR, PR, or SD. 
For each cohort, an event/censoring summary, Kaplan-Meier plots, and Kaplan-Meier quartile estimates 
(with 90% CIs) will be provided. 


Statistical Analysis Plan 
Version Date: 03-Mar-2021 
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Protocol no: VE800-001 
Page 15 of 24 
 
 
13.7.3.3 Progression-Free Survival 
Progression-free survival (PFS) is defined as time from C1/D1 to progression or death due to any cause, 
whichever occurs earlier. PFS (in months) is calculated as (death or censor date – date of C1/D1 + 1) / 
30.4375. Patients who have not progressed or died at the time of analysis will be censored at the latest 
date of response assessment with a CR, PR, or SD. However, if the patient progresses or dies after two or 
more consecutive missed scheduled visits, the patient will be censored at the latest date of response 
assessment with a CR, PR, or SD. Patients who have not died or who died after end of study and have no 
evaluable response assessment (CR, PR, or SD) or do not have a baseline assessment will be censored 
at C1/D1. 
For each cohort, an event/censoring summary, Kaplan-Meier plots, Kaplan-Meier quartile estimates (with 
90% CIs), and Kaplan-Meier estimates (with 90% CIs) at 6- and 12-month landmarks will be provided. 
 
13.7.3.4 Overall Survival 
Overall survival (OS) is defined as time from C1/D1 to death due to any cause. OS (in months) is calculated 
as (death or censor date – date of C1/D1 + 1) / 30.4375. For patients alive, censoring for survival will be 
done on the date of the last on study follow-up that the patient is reported to be alive. 
For each cohort, an event/censoring summary, Kaplan-Meier plots, Kaplan-Meier quartile estimates (with 
90% CIs), and Kaplan-Meier estimates (with 90% CIs) at 6- and 12-month landmarks will be provided. 
 
13.8 Safety Analyses 
13.8.1 Adverse Events 
Treatment-emergent adverse events (TEAE) are defined in Section 10.3. Only TEAE will be included in this 
section unless otherwise mentioned. All AE will be coded according to the MedDRA Version 21.0 or higher 
dictionary by system organ class (SOC), preferred term (PT), and severity grade using NCI CTCAE v. 5.0. 
All adverse event summary tables will be based on the Safety Population. 
A breakdown of the number and percentage of subjects reporting each TEAE, categorized by SOC and PT 
coded according to the MedDRA dictionary, will be presented. Note that counting will be by subject and not 
by event and subjects are only counted once within each SOC or PT. Relationships to either VE800 or 
nivolumab are categorized as related, possibly related, unlikely related or as recorded on the CRF. 
 


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TEAE will be presented by PT in descending order of frequency. A further summary of the number and 
percentage of patients reporting each adverse event in at least 5% of patients in the Safety population as 
well as summary of adverse events reported categorized by CTCAE grade will be presented by PT in 
descending order of frequency. 
All AEs (including non-treatment-emergent events) recorded on the CRF will be listed using the Enrolled 
Population. 
 
13.8.2 Deaths and Serious Adverse Events 
SAEs are a subset of collected AEs with a Yes to the question of “Was the adverse event serious?” in the 
Adverse Event Form in CRF. 
TEAEs that lead to death and SAEs will be summarized by SOC and PT. The following summaries will be 
presented: 
• 
Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
• 
Serious Treatment-related Treatment-Emergent Serious Adverse Events by System Organ Class 
and Preferred Term 
• 
Serious VE800-related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
• 
Serious Nivolumab-related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
• 
Serious Vancomycin-related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
• 
Treatment-related Treatment-Emergent Adverse Events with an Outcome of Death by System 
Organ Class and Preferred Term 
• 
VE800-related Treatment-Emergent Adverse Events with an Outcome of Death by System Organ 
Class and Preferred Term 


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• 
Nivolumab-related Treatment-Emergent Adverse Events with an Outcome of Death by System 
Organ Class and Preferred Term 
 
 
13.8.5 Laboratory Data 
Table 1 lists all laboratory assessments and they will be done by local laboratories. All laboratory data will 
be summarized in International System (SI) units. In general, laboratory data will be presented by scheduled 
visits. Values at unscheduled visits will be included in the summary of maximum for all visits and minimum 
for all visits, which will present the largest and smallest post-baseline values observed for each patient for 
each test. 
Selected parameters will be presented in shift tables of baseline against maximum grade (NCI CTCAE v. 
5.0) test result. The shift from baseline to maximum post baseline (including unscheduled visit) will be 
presented by cohort for AST (AST increased), ALT (ALT increased), bilirubin (bilirubin increased), creatinine 
(creatinine increased), sodium (hyponatremia and hypernatremia), potassium (hypokalemia and 
hyperkalemia), calcium (hypocalcemia and hypercalcemia). 
For sodium, potassium, and calcium, separate grading criteria exist depending whether the analyte is high 
or low. For shift tables, all low values will be included in the Grade 0 group in the shift tables for high values, 
and vice versa (all high values should be included in the Grade 0 group in the shift tables for low values). 
Patients with at least 1 on-study measurement for each laboratory parameter will be included, regardless 
of whether a baseline assessment is present. 
Clinical laboratory results, including unscheduled visits, will be listed by subject. 
Table 1 Laboratory Tests in the Study 
 
Category 
Parameter 
Hematology 
Hemoglobin 
Hematocrit 
Total leukocyte count, including differential 
Platelet count 
Coagulation - at screening 
only, or if clinically indicated 
Prothrombin time (PT)/international normalized ratio (INR) 
Activated partial thromboplastin time (aPTT) 
Chemistry 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Amylase 
Alkaline phosphatase (ALP) 
Total bilirubin 
Albumin - screening only 
Sodium 


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. 
 
 
 
Potassium 
Lactate dehydrogenase (LDH) 
Lipase 
Creatinine 
Blood urea nitrogen (BUN) or serum urea 
Fasting glucose - at screening only, or if clinically indicated 
Chloride 
Calcium 
Phosphorus 
Thyroid Panel 
Thyroid stimulating hormone (TSH), free triiodothyronine (fT3) and free 
thyroxine (fT4) – at screening only, or if clinically indicated 
Urinalysis 
pH 
Specific gravity 
Turbidity 
Color 
Protein 
Occult blood 
Ketones 
Glucose 
Bilirubin 
Nitrite 
Urobilinogen 
Leukocyte esterase 
Serology 
Hepatitis B/C, (HBsAG, anti-HCV, or HCV RNA) – at screening only, or if 
clinically indicated 
HIV testing (where mandated locally) 
Other Analyses 
Pregnancy test (women of childbearing potential only: minimum 
sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin 
[HCG]) 
Follicle stimulating hormone (FSH) screening (only required to confirm 
menopause in women <55 years of age) 
 
13.8.5.1 Hematology 
Hematology parameters include CBC, hemoglobin, hematocrit, neutrophil count, lymphocyte count, and 
platelet count. 
Descriptive statistics will be provided for each test result and for change from baseline by scheduled visit. 
Multiple measurements taken during the visit for a patient will be represented by the most severe value for 
each hematology test. The most severe value will be determined first by the value closest to the upper or 
lower limit of the normal limits (dependent on which direction is considered severe) if the value is within the 
normal limits. If the value is outside the normal limits, the value furthest from the upper or lower limit will be 
selected (dependent on which direction is considered severe). If this algorithm does not allow for 
determining the most severe (e.g. a tie, etc.) the first chronological value will be selected. Low values are 
considered the most severe for all hematology parameters. Hematology results for each patient and 
patients who develop a ≥Grade 3 toxicity will be listed. 
 
13.8.5.2 Chemistry 
Descriptive statistics will be provided for each test result and for change from baseline by scheduled visit. 
Multiple measurements taken during the visit for a patient will be represented by the most severe value as 
noted in Section 13.8.5.1. For all chemistry analytes, the most severe value is the highest value, except for 
albumin, and chloride. The most severe could be in either direction for potassium, sodium, and calcium. 
For these analytes, if within the normal limits, then the value closest to the normal limit (either direction) will 


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be selected. If outside the normal limits, then the value most distant from the normal limit (either direction) 
will be used. Chemistry results for each patient and patients who develop a ≥Grade 3 toxicity will be listed. 
 
13.8.5.3 Urinalysis 
Results and change from baseline by scheduled visit will be summarized for pH and specific gravity. For 
other parameters, including turbidity, color, protein, occult blood, ketones, glucose, bilirubin, nitrite, 
urobilinogen, and leukocyte esterase, their results will be categorized as normal, abnormal but not clinically 
significant, abnormal and clinically significant and summarized by scheduled visit. Urinalysis results for 
each patient and patients who develop a ≥Grade 3 toxicity will be listed. 
 
13.8.5.4 CTCAE Coding of Laboratory Data 
Where laboratory values are categorized into NCI CTCAE v5.0, the categories are defined according to the 
criteria available on the following website: http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
Note that grades are applied based only on the numeric SI value of the parameter assessed; clinical signs 
and symptoms are not considered. Where categories are only distinguished by clinical signs or symptoms, 
the lowest of the possible grades will be assigned. 
Laboratory measurements that are within their institutional limits of normal and are not graded as 1-4, per 
the CTCAE, will be summarized as “Grade 0,” which is defined as normal. 
 
13.8.6 Vital Signs and ECOG Performance Status 
The vital signs collected on this study are height (m, at screening only), weight (kg), body temperature (°C), 
systolic and diastolic blood pressure (mmHg), and pulse (beats/min). These are entered on the Vital Signs 
CRFs. The Eastern Cooperative Oncology Group (ECOG) performance status will be entered on the ECOG 
Performance Status Questionnaire at screening, Day 1 of every cycle, and at end of treatment (EOT). 
ECOG performance will be graded according to the ECOG Scale of Performance Status: 
Table 2: ECOG Scale of Performance Status 
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
 
Vital signs and their change from baseline will be summarized by scheduled visits and by cohort. 
Summaries will include the maximum and minimum post-baseline values observed and change from 
baseline to that observed value. 
ECOG performance status will be listed for all visits and summarized at baseline and scheduled visits. 
All vital signs and ECOG performance status will be listed. 
13.8.7 Physical Examinations 
Results of physical examinations of body systems (normal/abnormal) are captured on the Physical 
Examinations CRF. Physical examinations will be summarized by scheduled visits and by body system. 
Physical examination data will also be listed. 


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13.8.8 ECGs 
Single 12-lead ECGs will be performed and heart-rate corrected QT interval using Fridericia's formula 
(QTcF) will be collected. Post-baseline abnormal ECG measurements will be recorded as AEs if they are 
reported as clinically significant by the Investigator. 
A summary of QTcF (msec) and change from baseline will be presented for each planned visit as well as 
the minimum, maximum . A shift from baseline to maximum CTCAE grade summary will also be presented. 
A summary of maximum QTcF and maximum change from baseline will be generated following the ICH 
E14 Category. Categories for maximum QTcF include ≤ 450 msec, > 450 to ≤ 480 msec, > 480 to ≤ 500 
msec, and > 500 msec. Categories of maximum change include ≤ 30 msec, > 30 to ≤ 60 msec, and > 60 
msec. A separate listing of the ECG results along with the overall interpretation will be presented. 
 
13.8.9 Important Protocol Deviation Identification Listings 
Potential planned or unplanned protocol deviations noted during clinical monitoring will be documented by 
category (i.e., inclusion criteria, exclusion criteria, study drug administration, study procedures and 
assessments, study visit schedule, informed consent, and other). All deviations will be reviewed, 
categorized, designated important or not important, and finalized prior to database lock. Important 
protocol deviations will be defined as those potentially impacting safety or efficacy assessments. 
Additional details of what will be considered important can be found in the Protocol Deviation Guidance 
document. 
 
13.8.10 Long Term Follow-up 
Long term follow-up/survival data will be listed for the safety population. Additionally, all follow-up disease 
recurrence will be listed. 
 
13.8.11 Death Report 
Death report data will be summarized and listed for the Enrolled Population. 


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References 
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P. (1982). 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 5, 649-655. 
OPDIVO (nivolumab) injection for intravenous use [package insert]. Princeton (NJ): Bristol-Myers Squibb. 
(March 2019). Retrieved from https://packageinserts.bms.com/pi/pi_opdivo.pdf. 
 
OPDIVO Summary of Product Characteristics. (2018). Retrieved from 
https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf. 
Pardoll, D. (2003). Does the immune system see tumors as foreign or self? Annu Rev Immunol. 21, 807- 
839. 
 
US Department of Health and Human Services. Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0. (27 November 2017). Retrieved from 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_ 
5x7.pdf. 
 
Wolchok, J.D., Hoos, A., O’Day, S., Weber, J.S., Hamid, O., Lebbè, C., et al. (2009). Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 
15, 7412-7420. 
 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5:649-655. 
 


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Glossary of Abbreviations 
Glossary of Abbreviations: 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CR 
Complete response 
CRC 
Colorectal cancer 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
C1/D1 
Cycle 1, Day 1 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of treatment 
FSH 
Follicle stimulating hormone 
fT3 
Free triiodothyronine 
fT4 
Free thyroxine 
GEJ 
Gastroesophageal Junction 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
iCPI 
Immune checkpoint inhibitor 
INR 
International normalized ratio 
 
 
IV 
Intravenously 


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LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSS 
Microsatellite-stable 
NCI 
National Cancer Institute 
NE 
Not evaluable 
OR 
Objective response 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PT 
Prothrombin time 
QD 
Once per day 
QID 
Four times per day 
QTcF 
Heart-rate corrected QT interval using Fridericia's formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
SAP 
Statistical analysis plan 
SAE 
Serious adverse event 
SD 
Stable disease 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid stimulating hormone 
WHO 
World Health Organization 
 

Prot_001.pdf: 
 
 
 
Phase 1 Study of VE800 and Nivolumab in Patients with Selected Types of Advanced or 
Metastatic Cancer 
 
 
NCT04208958 
 
 
Submitter: John Caccaviello, MS – Clinical Trial Associate at Vedanta Biosciences 
 
 
Included in this submission:  
Redacted Protocol (Version 2.0. 11DEC19) 
 
Document Date: 29AUG22 
 
 


Clinical Study Protocol  
VE800 
VE800-001 
Version 2.0 
Vedanta Biosciences 
2 
Confidential 
 
Phase 1 Study of VE800 and Nivolumab in Patients 
with Selected Types of Advanced or Metastatic Cancer 
Investigational Product(s) 
VE800 
Protocol Number 
VE800-001 
Version Number 
2.0 
Version Date 
11 December 2019 
Amendment 
[IND 19293]1 
IND Number 
 
Sponsor 
Vedanta Biosciences, Inc. 
19 Blackstone Street 
Cambridge, MA 02139 
Phone: (857) 706-1427 
Responsible Medical Officer: 
Dmitri Bobilev, MD 
Office: (617) 665-5270 
Mobile: (617) 659-3659 
Email: dbobilev@vedantabio.com 
Confidentiality Statement 
CONFIDENTIAL INFORMATION: This protocol contains trade secrets and other confidential information. 
Accordingly, this protocol shall be treated as confidential and restricted to its intended use, namely, the guidance of 
the clinical Investigator. This material is the sole property of Vedanta Biosciences, Inc and shall not be disclosed or 
used by others except as authorized in writing by Vedanta Biosciences, Inc. This material may be disclosed to and 
used by your staff and associates only to the extent necessary to conduct the clinical study. 
 


Clinical Study Protocol  
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Version 2.0 
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Confidential 
STATEMENT OF COMPLIANCE 
The study will be conducted in compliance with this clinical study protocol, Good Clinical 
Practice (GCP) as outlined by International Council for Harmonisation (ICH) E6(R2), and all 
applicable local and national regulatory requirements. Enrollment at any clinical study site may 
not begin prior to that site receiving approval from the ethics committee of record for the 
protocol and all materials provided to potential study patients. 
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment. Reconsent of previously enrolled study patients may be 
necessary depending on the nature of the amendment. 
The Principal Investigator will ensure that changes to the study plan as defined by this protocol 
will not be made without prior agreement from the Sponsor and documented approval from the 
ethics committee of record, unless such a change is necessary to eliminate an immediate hazard 
to the study patients. 
All personnel involved in the conduct of this study have completed Human Subjects Protection 
and GCP Training as outlined by their governing institution. 


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Version 2.0 
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Confidential 
SPONSOR’S APPROVAL 
Title 
Phase 1 Study of VE800 and Nivolumab in Patients with Selected Types of Advanced 
or Metastatic Cancer 
Protocol Number 
VE800-001 
Version Number 
Version 2.0 
Version Date 
11 December 2019  
Amendment 
1 
This study protocol was subjected to critical review and has been approved by the Sponsor. The 
information it contains is consistent with the current risk/benefit evaluation of the investigational 
product as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki and the guidelines on Good Clinical Practice. 
Medical Representative 
Name: 
Title: 
Signature: 
Date: 
Dmitri Bobilev, MD 
VP of Clinical Development 
Vedanta Biosciences, Inc. 
 
 


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INVESTIGATOR’S AGREEMENT 
I have read the protocol, appendices, and accessory materials related to Study VE800-001 and 
agree to the following: 
• To conduct this study as described by the protocol 
• To protect the rights, safety, and welfare of the patients under my care 
• To provide oversight to all personnel to whom study activities have been delegated 
• To control all investigational products provided by the Sponsor and maintain records of 
the disposition of those products 
• To conduct the study in accordance with all applicable local and national regulations, the 
requirements of the ethics committee of record for my clinical site, and Good Clinical 
Practices as outlined by ICH E6(R2). 
• To obtain approval for the protocol and all written materials provided to patients prior to 
initiating the study at my site 
• To obtain informed consent – and updated consent in the event of new information or 
amendments – from all patients enrolled at my study site prior to initiating any 
study-specific procedures or administering investigational products to those patients 
• To maintain records of each patient’s participation and all data required by the protocol 
Name 
Title 
Institution 
[Insert last name, first name] 
[Insert title (at institution)] 
[Insert address] 
Signature 
Date 
 
[DD Month YYYY] 


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1 
SYNOPSIS 
Name of Sponsor/Company: Vedanta Biosciences, Inc. 
Name of Investigational Product: VE800 
Name of Active Ingredient: Live biological product of 11 commensal bacterial strains 
Title of Study: Phase 1 Study of VE800 and Nivolumab in Patients with Selected Types of 
Advanced or Metastatic Cancer 
Study Center(s): Up to 45 centers /United States (US) 
Planned Study Period (years): 
Estimated date first patient enrolled: December 2019 
Estimated date last patient completed: February 2022 
Objectives: 
Primary objectives: 
• To evaluate the safety and tolerability of VE800 in combination with nivolumab in 
terms of adverse event (AE) rates using Common Terminology Criteria for Adverse 
Events (CTCAE, v. 5.0) 
• To evaluate clinical activity as measured by objective response rate (ORR) of the 
study drug combination using Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 
Secondary objectives: 
• To evaluate additional measures of clinical benefit, including: 
− Duration of response (DOR) according to RECIST 1.1 
− Best overall response according to RECIST 1.1 
− Disease control rate (DCR) according to RECIST 1.1 
− Progression-free survival (PFS) according to RECIST 1.1 
− Overall survival (OS) 
• To evaluate the pharmacokinetics (PK) of VE800 
− Detection of each VE800 strain in stool 
− Degree and duration of VE800 strain colonization 
Exploratory objectives: 
• To evaluate additional measures of clinical benefit, including ORR, DOR, and PFS 
according to RECIST for immunotherapeutics (iRECIST) 
• To correlate clinical activity with pharmacodynamic changes in stool composition, 
peripheral blood and/or tumor tissue 
• To explore the biomarker-based patient population that would potentially derive 
benefit from the combination treatment based on the tumor tissue molecular profile 
and microbiome composition 
• To determine global changes in microbiome composition and metabolomics 


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Methodology: 
This is a first-in-human multicenter, open-label study evaluating the safety and clinical 
activity of VE800 in combination with nivolumab in patients with selected types of advanced 
or metastatic cancer, regardless of programmed death ligand 1 (PD-L1) expression status, 
where efficacy of an anti-programmed cell death protein 1 (PD-1) antibody is expected to be 
modest to null (e.g., in colorectal cancer - metastatic microsatellite-stable [CRC-MSS]). 
Safety, clinical activity, PK, and pharmacodynamics (stool, blood and/or tumor biomarker 
changes) will be evaluated. 
Eligible patients will receive a 5-day course of vancomycin followed by daily VE800 dosing 
in combination with nivolumab administered every 4 weeks, as described in the Dosage and 
Administration Section. 
Initial safety monitoring and dose-limiting toxicity (DLT) evaluation period: 
The safety committee, comprising investigators and the Sponsor, will oversee the emerging 
safety data. 
Patients will be evaluated for safety for a DLT period encompassing 28 days of VE800 
dosing with nivolumab starting on Day 1. 
Each of the first two enrolled study patients will be followed for at least 1 week from the first 
dose of VE800 for acute AEs in between and before the second and the subsequent patients 
are enrolled. 
Study treatment of new patients will be paused until the first 6 have completed the first 
28 days of combination treatment with VE800 and nivolumab or have experienced a DLT. 
Enrollment may resume if <2 of 6 patients experience DLTs in first 28 days. 
The committee will meet on a bi-weekly basis to review the safety data until the first 
12 patients have completed the first 28 days of combination treatment of VE800 and 
nivolumab administration or have experienced a DLT. After the first 12 patients have 
completed the DLT period, the safety committee will meet on an ongoing basis defined by 
the safety committee charter. 
The committee may pause enrollment at any time, if warranted, based on incidence of DLTs 
(e.g., if DLTs are observed in >33% of at least 6 patients, as defined in the safety committee 
charter). The study will be stopped if the DLT rate exceeds 33% or if Grade 4 serious AEs 
(SAEs) that are at least possibly related to VE800 or the combination regimen are reported in 
more than 30% of study patients. A decision to re-open enrollment at the current or reduced 
dose of VE800 will be made by the safety committee based on the overall safety profile of 
combination treatment. 
Safety information collected throughout the entire treatment period, i.e., beyond 28 days of 
DLT period, will be reported and taken into account for decisions of recommended dose for 
later phases of development. 
Patients who do not complete study treatment (vancomycin, VE800, and nivolumab) and/or 
scheduled safety assessments required for the DLT period, for reasons other than study 
treatment-related safety event, will not be considered towards the DLT-evaluable safety 
population. Additionally, AEs observed during the vancomycin administration phase or an 


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event clearly attributed by the Investigator to an alternative cause will not be considered a 
DLT. 
Dose-limiting toxicity (DLT) criteria 
The following treatment related AEs will be considered dose-limiting if determined to be at 
least possibly related to VE800 or to the combination of VE800 and nivolumab: 
• ≥ Grade 2 uveitis or eye pain, that does not resolve with topical therapy 
(i.e., corticosteroids) within 2 weeks 
• Grade 4 rash, or Grade 3 if no improvement (i.e., resolution to ≤ Grade 1 after a 
1-2 week dose delay) 
• Grade ≥ 4 hypersensitivity reaction, or Grade 3 that does not resolve to Grade 1 in 
<6 hrs 
• Grade 2 or 3 colitis or diarrhea that persists without resolution to ≤ Grade 1 for 
≥7 days despite adequate immune suppressive and anti-diarrheal therapy 
• Grade 3 or 4 immune-mediated adverse event (imAE) without resolution to Grade ≤ 1 
or baseline within 8 days despite adequate immune suppressive therapy 
• Any grade clinically significant imAE (e.g., myocarditis, encephalitis) requiring 
treatment discontinuation 
• Any other ≥ Grade 3 non-hematologic clinical (non-laboratory) toxicity excluding:  
− Nausea and vomiting resolving to ≤ Grade 1 within 48 hours with adequate 
treatment 
− Grade 3 fatigue with duration <7 days 
− Grade 3 or Grade 4 electrolyte abnormalities that last less than 48 h with adequate 
treatment 
− Grade 3 fever not associated with hemodynamic compromise 
− Grade 3 endocrinopathy that is well controlled by hormone replacement 
− Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to sites of 
known or suspected tumor) 
• Any clinically-significant Grade ≥ 3 non-hematologic laboratory abnormality, except 
Grade 3 or Grade 4 elevation of amylase or lipase not associated with clinical or 
radiographic evidence of pancreatitis 
• Any clinically-significant hematologic toxicity specifically defined as: 
− Grade 4 thrombocytopenia for ≥7 days, or Grade 3 or 4 associated with bleeding 
or requiring platelet transfusion 
− Grade 4 neutropenia for ≥7 days, or Grade 3 or 4 associated with infection or 
febrile neutropenia 
− Grade 4 anemia, or Grade 3 requiring blood transfusion 
• Any death that is not clearly attributed to the underlying disease or extraneous causes 
Toxicities will be assessed according to CTCAE v5.0. If multiple toxicities occur, the 
presence of DLT will be graded based on the most severe toxicity observed. 
Patients will be treated with nivolumab 480 mg every 4 weeks (Q4W) in combination with 
daily VE800. All patients will continue study treatment until progression, unacceptable 


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toxicity, withdrawal of consent, study discontinuation criteria are met, completion of 2 years 
of treatment, or the study ends, whichever occurs first. 
In each disease-specific expansion cohort, a Simon’s two-stage design will be used to 
provide an initial assessment of the clinical activity at Stage 1 and advancement into Stage 2. 
Reporting of AEs: 
All AEs and SAEs will be collected and recorded for each patient from the day of signing the 
informed consent form (ICF) until 100 days after the last dose of the study treatment or until 
alternate anticancer therapy is initiated, whichever occurs first. Thereafter, only SAEs will be 
collected and recorded during the survival follow-up period or until alternate anticancer 
therapy is initiated. Any SAE occurring after the start of a new treatment that is considered to 
be related to study treatment by the investigator will be reported. All AEs and SAEs 
experienced by a study patient, irrespective of the suspected causality, will be monitored 
until the AE or SAE has resolved or stabilized (e.g., until abnormal laboratory values have 
returned to baseline or normalized, until there is a satisfactory explanation for the changes 
observed), until the patient is lost to follow-up, until the patient has died, or for at least 
30 days after onset of AE/SAE, whichever is earlier. 
Biomarker sample collection and analysis: 
Archival tumor tissue is required for all patients entering the study and fresh tumor biopsies 
are optional but recommended; one biopsy will be obtained prior to VE800 administration. 
Archival tissue will be acceptable as the fresh baseline biopsy if collected within 60 days of 
dosing. Archival tissue must be requested and confirmed available prior to dosing. In 
melanoma patients previously treated with iCPI, the archival tissue will be acceptable if no 
intervening therapy was given to a patient since obtaining the biopsy, otherwise, fresh biopsy 
will be required. Additional tumor biopsies will be highly recommended but optional after 
approximately 4-6 weeks of study treatment and at the time of progression.  
Biomarker analyses will be conducted on fresh and/or archival tumor tissue samples, and 
stool samples to correlate with the clinical outcome to identify the biomarker signature of 
treatment outcomes to the combination treatment. Stool samples will be collected for VE800 
bacterial components detection, colonization duration, and evaluation of other microbiome 
components such as overall diversity. 
The study will be conducted in conformance with Good Clinical Practice (GCP). 
Number of Patients Planned: 
A total of up to approximately 111 evaluable patients will be enrolled: 42 patients with 
melanoma, 42 patients with gastric/gastroesophageal junction (GEJ) adenocarcinoma, and 
27 patients with microsatellite-stable (MSS) colorectal cancer (CRC). 


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Study population: 
Inclusion Criteria: 
1. Patients able and willing to provide written informed consent prior to initiation of any 
study-specific procedure or study drug administration and that understand the 
potential risks and benefits of study enrollment and study drug administration. 
2. Patients with advanced or metastatic cancer who have received no more than 3 lines 
of prior systemic therapy for advanced/metastatic disease: 
a. Patients with advanced or metastatic melanoma who have progressed while 
receiving an anti-PD-1 or anti-PD-L1 antibody or within 3 months of discontinuation 
i. Patients must have RECIST 1.1 confirmed progressive disease (PD) (at least 
2 consecutive scans at least 4 weeks apart) on or within 3 months of 
discontinuation of prior PD-1 or PD-L1 antibody either as a single agent or in 
combination with a standard or an investigational therapy 
ii. Patients who progressed on/within 3 months of adjuvant therapy with iCPI 
will be allowed; an adjuvant therapy will count as 1 prior line of therapy 
iii. Prior treatment with an anti-cytotoxic T lymphocyte-associated antigen 4 
(CTLA-4) antibody will be allowed 
iv. An anti-PD-1/PD-L1 must be the most recent therapy received 
b. Patients with recurrent locally advanced or metastatic gastric or GEJ 
adenocarcinoma with disease progression on or after at least one line of therapy 
including fluoropyrimidine-and platinum-containing chemotherapy and, if 
appropriate, human epidermal growth factor receptor 2 (HER2)/neu-targeted therapy 
c. Patients with histologically confirmed advanced/metastatic CRC-MSS based on 
either an analysis of tissue from a prior biopsy or based on tissue from a new biopsy 
(patient’s microsatellite/mismatch repair status should be known); who have 
progressed following at least one line of standard treatment for advanced/metastatic 
disease which must include fluoropyrimidine, oxaliplatin, or irinotecan, unless 
contraindicated. Patients who relapse within 6 months of adjuvant chemotherapy 
composed of oxaliplatin and a fluoropyrimidine will have their adjuvant therapy 
count as one prior regimen. 
3. Age at least 18 years; any gender 
4. Histologically diagnosed advanced (unresectable) or metastatic cancer with at least 
one measurable lesion as per RECIST 1.1 
5. Tumor lesions amenable for biopsy, if deemed safe by the investigator 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
7. Adequate organ function, defined as 
a. Absolute neutrophil count (ANC) ≥1,500/µL 
b. Platelets ≥100,000/µL 
c. Hemoglobin ≥9 g/dL 


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d. Serum creatinine ≤1.5 × upper limit of normal (ULN) or calculated creatinine 
clearance ≥50 mL/min using Cockcroft-Gault equation 
e.  Total bilirubin ≤1.5 × ULN; for patients with documented/suspected Gilbert’s 
disease, total bilirubin ≤3 × ULN 
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN  
g. Serum albumin ≥3 g/dL 
8. Toxicity from prior cancer therapy should resolve to CTCAE Grade ≤ 1 (excluding 
alopecia and neuropathy, where up to Grade 2 residual is allowed) 
9. Expected to be able to take daily oral medications including the size 0 VE800 
capsules for the entire study duration 
10. Women of childbearing potential must use adequate birth control for the duration of 
study participation and for 5 months after last dose of study drug (nivolumab) 
11. Men must use contraception for 7 months following the last dose of study drug 
(nivolumab) 
Exclusion Criteria: 
1. Prior total colectomy or current ileostomy. 
2. Prior treatment with immune checkpoint inhibitor (iCPI), which is defined as an 
anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody or any other antibody 
or drug specifically targeting T-cell co-stimulation or checkpoint pathways 
(Note: this criterion does not apply to patients with melanoma) 
3. History of life-threatening toxicity related to prior immune therapy (e.g., anti-CTLA-4 
or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting 
T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely 
to re-occur with standard countermeasures (e.g., hypo/hyperthyroidism) 
4. Palliative radiotherapy within 1 week of the first dose of study drug administration 
5. Receipt of any conventional or investigational systemic anti-cancer therapy within 
21 days prior to the first dose of vancomycin 
6. Concurrent chemotherapy, immunotherapy, biologic, or hormonal anti-cancer 
therapy. Agents such as bisphosphonates or denosumab are acceptable as prophylaxis 
for bone metastasis. 
7. Prior malignancy active within the previous 2 years except for locally curable cancers 
that have been apparently cured, such as basal or squamous cell skin cancer, 
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8. Symptomatic uncontrolled brain or leptomeningeal metastases. (To be considered 
“controlled,” central nervous system [CNS] disease must have undergone treatment 
[e.g., radiation or chemotherapy at least 1 month prior to study entry]. The patient 
must have no new or progressive signs or symptoms related to the CNS disease and 
must no longer be on corticosteroids for this indication.) For these patients, a scan to 
confirm the absence of new lesions or stability of brain metastases is required. 
Patients with spinal cord compression may be considered if they have received 
definitive treatment for this and evidence of clinically stable disease for 28 days. 
9. Major surgery within 28 days of first dose of the study drug 
10. Patients considered a poor risk due to a serious, uncontrolled medical condition, 
nonmalignant systemic disease, or active uncontrolled infection. Examples include, 
but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) 
myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord 
compression, superior vena cava syndrome, or any psychiatric disorder that prohibits 
obtaining informed consent. 
11. Clinically significant ascites (requiring drainage every 14 days or less) 
12. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the patient’s participation for 
the full duration of the study drug administration, or is not in the best interest of the 
patient to participate 
13. History or current evidence of celiac disease, inflammatory bowel disease, short gut, 
or current gastrointestinal tract fistulas or ischemia  
14. Patients must not have received a transfusion (platelets or red blood cells) within 
4 weeks of the first dose of study treatment 
15. Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study 
within 2 weeks prior to start of the study treatment. Use of medical marijuana is 
allowed if legally permitted in the State where the patient is treated. 
16. Patient is pregnant or breastfeeding, or expecting to conceive children within the 
projected duration of the study 
17. Patients with an active, known or suspected autoimmune disease. Patients with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are 
permitted to enroll. 
18. Patients with a condition requiring systemic treatment with either corticosteroids 
(>10 mg daily prednisone equivalent) or other immunosuppressive medications 
within 14 days prior to the start of study treatment. Inhaled or topical steroids and 
adrenal replacement steroid doses of 10 mg daily prednisone equivalent are permitted 
in the absence of autoimmune disease (e.g., inflammatory bowel disease, celiac, 
vasculitis, systemic lupus erythematous, Grave’s). 


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19. Patients with known active hepatitis (e.g., hepatitis B or C) or any positive test result 
for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating presence of virus 
(e.g., hepatitis B surface antigen [HBsAg, Australia antigen] positive or hepatitis C 
antibody [anti-HCV] positive [except if HCV-RNA negative]). NOTE: Patients with 
previously treated hepatitis B or C are permitted to enroll if there is evidence of 
documented resolution of infection. 
20. Patients with a condition requiring any live/attenuated vaccine (e.g., varicella, zoster, 
yellow fever, rotavirus, oral polio, and measles, mumps, rubella [MMR]) within the 
last 30 days. Vaccines are permitted after the first 28 days of study treatment. 
21. Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be 
performed at sites where mandated locally. 
22. Known hypersensitivity to VE800 components, nivolumab, vancomycin, or 
excipients contained in these products 
23. Received a fecal transplant, spore or other preparation of fecal material, isolated 
bacterial products, genetically modified bacteria, or VE800 
Investigational Product, Dosage, and Mode of Administration: 
All patients will receive vancomycin followed by concurrent VE800 and nivolumab as 
described below: 
VE800 is a live biotherapeutic product (LBP) consisting of 11 distinct nonpathogenic, 
nontoxigenic, commensal bacterial strains clonally derived from healthy donor stool. VE800 
is formulated as an enteric capsule that contains approximately 400 mg of a mixture of 5 × 
107 CFU of lyophilized bacteria from each of 11 clonally-derived and distinct bacterial 
species for a total bacterial content of 5 × 108 CFU per capsule, respectively. 
Eligible patients will receive oral (PO) vancomycin, 125 mg 4 times a day (QID) for 5 days 
followed by a first cycle (4-week) consisting of VE800 PO 5 capsules QD for the first 7 days 
only followed by 1 capsule QD continuously. In the next cycles patients will only receive 
VE800 PO 1 capsule QD continuously (4-week cycles) 
Nivolumab will be administered intravenously (IV) at a dose of 480 mg as a 30-minute IV 
infusion on Day 1 of each 4-week treatment cycle. Patients may be dosed within a ±3-day 
window. 
Patients will be instructed to take their dose of VE800 at the same time of the day, preferably 
in the morning after an overnight fast. Patients must swallow all capsules whole and not 
chew any. The consumption of clear beverages prior to, during, and after VE800 
administration is permissible. Patients must abstain from solid food, liquids containing solid 
food (e.g., soup, energy drinks, and nutritional supplements) for at least one hour before and 
at least one hour after VE800 ingestion. 
Dose modifications: 
In patients for whom a safety issue arises that is assessed as related to VE800, depending on 
the type and severity of AE, treatment with VE800 may be withheld permanently or 


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temporarily upon consultation with the Sponsor. These patients may continue on nivolumab 
as a single agent. These patients will have an end of VE800 visit in addition to the end of 
treatment (EOT) visit. 
Dose and schedule modifications of VE800 (modified dose or frequency of administration) 
will be allowed, if warranted by the study safety findings, after consultation with the 
Sponsor. The Sponsor in consultation with the study investigators may consider introducing 
additional dosing regimen/s if warranted based on emerging overall safety, tolerability, and 
biomarker data. 
If a course of antibiotics listed in Appendix 6 is required for an infection, VE800 
administration will continue at 1 capsule per day (QD) during the antibiotic administration. 
Upon completion of the course of antibiotics, VE800 should be administered at a dose of 5 
capsules per day for 7 days only, followed by 1 capsule QD continuously. Nivolumab dosing 
regimen will remain unchanged in this instance.  
Nivolumab dosing delays up to 28 days are permitted for medical/surgical events, logistical 
reasons, or reasons unrelated to study treatment after discussion with the medical monitor. 
Nivolumab will be administered until progression, unacceptable toxicity, withdrawal of 
consent or until the study ends, whichever occurs first. No dose and schedule modifications 
of nivolumab will be allowed, except as described in Section 7.1.3. In patients for whom a 
safety issue arises that is related to nivolumab, nivolumab should be withheld permanently 
and/or supportive care measures as described in Appendix 1. In such a case, continuing 
VE800 may be allowed upon consultation between Investigator and Sponsor. 
Duration of Study: 
Patients benefiting from study treatment, as judged by the Investigator, may continue study 
treatment for up to 2 years or Sponsor decision to discontinue the study. 
Criteria for Evaluation: 
Efficacy: 
ORR will be evaluated using RECIST 1.1, including the following: 
• Antitumor response based on change in measurable tumor burden 
• Time-point response assessment: percentage changes in tumor burden per assessment 
time point 
• Best overall response assessment (complete response [CR], partial response [PR], 
stable disease [SD], progressive disease [PD]) 
• DCR (CR+PR+SD) 
• DOR, defined as the time from first documentation of CR or PR until the time of first 
documentation of PD 
• Landmark PFS at 6 and 12 months 
• PFS, defined as the time from start of treatment to the earlier date of assessment of 
progression or death by any cause in the absence of progression 
Response will also be evaluated using iRECIST, including ORR, DOR, and PFS. 


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All radiographic images/scans will be sent to a central imaging vendor upon acquisition and 
archival for potential future evaluation. 
OS as measured from the date of start of treatment to the date of death by any cause will also 
be evaluated. 
Safety: 
• Incidence of treatment-emergent AEs (TEAEs) occurring while patients are on study 
drug and any SAEs occurring while patients are on treatment or up to 100 days after 
EOT 
• Changes in clinical laboratory parameters (hematology, chemistry), vital signs, 
electrocardiogram (ECG) parameters, ECOG performance status, physical 
examinations, and usage of concomitant medications 
Pharmacokinetics/Biomarkers: 
Stool samples will be collected before, during, and at the end of VE800 administration 
according to a specified schedule for: metagenomic analysis to determine detection of each 
strain, degree and duration of colonization of strains, determination of global changes in 
microbiome composition, metabolomic analysis, and culture and recovery of live bacteria. 
Blood samples will be collected for peripheral blood mononuclear cell (PBMC) isolation, for 
cytokine and immunoglobin analysis, and for plasma collection.  
Statistical Considerations: 
The study will use a Simon two-stage design. In each disease-specific expansion cohort, a 
Simon two-stage design will be used to provide an initial assessment of the clinical activity at 
Stage 1 for continuation to Stage 2. ORR will be evaluated using RECIST 1.1. 
In the melanoma and the gastric/GEJ adenocarcinoma cohorts, with an undesirable ORR of 
10% or less, a desirable ORR of 25% or more, and Type 1 error rate of 10%, 42 patients give 
85% power to detect the minimal desirable or indecision ORR of 25%. After the first stage 
(enrollment of 14 patients), enrollment (of another 28 patients) maybe discontinued to the 
second stage if less than 2 patients achieve objective response. The cohort will be declared a 
success at the end of the second stage if more than 6 patients achieve objective response. 
Similarly, in the CRC-MSS cohort, with an undesirable ORR of 2% or less, a desirable ORR 
of 15% or more, and Type 1 error rate of 10%, 27 patients give 85% power to detect the 
minimal desirable or indecision ORR of 15%. After the first stage (enrollment of 
13 patients), enrollment (of another 14 patients) maybe discontinued to the second stage if no 
patients achieve objective response. The cohort will be declared a success at the end of the 
second stage if more than 1 patient achieves objective response. 
1.1 
Schedule of Events 
The schedule of events is presented in Table 1. 
 


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Table 1 
Schedule of Events for Study VE800-001 
Dose/Visit: 
Screen
-ing 
Vancomycin 
VE800 daily and Nivolumab Q4W 
EOT 
Survival 
Every 
90 days 
(±2w) 
Visit / 
Phone 
Call (b) 
Day: 
-21 
to -5 
-4 
D -3-0 
C1/D1 
C1/D3 
C1/D7 
C1/D14 
(±1d) 
C1/D21 
C2/D1 
(1 mo) 
(±3d) 
C3/D1 
(2 mo) 
(±3d) 
C4/D1 
(3 mo) 
(±3d) 
C5-n/ 
D1 
(Q4W) 
(±3d) 
Within 
7 days 
of 
Decision 
to DC 
At least 
100 days 
from end 
of 
nivolumab 
treatment 
Visit # 
Screen
-ing 
BL 
(V 1) 
 
V 2 
At home 
stool 
collection 
At home 
stool 
collection 
V 2a 
At home 
stool 
collection 
V 3 
V 4 
V 5 
V6 to 
EOT 
EOT (a) 
Safety Visit  
 
Procedure: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF 
X 
 
 
Inclusion/Exclusion Review  
X 
X 
X 
 
 
Demographics 
X 
 
 
Medical, surgical, and cancer 
history  
X 
X 
 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X(c) 
X(c) 
Sample Collection: 
 
 
Tumor assessment and imaging 
X (d) 
X (d) 
X (d) 
 
 
Biopsy 
X (e) 
X (f) 
X (f) 
X (f) 
X (f) 
X(f) 
 
 
Blood sample - (PBMC/Serum) 
(g) 
 
 
Blood sample – (Plasma) (h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Labs and Assessments:  
 
 
CBC w/differential (safety lab) 
X 
X (i) 
X (j) 
X 
X 
X 
X 
X 
X 
 
Serum chemistry (safety lab) 
X 
X (i) 
X (j) 
X 
X 
X 
X 
X 
X 
 
Coagulation (k) 
X 
 
 
Serum Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum-based tumor markers (l) 
X 
X 
X 
 
 
Thyroid Panel (k) 
X 
 
 


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Dose/Visit: 
Screen
-ing 
Vancomycin 
VE800 daily and Nivolumab Q4W 
EOT 
Survival 
Every 
90 days 
(±2w) 
Visit / 
Phone 
Call (b) 
Day: 
-21 
to -5 
-4 
D -3-0 
C1/D1 
C1/D3 
C1/D7 
C1/D14 
(±1d) 
C1/D21 
C2/D1 
(1 mo) 
(±3d) 
C3/D1 
(2 mo) 
(±3d) 
C4/D1 
(3 mo) 
(±3d) 
C5-n/ 
D1 
(Q4W) 
(±3d) 
Within 
7 days 
of 
Decision 
to DC 
At least 
100 days 
from end 
of 
nivolumab 
treatment 
Visit # 
Screen
-ing 
BL 
(V 1) 
 
V 2 
At home 
stool 
collection 
At home 
stool 
collection 
V 2a 
At home 
stool 
collection 
V 3 
V 4 
V 5 
V6 to 
EOT 
EOT (a) 
Safety Visit  
 
ECG 
X 
X 
X 
 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical exam  
X 
X 
X 
 
Symptom-directed physical 
exam 
X 
X (j) 
X 
X 
X 
X 
 
 
Vital signs, weight, and height 
(height at screening only) (m) 
X 
X 
X 
X (j) 
X 
X 
X 
X 
X 
X 
 
Collection of microsatellite 
stability data (MSS/MSI-high); 
PD-L1 expression(n) 
X 
 
 
Stool Sample: 
 
 
Stool Sample - microbiota 
composition/VE800 detection 
 
 
Stool Sample Raw (v) 
 
 
Stool Sample Glycerol-
preserved (v) 
 
 
Drug Administration: 
 
 
Vancomycin  
X 
X 
 
 
VE800 (x) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Nivolumab 
X 
X 
X 
X 
X 
 
 
Telephone contact (y) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; BL = baseline; C = cycle; CBC = complete blood count; CRC= colorectal cancer; D or d = day(s); DC = discontinue; 
ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EOT = end of treatment; GEJ = gastroesophageal junction; ICF = informed 
consent form; mo = month(s); MSI = microsatellite instable; MSS = microsatellite-stable; PBMC = peripheral blood mononuclear cell; Q4W = every 4 weeks; V = visit; 
w = weeks. 
Footnotes on next page 
Footnotes: 


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a. Patients that discontinue VE800 but continue with nivolumab treatment will have an end of VE800 visit within 7 days after the decision to discontinue VE800 and an EOT visit 
within 7 days after the decision to discontinue nivolumab. Likewise, patients that discontinue nivolumab but continue with VE800 treatment will have an end of nivolumab 
visit within 7 days after the decision to discontinue nivolumab and an EOT visit within 7 days after the decision to discontinue VE800. The same assessments will be done at 
the end of VE800/nivolumab and EOT visits. Patients that discontinue VE800 and nivolumab at the same time will have only one EOT visit. 
b. If patient cannot return to clinic for this visit, a phone call is allowed. Subsequent follow-up assessments are via phone call. 
c. All AEs and SAEs will be collected until 100 days after the last dose of study treatment or until alternate anticancer therapy is initiated, whichever occurs first. Only SAEs will 
be collected during survival follow-up or until alternate anticancer therapy is initiated. Any SAE occurring after the start of a new treatment that is considered to be related to 
study treatment by the investigator will be reported.. 
d. Baseline assessment may be done during the screening period. Should be obtained every 8 weeks after baseline (every 12 weeks after 1 year); confirmation of change should be 
at least 4 weeks between previous tumor assessment/imaging and confirmation. Tumor assessment per RECIST via CT or MRI. 
e. Archival tissue will be acceptable as the fresh baseline biopsy if collected within 60 days of dosing. Archival tissue must be requested and confirmed available prior to dosing. In 
melanoma patients previously treated with iCPI the archival tissue will be acceptable if no intervening therapy was received to a patient since obtaining the biopsy, otherwise, 
fresh biopsy will be required. 
f. Additional tumor biopsies will be highly recommended but optional after approximately 4-6 weeks of study treatment and at the time of progression. If possible, biopsy should 
be from the same lesion as pre-treatment biopsy. 
g. Fixed PBMC/Serum collection. Sample also to be collected at the time of progression. 
h. Plasma sample also to be collected at the time of progression. 
i. These safety assessments may be drawn 24 hours prior to C1/D1. 
j. Symptom directed physical exam, CBC with differential, and serum chemistry at C1/D14 visit required for first 12 patients only. 
k. At screening or if clinically indicated. 
l. After baseline, this assessment will be done if applicable per standard of care at the time of radiological tumor assessment. For the radiological tumor assessment at baseline, 
these assessments can be taken at screening or baseline. 
m. On dosing days, vital signs will be measured prior to administration of study drug. 
n. Collection of microsatellite stability data only for patients with gastric/GEJ adenocarcinoma or CRC. MSS/MSI status for CRC is mandatory for inclusion. MSS/MSI status and 
PD-L1 expression is to be collected for all cohorts, if available. 
o. If patient cannot produce sample on these visits, site should send patient home with stool collection kit and patient should collect on next bowel movement at home. Sample 
should be collected within 48 hours from study visit.  
p. Sample should be collected before starting vancomycin. 
q. at home 
r. ± 1 day 
s. -1 day/ +2 days 
t. Every 3 months during study starting C4/D1 (thus, next collections would be the start of Cycles 7, 10, 13, etc.) until EOT 
u. If patient cannot produce sample on these visits, site should send patient home with stool collection kit and patient should collect on next bowel movement at home. Site should 
include shipper (method of shipping back to the site) for this collection. Sample should be collected within 48 hours from study visit. 
v. If not collected due to patient not being able to produce sample at clinic, is not a deviation 
w. Patient will be asked if he/she wants to produce sample at screening, if possible; this does not need to be taken at both baseline and screening (sample taken on one day or the 
other) 
x. VE800 PO 5 capsules per day for the first 7 days only followed by 1 capsule per day continuously. 
y. Telephone call on C1D7 to review symptoms and ensure compliance with oral dosing. 
 


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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................... 3 
SPONSOR’S APPROVAL ............................................................................................................ 4 
INVESTIGATOR’S AGREEMENT ............................................................................................. 5 
1 
SYNOPSIS ......................................................................................................................... 6 
1.1 
Schedule of Events ........................................................................................................ 15 
TABLE OF CONTENTS ............................................................................................................. 19 
LIST OF TABLES ....................................................................................................................... 23 
LIST OF FIGURES ..................................................................................................................... 23 
LIST OF APPENDICES .............................................................................................................. 23 
LIST OF ABBREVIATIONS ...................................................................................................... 24 
2 
INTRODUCTION ........................................................................................................... 27 
2.1 
Background ................................................................................................................... 27 
2.1.1 
Target Population ....................................................................................................... 27 
2.1.2 
Description of VE800 ................................................................................................ 27 
2.1.3 
Description of Nivolumab .......................................................................................... 27 
2.1.4 
Supportive Nonclinical Data ...................................................................................... 28  
2.1.4.1 
Pharmacology ......................................................................................................... 29 
2.1.4.2 
Toxicology .............................................................................................................. 29 
2.1.4.3 
Pharmacokinetics .................................................................................................... 29 
2.1.4.4 
Antibiotic Susceptibility of VE800 Bacterial Strains and Rescue Therapy Guidance
 ................................................................................................................................ 30 
2.2 
Study Rationale ............................................................................................................. 30 
3 
OBJECTIVES .................................................................................................................. 31 
4 
DETERMINATION OF GLOBAL CHANGES IN MICROBIOME COMPOSITION, 
STUDY PLAN ................................................................................................................. 32 
4.1 
Study Schematic............................................................................................................ 32 
4.2 
Study Design ................................................................................................................. 32 
5 
POPULATION ................................................................................................................ 34 
5.1 
Recruitment ................................................................................................................... 34 
5.2 
Inclusion Criteria .......................................................................................................... 34 
5.3 
Exclusion Criteria ......................................................................................................... 35 
6 
STUDY CONDUCT ........................................................................................................ 38 


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6.1 
Study Procedures .......................................................................................................... 38 
6.1.1 
Informed Consent....................................................................................................... 38 
6.1.2 
Screening Assessments .............................................................................................. 38 
6.1.3 
Efficacy Assessments ................................................................................................. 38 
6.1.3.1 
Tumor Assessment and Imaging ............................................................................. 38 
6.1.4 
Biomarkers ................................................................................................................. 39 
6.1.4.1 
Biopsy ..................................................................................................................... 39 
6.1.4.2 
Blood Sample (PBMC/serum) ................................................................................ 39 
6.1.4.3 
Blood Sample (Plasma) ........................................................................................... 39 
6.1.4.4 
Serum Tumor Markers ............................................................................................ 39 
6.1.5 
Safety Assessments .................................................................................................... 39 
6.1.5.1 
Adverse Events ....................................................................................................... 40 
6.1.5.2 
Laboratory Assessments ......................................................................................... 40 
6.1.5.3 
Physical Examination.............................................................................................. 41 
6.1.5.4 
Vital Signs, Weight, and Height ............................................................................. 41 
6.1.5.5 
Electrocardiogram ................................................................................................... 42 
6.1.5.6 
ECOG Performance Status ..................................................................................... 42 
6.1.5.7 
Imaging Scan (Radiographic Disease Assessments) .............................................. 42 
6.1.6 
Stool Analyses ........................................................................................................... 43 
6.1.7 
Survival Follow-up .................................................................................................... 43 
6.2 
Discontinuation or Withdrawal ..................................................................................... 43 
6.2.1 
Individual Patients ..................................................................................................... 43 
6.2.2 
Nivolumab Treatment Beyond Disease Progression ................................................. 44 
6.2.3 
Replacement of Patients ............................................................................................. 45 
6.3 
Study Termination ........................................................................................................ 45 
7 
INVESTIGATIONAL MEDICAL PRODUCT .............................................................. 46 
7.1 
Description of Products................................................................................................. 46 
7.1.1 
VE800 ........................................................................................................................ 46 
7.1.1.1 
Formulation, Storage, Preparation, and Handling .................................................. 46 
7.1.1.2 
Dosing and Administration ..................................................................................... 46 
7.1.2 
Vancomycin ............................................................................................................... 47 
7.1.2.1 
Dosing and Administration ..................................................................................... 47 


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Nivolumab.................................................................................................................. 47 
7.1.3.1 
Dose Rationale ........................................................................................................ 47 
7.1.3.2 
Formulation, Storage, Preparation and Handling ................................................... 48 
7.1.3.3 
Dosing and Administration ..................................................................................... 48 
7.2 
Dose-limiting Toxicity Criteria ..................................................................................... 49 
7.3 
Treatment Assignment and Bias Minimization ............................................................ 50 
7.4 
Assessment and Verification of Compliance ................................................................ 50 
7.5 
Prior and Concomitant Therapies ................................................................................. 50 
7.5.1 
Permitted Therapies ................................................................................................... 50 
7.5.2 
Concomitant Antacids and Acid Reducers ................................................................ 50 
7.5.3 
Prohibited Therapies .................................................................................................. 51 
7.5.4 
Antibiotic Use During the Study................................................................................ 51 
8 
SAFETY MONITORING ................................................................................................ 52 
8.1 
Definitions..................................................................................................................... 52 
8.2 
Documenting Adverse Events....................................................................................... 53 
8.2.1 
Timeframe for Collection .......................................................................................... 53 
8.2.2 
Classification of Events ............................................................................................. 53 
8.2.2.1 
Assessment of Toxicity Grade ................................................................................ 53 
8.2.2.2 
Assessment of Causality ......................................................................................... 54 
8.2.2.3 
Action Taken with Study Drug(s) ........................................................................... 54 
8.2.2.4 
Outcome of Adverse Event ..................................................................................... 55 
8.3 
Reporting Serious Adverse Events ............................................................................... 55 
8.3.1 
Submission and Distribution of Serious Unexpected Suspected Adverse Reaction 
Reports ....................................................................................................................... 55 
8.4 
Adverse Events of Special Interest ............................................................................... 56 
8.5 
Clinical Laboratory Findings ........................................................................................ 56 
8.6 
Pregnancy ...................................................................................................................... 56 
8.7 
Overdose or Misuse ...................................................................................................... 57 
9 
ANALYSIS ...................................................................................................................... 58 
9.1 
Sample Size Determination ........................................................................................... 58 
9.2 
Analysis Sets ................................................................................................................. 58 
9.3 
Analysis of the Primary Efficacy Endpoint .................................................................. 58 
9.4 
Analysis of Secondary Efficacy Endpoints ................................................................... 59 


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9.5 
Analysis of Exploratory Efficacy Endpoints ................................................................ 59 
9.6 
Population Analysis ...................................................................................................... 59 
9.6.1 
Disposition ................................................................................................................. 59 
9.6.2 
Demographics and Baseline Characteristics .............................................................. 60 
9.6.3 
Disease History .......................................................................................................... 60 
9.7 
Safety Analysis ............................................................................................................. 60 
9.7.1 
Adverse Events .......................................................................................................... 60 
9.7.2 
Clinical Laboratory Analysis ..................................................................................... 61 
9.7.3 
Other Safety Endpoint ................................................................................................ 61 
9.8 
Pharmacokinetics Analysis ........................................................................................... 61 
9.9 
Pharmacodynamics and Biomarker Analysis ............................................................... 61 
9.10 
Specified Analyses for Safety Committee Review ....................................................... 61 
9.11 
Procedures for Reporting Changes to the Planned Analysis ........................................ 62 
10 
ETHICAL CONSIDERATIONS ..................................................................................... 63 
10.1 
Good Clinical Practice .................................................................................................. 63 
10.2 
Ethics Review ............................................................................................................... 63 
10.3 
Informed Consent.......................................................................................................... 63 
10.4 
Data Privacy .................................................................................................................. 64 
10.5 
Disclosure ..................................................................................................................... 64 
10.6 
Biological Specimens and Data .................................................................................... 64 
11 
OVERSIGHT ................................................................................................................... 65 
11.1 
Quality Control and Assurance ..................................................................................... 65 
11.1.1 
Monitoring ................................................................................................................. 65 
11.1.2 
Audits ......................................................................................................................... 65 
11.1.3 
Protocol Deviations .................................................................................................... 65 
11.1.4 
Records ...................................................................................................................... 66 
11.1.4.1 
Data Capture and Management ............................................................................... 66 
11.1.4.2 
Records Retention ................................................................................................... 66 
12 
PUBLICATION POLICY ............................................................................................... 67 
13 
REFERENCES ................................................................................................................ 68 
14 
APPENDICES ................................................................................................................. 71 
 


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LIST OF TABLES 
Table 1 ............ Schedule of Events for Study VE800-001 ........................................................... 16 
 
LIST OF FIGURES 
Figure 1 ........... Flow Diagram of Study VE800-001—Simon Two-Stage Design ....................... 32 
 
LIST OF APPENDICES 
Appendix 1 ..... Nivolumab Management Algorithms .................................................................. 72 
Appendix 2 ..... Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 ......................... 81 
Appendix 3 ..... iRECIST: Guidelines for Response Criteria in Solid Tumors in Trials Testing 
immunotherapuetics ............................................................................................. 83 
Appendix 4 ..... ECOG Performance Status .................................................................................. 84 
Appendix 5 ..... Women of Childbearing Potential Definitions and Methods of Contraception ... 85 
Appendix 6 ..... Microbiota-Perturbing Antibiotics ....................................................................... 88 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AVMN 
Ampicillin, vancomycin, metronidazole, and neomycin 
BATF3 
Basic leucine zipper ATF-like transcription factor 3 
BTLA 
B and T lymphocyte attenuator 
CBC 
Complete blood count 
cHL 
Classic Hodgkin lymphoma  
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete response 
CRA 
Clinical research associate 
CRC 
Colorectal cancer 
CRO 
Clinical research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte-associated antigen 4 
DC 
Dendritic cells 
DCR 
Disease control rate 
DDI 
Drug-drug interaction 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOT 
End of treatment 
E-R 
Exposure-response 
FSH 
Follicle stimulating hormone 
fT3 
Free triiodothyronine 


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fT4 
Free thyroxine 
GCP 
Good Clinical Practice 
GEJ 
Gastroesophageal junction 
GF 
Germ-free 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HER2 
Human epidermal growth factor receptor 2 
HIV 
Human immunodeficiency virus 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICOS 
Inducible co-stimulatory molecule 
iCPI 
Immune checkpoint inhibitor 
IFN-γ 
Interferon-gamma 
IL 
Interleukin 
IND 
Investigational New Drug (Application) 
imAE 
Immune-mediated adverse event 
iRECIST 
Response Evaluation Criteria in Solid Tumors 1.1 for immunotherapeutics 
IRB 
Institutional Review Board 
iUPD 
Immune-unconfirmed progressive disease 
IV 
Intravenous(ly) 
LBP 
Live biotherapeutic product 
LP 
Lamina propria 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimal inhibitory concentration 
MMR 
Measles, mumps, rubella 
MSI 
Microsatellite-instable 
MSS 
Microsatellite-stable 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 


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PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death ligand 1 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PO 
Oral 
PPK 
Population pharmacokinetic 
PR 
Partial response 
Q4W 
Every 4 weeks 
QD 
Once a day 
QID 
Four times a day 
QTc 
Heart-rate corrected QT interval 
RCC 
Renal cell cancer 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Suspected adverse reaction 
SD 
Stable disease 
SI 
Small intestine 
SPF 
Specific-pathogen-free 
TCR 
T-cell receptor 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WOCBP 
Women of childbearing potential 
 


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2 
INTRODUCTION 
2.1 
Background 
2.1.1 
Target Population 
VE800 was shown to enhance tumor growth inhibition of immune checkpoint inhibitors (iCPIs) 
in preclinical models. This study will enroll patients with advanced/metastatic cancer for whom 
efficacy of an anti-programmed cell death protein 1 receptor (PD-1) antibody is expected to be 
modest to null. 
2.1.2 
Description of VE800 
VE800 is an orally administered (PO) live biotherapeutic product (LBP) consisting of 11 distinct 
nonpathogenic, nontoxigenic, commensal bacterial strains clonally derived from healthy donor 
stool.  
Discovery of the VE800 strains was based on the observation that interferon-gamma 
(IFN-γ)-expressing CD8+ T-cells were constitutively present at high frequencies in the colonic 
and small intestinal (SI) lamina propria (LP), as compared to other organs, in 
specific-pathogen-free (SPF) mice. The frequency and number of both colonic and SI LP 
IFNγ+CD8+ T-cells are markedly decreased in germ-free (GF) mice as compared to SPF mice, 
suggesting the microbiota plays a critical role in IFNγ+CD8+ T-cell accumulation. Oral 
administration of fecal suspensions from SPF mice ameliorated the deficit in colonic 
IFNγ+CD8+ T-cells in GF mice while conversely, treatment of adult SPF mice with an antibiotic 
mixture of ampicillin, vancomycin, metronidazole, and neomycin (AVMN) markedly reduced 
IFNγ+CD8+ T-cell frequency. Collectively, these results suggested that specific members of the 
microbiota promote intestinal accumulation of IFNγ+CD8+ in an inducible and reversible 
manner. 
To identify human donor fecal microbiota enriched for bacterial strains that can induce the 
accumulation of IFNγ+CD8+ T-cells in the intestine, fecal samples were obtained from healthy 
volunteers and orally administered to GF mice. Fecal material that elicited the strongest 
induction was used as the source for VE800 bacterial strains. 
2.1.3 
Description of Nivolumab 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses 
(Pardoll, 2003; Zitvogel, 2006; Dunn, 2002). Current immunotherapy efforts attempt to break the 
apparent tolerance of the immune system to tumor cells and antigens by either introducing cancer 
antigens by therapeutic vaccination or by modulating regulatory checkpoints of the immune 
system. T-cell stimulation is a complex process involving the integration of numerous positive as 
well as negative co-stimulatory signals in addition to antigen recognition by the T-cell receptor 
(TCR) (Greenwald, 2004). Collectively, these signals govern the balance between T-cell 
activation and tolerance. 


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PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes 
CD28, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), inducible co-stimulatory 
molecule (ICOS), and B and T lymphocyte attenuator (BTLA) (Freeman, 2000). PD-1 signaling 
has been shown to inhibit CD28-mediated upregulation of interleukin (IL)-2, IL-10, IL-13, IFN-γ 
and B-cell lymphoma-extra large (Bcl-xL). PD-1 expression also been noted to inhibit T-cell 
activation, and expansion of previously activated cells. Evidence for a negative regulatory role of 
PD-1 comes from studies of PD-1 deficient mice, which develop a variety of autoimmune 
phenotypes (Sharpe, 2007). These results suggest that PD-1 blockade has the potential to activate 
anti-self T-cell responses, but these responses are variable and dependent upon various host 
genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens. 
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ± 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, 
CTLA-4 and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible 
enhancement of both proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). 
Using a cytomegalovirus (CMV) re stimulation assay with human peripheral blood mononuclear 
cells (PBMC), the effect of nivolumab on antigen specific recall response indicates that 
nivolumab augmented IFN-γ secretion from CMV specific memory T-cells in a dose-dependent 
manner versus isotype-matched control. In vivo blockade of PD-1 by a murine analog of 
nivolumab enhances the anti-tumor immune response and result in tumor rejection in several 
immunocompetent mouse tumor models (MC38, SA1/N, and PAN02) (Wolchok, 2009). 
Overall, the safety profile of nivolumab is manageable and generally consistent across completed 
and ongoing clinical trials with no maximum tolerated dose (MTD) reached at any dose tested up 
to 10 mg/kg. Most adverse events (AEs) were low-grade (Grade 1 to 2) with relatively few 
related high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or 
causality of AEs with respect to nivolumab dose level. 
Additional details on the safety profile of nivolumab, including results from other clinical 
studies, are also available in the nivolumab Investigator’s Brochure (IB). 
2.1.4 
Supportive Nonclinical Data 
Recent studies have reported the composition of the gut microbiome is associated with clinical 
response of cancer patients to checkpoint inhibitor therapy (Bhatt, 2017; Gao, 2016; 
Spranger, 2016; Wei, 2017). While intriguing, most of these studies have employed 16S rRNA 
sequencing which is not sufficient to pinpoint the nature of specific commensal organisms 
associated with benefit. Furthermore, the isolation and characterization of candidate beneficial 
bacteria strains from responder cancer patients has not been undertaken thus it is unclear which 
strains influence clinical response to immunotherapy agents and how they confer benefit. The 
hypothesis that the composition of the microbiome influences response to checkpoint inhibit 
therapy appears to be supported by recent retrospective analyses which report perturbation of the 
microbiome via administration of antibiotics either 2 months prior to commencement of 
immunotherapy or one month thereafter can have a detrimental effect on response rates (Routy, 
2018; Gopalakrishnan, 2018; Matson, 2018; Frankel, 2017). Furthermore, on-going exploratory 
clinical studies are assessing the impact of altering the composition of the gut microbiome of 
cancer patients who have failed to respond to immunotherapy via introduction of microbiota 


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from responder patients. Preliminary data suggest a subset of non-responder patients may be 
converted to responders as a result of this treatment (Baruch, 2019; Routy, 2018). While these 
clinical findings are intriguing, the nature of the commensals which confer benefit and the 
mechanisms by which they augment anti-tumor activity remain unknown. 
Recently, Tanoue, et al. determined healthy SPF mice contain IFN-γ-producing CD8+ T cells in 
the LP of the gut while the GF mice do not (Tanoue, 2019), which suggests that the endogenous 
bacteria within healthy mice promote or induce CD8+ T-cells. The study data by Tanoue, et al. 
further indicates that VE800 (LBP consisting of 11 strains of commensal bacteria) induces robust 
CD8+ T-cell induction in the LP of orally-inoculated animals and when combined with 
checkpoint inhibitor therapy, VE800 augments anti-tumor activity. The fact that VE800 
stimulates anti-tumor activity in two different syngeneic tumor models (MC38-derived tumors 
and BrafV600E Pten-/- melanoma tumors) suggests that VE800 does not promote a T-cell 
response to bacterial antigens which fortuitously cross reacts with cancer antigens. Rather, the 
data support a mechanism by which VE800 activates BATF3 positive antigen presenting cells in 
the LP which in turn stimulate IFN-γ-producing CD8+ T-cells (Tanoue, 2019). Full details on the 
nonclinical pharmacological studies of VE800 can be found in the VE800 IB. 
No AEs have been noted in any of the pharmacology studies in which VE800 was administered 
on a single or multiple dose basis to GF or SPF mice. Moreover, colonic tissue of 
VE800-inoculated GF mice has been examined and no signs of abnormal histology have been 
noted. Colonic tissue of VE800-inoculated SPF mice which either received VE800 alone or in 
combination with either anti-CTLA-4 or anti- PD-1 has been examined and no signs of abnormal 
histology have been noted.  
Additional details provided in the Investigator’s Brochure. 
2.1.4.1 
Pharmacology 
In experiments in non-tumor-bearing mice, VE800 demonstrated induction of IFN-γ-producing 
CD8+T-cells without producing any overt toxicity. In xenograft models, oral VE800 inoculation 
promoted an enhanced level of IFN-γ-producing CD8+ T-cell infiltrates at the tumor site. When 
used in conjunction with iCPIs such as anti-CTLA-4 or anti-PD-1 monoclonal antibodies, VE800 
enhanced tumor growth inhibition. 
2.1.4.2 
Toxicology 
VE800 comprises 11 commensal species that were isolated from a healthy human donor and 
shown to be present in a healthy human population. The sequences of the individual strains 
constituting this LBP have been shown to lack known antibiotic resistance genes and virulence 
factors. No overt toxicity was observed in any of the in vivo or in vitro pharmacology studies. 
Given the nature of this product, no toxicology studies have been conducted. 
2.1.4.3 
Pharmacokinetics 
VE800 consists of 11 strains of commensal bacteria. No systemic exposure with bacteria was 
observed or expected to be observed. VE800 gut colonization was observed in treated animals. 
VE800 strains detection and quantification will be performed in feces of the study patients. 
Full details on the clinical pharmacology and pharmacokinetic aspects of nivolumab can be 
found in the nivolumab IB. 


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2.1.4.4 
Antibiotic Susceptibility of VE800 Bacterial Strains and Rescue Therapy 
Guidance 
Based on MICs established, all VE800 strains were considered susceptible to ertapenem, 
piperacillin/tazobactam, tigecycline, and metronidazole treatment. These antibiotics represent 
four distinct classes of antibiotics: penicillins (piperacillin/tazobactam), carbapenems 
(ertapenem), tetracyclines (tigecycline), and nitroimidazoles (metronidazole). In addition, all 
strains, except VE800-01 (Fusobacterium varium), were determined to be fully susceptible to 
imipenem and all strains, except VE800-07 (Parabacteroides distasonis), were determined to be 
fully susceptible to cefoxitin. These results demonstrate that the 11 human commensal bacterial 
strains that comprise the VE800 consortium are susceptible to treatment with commonly 
prescribed antibiotics in the unlikely event of a systemic infection due to translocation. 
Additional details can be found in the Investigator’s Brochure.  
NOTE: If VE800 component bacteria are implicated in an intestinal or systemic infection and an 
oral antibiotic is desired, oral metronidazole should be considered. 
2.2 
Study Rationale 
Anti-PD-1 and Anti-PD-L1 antibodies have demonstrated improved outcomes, including the 
overall survival, in a variety of cancer types. Despite this success, the outcomes continue to be 
suboptimal in a large proportion of cancer patients. Mechanisms of resistance are multifactorial. 
Among resistance mechanisms, use of certain antibiotics and resulting change in the microbiome 
in general and gut microbiota, specifically, have been implicated in reduced response rate in 
some tumor types based on non-comparative studies. Other studies suggest modulation of 
immune response is different based on the type of antibiotics, with vancomycin potentiating 
activity of T-cells (Uribe-Herranz, 2018). Gut microbiome is implicated in reduced anti-cancer 
immune responsiveness in the liver mediated through bile acid metabolism (Ma, 2018). It has 
also been shown that use of vancomycin improved the VE800 immune induction activity 
compared to other antibiotics (Tanoue, 2019). VE800 is expected to improve treatment outcomes 
with anti-PD-1 antibodies by increasing overall response rates, depth and/or duration of response 
and increasing the clinical benefit response. Efficacy of an anti-PD-1 antibody is expected to be 
limited in these populations, with ORR of 15% or less reported for gastric cancer (xxxxxxx2018; 
Fuchs, 2017), 1% or less reported for CRC-MSS (Le, 2015); and ORR to anti-PD-1 antibody 
treatment of melanoma patients treated beyond progression is reported at 14% (Beaver, 2018), 
but in patients with confirmed progression on or after anti-PD-1 antibody immediately preceding 
the study regimen is expected to be in the 7% range.  . 


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3 
OBJECTIVES 
Primary objectives: 
• To evaluate the safety and tolerability of VE800 in combination with nivolumab in terms 
of AE rates using Common Terminology Criteria for Adverse Events (CTCAE, v. 5.0) 
• To evaluate clinical activity as measured by objective response rate (ORR) of the study 
drug combination using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Secondary objectives: 
• To evaluate additional measures of clinical benefit, including: 
− Duration of response (DOR) according to RECIST 1.1 
− Best overall response according to RECIST 1.1 
− Disease control rate (DCR) according to RECIST 1.1 
− Progression-free survival (PFS) according to RECIST 1.1 
− Overall survival (OS) 
• To evaluate the pharmacokinetics (PK) of VE800 
− Detection of each VE800 strain in stool 
− Degree and duration of VE800 strain colonization 
Exploratory objectives: 
• To evaluate additional measures of clinical benefit, including ORR, DOR, and PFS 
according to RECIST for immunotherapeutics (iRECIST) 
• To correlate clinical activity with pharmacodynamic changes in stool composition, 
peripheral blood and/or tumor tissue 
• To explore the biomarker-based patient population that would potentially derive benefit 
from the combination treatment based on the tumor tissue molecular profile and 
microbiome composition 
• To determine global changes in microbiome composition and metabolomics 


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4 
DETERMINATION OF GLOBAL CHANGES IN MICROBIOME 
COMPOSITION, STUDY PLAN 
4.1 
Study Schematic 
Figure 1 
Flow Diagram of Study VE800-001—Simon Two-Stage Design 
 
 
Abbreviations: CRC = Colorectal cancer; GEJ = Gastroesophageal junction; MSS = Microsatellite-stable  
4.2 
Study Design 
This is a first-in-human multicenter, open-label study evaluating the safety and clinical activity 
of VE800 in combination with nivolumab in patients with selected types of advanced or 
metastatic cancer, where efficacy of an anti-PD-1 antibody is expected to be modest to null. 
Safety, clinical activity, PK, and pharmacodynamics (stool, blood and/or tumor biomarker 
changes) will be evaluated. 
The following cohorts of patients with advanced/metastatic cancer will be enrolled: 
• Melanoma 
• Gastric/gastroesophageal junction (GEJ) adenocarcinoma 
• Colorectal cancer microsatellite-stable (CRC-MSS) 
Forty-two patients each are planned for enrollment in the melanoma cohort and in the 
gastric/GEJ adenocarcinoma cohort, and 27 patients are planned for enrollment in the CRC-MSS 
cohort. The study will use a Simon two-stage design; the number of patients planned for each 
stage are shown in Figure 1. 
Eligible patients will receive a 5-day course of PO vancomycin (125 mg 4 times a day [QID]) to 
modulate the intestinal microbiota, followed by VE800 dosing. Patients will receive VE800 PO 


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5 capsules per day for 7 the first days only followed by 1 capsule per day (QD) continuously, in 
combination with intravenous (IV) nivolumab 480 mg every 4 weeks. All patients will continue 
study treatment until progression, unacceptable toxicity, withdrawal of consent, study 
discontinuation criteria are met, completion of 2 years of treatment, or the study ends, whichever 
occurs first. Patients benefiting from study treatment, as judged by the Investigator, may 
continue study treatment for up to 2 years. 
The safety committee, comprising Investigators and the Sponsor, will oversee the emerging 
safety data. 
Patients will be evaluated for safety for a dose-limiting toxicity (DLT) period encompassing 
28 days of VE800 dosing with nivolumab starting on Day 1. 
Each of the first two enrolled study patients will be followed for at least 1 week from the first 
dose of VE800 and nivolumab for acute AEs in between and before the second and the 
subsequent patients are enrolled. 
Study treatment of new patients will be paused until the first 6 have completed the first 28 days 
of combination treatment with VE800 and nivolumab or have experienced a DLT. Enrollment 
may resume if <2 of 6 patients experience DLTs in first 28 days. 
The committee will meet on a bi-weekly basis to review the safety data until the first 12 patients 
have completed the first 28 days of combination treatment of VE800 and nivolumab 
administration or have experienced a DLT. After the first 12 patients have completed the DLT 
period, the safety committee will meet on an ongoing basis defined by the safety committee 
charter. 
The committee may pause enrollment at any time if warranted based on incidence of DLTs (e.g., 
if DLTs are observed in >33% of at least 6 patients, as defined in the safety committee charter). 
The study will be stopped if the DLT rate exceeds 33% or if Grade 4 serious adverse events 
(SAEs) that are at least possibly related to VE800 or the combination regimen are reported in 
more than 30% of study patients. 
In each disease-specific expansion cohort, a Simon two-stage design will be used to provide an 
initial assessment of the clinical activity at Stage 1. ORR will be evaluated using RECIST 1.1. 
As VE800 is a consortium of commensal bacteria derived from healthy donor and shown to be 
present in healthy human population, no significant toxicity is expected, but not excluded. 
Patients will be monitored for safety throughout duration of the study to identify a potential 
increase in incidence and/or severity of immune-mediated adverse events (imAEs). 
In patients for whom a safety issue arises that is assessed as related to VE800, depending on the 
type and severity of AE, treatment with VE800 may be withheld permanently or temporarily 
upon consultation with the Sponsor. These patients may continue on nivolumab as a single agent. 
These patients will have an end of VE800 visit in addition to the end of treatment (EOT) visit. 
In patients for whom a safety issue arises that is related to nivolumab, nivolumab should be 
withheld permanently, as described in Section 6.2.1, and/or supportive care measures should be 
administered per the Management Algorithms for Nivolumab in Appendix 1. In such a case, 
continuing VE800 as a single agent may be allowed upon consultation between Investigator and 
Sponsor. These patients will have an end of nivolumab visit in addition to the EOT visit. 


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5 
POPULATION 
5.1 
Recruitment 
A total of up to approximately 111 patients will be enrolled at up to 45 centers in the United 
States (US). 
Before recruitment of patients, written Institutional Review Board (IRB)/Ethics Committee (EC) 
approval of the protocol, informed consent documents, advertising and patient-facing documents 
will be obtained. 
5.2 
Inclusion Criteria 
To be included in this study, each individual must satisfy all the following criteria: 
1. Patients able and willing to provide written informed consent prior to initiation of any 
study-specific procedure or study drug administration and that understand the potential 
risks and benefits of study enrollment and study drug administration. 
2. Patients with advanced or metastatic cancer who have received no more than 3 lines of 
prior systemic therapy for advanced/metastatic disease: 
a. Patients with advanced or metastatic melanoma who have progressed while receiving 
an anti-PD-1 or anti-PD-L1 antibody or within 3 months of discontinuation 
i. Patients must have RECIST 1.1 confirmed Progressive Disease (PD) (at least 
2 consecutive scans at least 4 weeks apart) on or within 3 months of 
discontinuation of prior PD-1 or PD-L1 antibody either as a single agent or in 
combination with a standard or an investigational therapy  
ii. Patients who progressed on/within 3 months of adjuvant therapy with iCPI will be 
allowed; an adjuvant therapy will count as 1 prior line of therapy 
iii. Prior treatment with an anti-CTLA-4 antibody will be allowed 
iv. An anti-PD-1/PD-L1 must be the most recent therapy received 
b. Patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma 
with disease progression on or after at least one line of therapy including 
fluoropyrimidine-and platinum-containing chemotherapy and, if appropriate, human 
epidermal growth factor receptor 2 (HER2)/neu-targeted therapy 
c. Patients with histologically confirmed advanced/metastatic microsatellite-stable 
(MSS) Colorectal cancer (CRC) based on either an analysis of tissue from a prior 
biopsy or based on tissue from a new biopsy (patient’s microsatellite/mismatch repair 
status should be known); who have progressed following at least one line of standard 
treatment for advanced/metastatic disease which must include fluoropyrimidine, 
oxaliplatin, or irinotecan, unless contraindicated. Patients who relapse within 
6 months of adjuvant chemotherapy composed of oxaliplatin and a fluoropyrimidine 
will have their adjuvant therapy count as one prior regimen. 
3. Age at least 18 years; any gender 


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4. Histologically diagnosed advanced (unresectable) or metastatic cancer with at least one 
measurable lesion as per RECIST 1.1 
5. Tumor lesions amenable for biopsy, if deemed safe by the investigator 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
7. Adequate organ function, defined as 
a. Absolute neutrophil count (ANC) ≥1,500/µL 
b. Platelets ≥100,000/µL 
c. Hemoglobin ≥ 9 g/dL 
d. Serum creatinine ≤1.5 × upper limit of normal (ULN) or calculated creatinine 
clearance ≥50 mL/min using Cockcroft-Gault equation 
e.  Total bilirubin ≤1.5 × ULN; for patients with documented/suspected Gilbert’s 
disease, total bilirubin ≤3 × ULN 
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN  
g. Serum albumin ≥ 3 g/dL 
8. Toxicity from prior cancer therapy should resolve to CTCAE Grade ≤ 1 (excluding 
alopecia and neuropathy, where up to Grade 2 residual is allowed) 
9. Expected to be able to take daily oral medications including the size 0 VE800 capsules 
for the entire study duration 
10. Women of childbearing potential must use adequate birth control for the duration of 
study participation and for 5 months after last dose of study drug (nivolumab) 
11. Men must use contraception for 7 months following last dose of study drug (nivolumab) 
5.3 
Exclusion Criteria 
Individuals who meet any of the following criteria are ineligible for this study: 
1. Prior total colectomy or current ileostomy 
2. Prior treatment with iCPI, which is defined as an anti-PD-1, anti-PD-L1, anti-PD-L2, or 
anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways (Note: this criterion does not apply to patients 
with melanoma.) 
3. History of life-threatening toxicity related to prior immune therapy (e.g., anti-CTLA-4 or 
anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell 
co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur 
with standard countermeasures (e.g., hypo/hyperthyroidism) 
4. Palliative radiotherapy within 1 week of the first dose of study drug administration 
5. Receipt of any conventional or investigational systemic anti-cancer therapy within 
21 days prior to the first dose of vancomycin 


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6. Concurrent chemotherapy, immunotherapy, biologic, or hormonal anti-cancer therapy. 
Agents such as bisphosphonates or denosumab are acceptable as prophylaxis for bone 
metastasis. 
7. Prior malignancy active within the previous 2 years except for locally curable cancers 
that have been apparently cured, such as basal or squamous cell skin cancer, superficial 
bladder cancer, prostate cancer, or carcinoma in situ of the cervix or breast 
8. Symptomatic uncontrolled brain or leptomeningeal metastases. (To be considered 
“controlled,” central nervous system [CNS] disease must have undergone treatment 
[e.g., radiation or chemotherapy at least 1 month prior to study entry]. The patient must 
have no new or progressive signs or symptoms related to the CNS disease and must no 
longer be on steroids for this indication.) For these patients, a scan to confirm the absence 
of new lesions or stability of brain metastases is required. Patients with spinal cord 
compression may be considered if they have received definitive treatment for this and 
evidence of clinically stable disease for 28 days. 
9. Major surgery within 28 days of first dose of the study drug  
10. Patients considered a poor risk due to a serious, uncontrolled medical condition, 
nonmalignant systemic disease, or active uncontrolled infection. Examples include, but 
are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) 
myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord 
compression, superior vena cava syndrome, or any psychiatric disorder that prohibits 
obtaining informed consent. 
11. Clinically significant ascites (requiring drainage every 14 days or less) 
12. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the patient’s participation for the 
full duration of the study drug administration, or is not in the best interest of the patient to 
participate 
13. History or current evidence of celiac disease, inflammatory bowel disease, short gut, or 
current gastrointestinal tract fistulas or ischemia  
14. Patients must not have received a transfusion (platelets or red blood cells) within 4 weeks 
of the first dose of study treatment 
15. Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to start of the study treatment. Use of medical marijuana is allowed if 
legally permitted in the State where the patient is treated. 
16. Patient is pregnant or breastfeeding, or expecting to conceive children within the 
projected duration of the study 
17. Patients with an active, known or suspected autoimmune disease. Patients with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to 
enroll. 


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18. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days 
prior to the start of study treatment. Inhaled or topical steroids and adrenal replacement 
steroid doses of 10 mg daily prednisone equivalent are permitted in the absence of 
autoimmune disease (e.g., inflammatory bowel disease, celiac, vasculitis, systemic lupus 
erythematous, Grave’s). 
19. Patients with known active hepatitis (e.g., hepatitis B or C) or any positive test result for 
hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating presence of virus 
(e.g., hepatitis B surface antigen [HBsAg, Australia antigen] positive or hepatitis C 
antibody [anti-HCV] positive [except if HCV-RNA negative]). NOTE: Patients with 
previously treated hepatitis B or C are permitted to enroll if there is evidence of 
documented resolution of infection. 
20. Patients with a condition requiring any live/attenuated vaccine (e.g., varicella, zoster, 
yellow fever, rotavirus, oral polio, and measles, mumps, rubella [MMR]) within the last 
30 days. Vaccines are permitted after the first 28 days of study treatment. 
21. Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be 
performed at sites where mandated locally. 
22. Known hypersensitivity to VE800 components, nivolumab, vancomycin, or excipients 
contained in these products (see Section 7.1) 
23. Received a fecal transplant, spore or other preparation of fecal material, isolated bacterial 
products, genetically modified bacteria, or VE800 


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6 
STUDY CONDUCT 
6.1 
Study Procedures 
The schedule for completing study procedures and assessments is detailed in Table 1 (Schedule 
of Events). 
6.1.1 
Informed Consent 
Informed consent must be obtained before any study-specific procedure is performed. For 
patients who sign a documented informed consent form (ICF) but are not enrolled, the reason for 
screen failure will be recorded. 
6.1.2 
Screening Assessments 
Results from screening evaluations are required to confirm eligibility and must be available 
before study drug administration. 
Screening assessments include collection of demographics, medical and medication history, 
safety assessments, and stool sample collection. 
6.1.3 
Efficacy Assessments 
6.1.3.1 
Tumor Assessment and Imaging 
Tumor assessment should be obtained at baseline and every 8 weeks thereafter and confirmation 
of change should be at least 4 weeks between previous tumor assessment/imaging. After 1 year, 
patients who remain on treatment will have imaging performed every 12 weeks (84 ±7 days). 
Primary response evaluation will be done by using RECIST 1.1, including the following (see 
Appendix 2): 
• ORR: The primary efficacy endpoint is ORR defined as the proportion of patients 
achieving complete response (CR) or partial response (PR) as determined by the 
Investigator 
• DOR: DOR will be assessed as a secondary endpoint defined as the time from first 
documentation of CR or PR until the time of first documentation of progressive disease 
(PD) 
• Progression-free survival (PFS): PFS will be assessed as a secondary endpoint defined as 
the time from start of treatment to the earlier date of assessment of progression or death 
by any cause in the absence of progression 
• OS: OS will be assessed as a secondary endpoint defined as the time from the date of 
start of treatment to the date of death by any cause 
• DCR (CR+PR+SD): DCR will be assessed as a secondary endpoint defined as the 
percentage of patients achieving CR, PR, or stable disease (SD) 
• Antitumor response based on change in measurable tumor burden 
• Time-point response assessment: percentage changes in tumor burden per assessment 
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• Best overall response assessment (CR, PR, SD, PD) 


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Response will also be evaluated by using iRECIST (see Appendix 3), including ORR, DOR, and 
PFS as exploratory endpoints. All radiographic images/scans will be sent to a central imaging 
vendor upon acquisition and archival for potential future evaluation.  
OS will be assessed as a secondary endpoint defined as the time from the date of start of 
treatment to the date of death by any cause. 
6.1.4 
Biomarkers 
6.1.4.1 
Biopsy 
Archival tumor tissue is required for all patients entering the study and fresh tumor biopsies are 
optional but recommended; one biopsy will be obtained prior to VE800 administration. Archival 
tissue will be acceptable as the fresh baseline biopsy if collected within 60 days of dosing. 
Archival tissue must be requested and confirmed available prior to dosing. In melanoma patients 
previously treated with iCPI the archival tissue will be acceptable if no intervening therapy was 
received to a patient since obtaining the biopsy, otherwise, fresh biopsy will be required.  
Additional tumor biopsies will be highly recommended but optional after approximately 
4-6 weeks of study treatment and at the time of progression. 
Biomarker analyses will be conducted on fresh and/or archival tumor tissue samples, and stool 
samples to correlate with the clinical outcome to identify the biomarker signature of treatment 
outcomes to the combination treatment. Stool samples will be collected for VE800 bacterial 
components detection, colonization duration, and evaluation of other microbiome components 
such as overall diversity. 
6.1.4.2 
Blood Sample (PBMC/serum) 
Blood samples will be collected for PBMC isolation and for cytokine and immunoglobulin 
analysis according to the schedule in Table 1 , and at the time of progression. All analyses will 
be exploratory. 
6.1.4.3 
Blood Sample (Plasma) 
Blood samples will be collected for plasma collection according to the schedule in Table 1, and 
at the time of progression. All analyses will be exploratory. 
6.1.4.4 
Serum Tumor Markers 
Serum tumor markers (carcinoembryonic antigen [CEA] for CRC or gastric cancer) will be done 
if the Investigator deems applicable per standard of care at the time of radiological tumor 
assessment. 
6.1.5 
Safety Assessments 
Safety will be assessed throughout the study and the safety data will include reported AEs, 
SAEs, clinical laboratory data, electrocardiograms (ECGs), ECOG performance status, 
concomitant medications, physical examinations, and vital signs. 


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If a patient shows pulmonary-related signs (hypoxia, fever) or symptoms (e.g., dyspnea, cough, 
fever) consistent with possible pulmonary AEs, the patient should be immediately evaluated to 
rule out pulmonary toxicity. 
6.1.5.1 
Adverse Events 
Adverse events will be assessed by direct observation and patient assessments/interviews. All 
nonserious AEs and SAEs (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following 
discontinuation of study treatment or until alternate anticancer therapy is initiated, whichever 
occurs first. Thereafter, only SAEs will be recorded through the survival follow-up period or 
until alternate anticancer therapy is initiated. Complete details on the definition, reporting, and 
management of AEs are provided in Section 8.2. Additional details on management of AEs 
related to nivolumab are provided in Appendix 1. 
Every AE must be assessed by the investigator with regard to whether it is considered immune-
mediated. For events which are potentially immune-mediated, additional information will be 
collected on the patient’s case report form. ImAEs are AEs consistent with an immune-mediated 
mechanism or immune-mediated component for which non-inflammatory etiologies (e.g., 
infection or tumor progression) have been ruled out. ImAEs can include events with an alternate 
etiology which were exacerbated by the induction of autoimmunity. Information supporting the 
assessment will be collected on the participant’s case report form. 
6.1.5.2 
Laboratory Assessments 
 All laboratory assessments below will be done by local laboratories. 
The following laboratory tests will be performed according to the schedule in Table 1: 
Hematology – Complete Blood Count (CBC) 
Hemoglobin 
Hematocrit 
Total leukocyte count, including differential 
Platelet count 
Coagulation - at screening only, or if clinically indicated 
Prothrombin time (PT)/international normalized ratio (INR) 
Activated partial thromboplastin time (aPTT) 
Chemistry 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Amylase 
Alkaline phosphatase (ALP) 
Total bilirubin 


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Albumin - screening only 
Sodium 
Potassium 
Lactate dehydrogenase (LDH) 
Lipase 
Creatinine 
Blood urea nitrogen (BUN) or serum urea 
Fasting glucose - at screening only, or if clinically indicated 
Chloride 
Calcium 
Phosphorus 
Thyroid stimulating hormone (TSH), free triiodothyronine (fT3) and free thyroxine (fT4) – at 
screening only, or if clinically indicated 
Serology 
Hepatitis B/C, (HBsAG, anti-HCV, or HCV RNA) – at screening only, or if clinically 
indicated 
HIV testing (where mandated locally) 
Other Analyses 
Pregnancy test (women of childbearing potential only: minimum sensitivity 25 IU/L or 
equivalent units of human chorionic gonadotropin [HCG]) 
Follicle stimulating hormone (FSH) screening (only required to confirm menopause in women 
<55 years of age) 
6.1.5.3 
Physical Examination 
Physical examinations will be performed by trained medical personnel. A complete physical 
examination will be performed at screening and at the EOT and Safety visits. Symptom-directed 
physical examinations are to be performed according to Table 1. Abnormal physical examination 
findings will be recorded as AEs only if they are considered to be clinically significant by the 
Investigator. 
6.1.5.4 
Vital Signs, Weight, and Height 
Vital signs, including pulse, blood pressure, and body temperature, will be collected according to 
the schedule in Table 1, as well as at unscheduled times as medically indicated. On dosing days, 
vital signs will be measured prior to administration of study drug. Abnormal vital sign 
measurements will be recorded as AEs only if they are considered to be clinically significant by 
the Investigator. 


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Height will be collected at screening only. Weight will be collected according to the schedule in 
Table 1. Weight is to be measured consistently in the same manner each time and noted in the 
source – with or without heavy items/shoes/bulky clothing, etc. 
6.1.5.5 
Electrocardiogram 
Single 12-lead ECGs will be performed at scheduled time points (see Table 1), as well as at 
unscheduled time points as medically indicated. ECG parameters to be evaluated include heart 
rate, QT interval corrected for heart rate (QTc), QRS, and PR intervals. Post-baseline abnormal 
ECG measurements will be recorded as AEs if they are considered to be clinically significant by 
the Investigator. 
6.1.5.6 
ECOG Performance Status 
Performance status will be determined according to the ECOG performance status scale (see 
Appendix 4) at scheduled time points in Table 1. 
6.1.5.7 
Imaging Scan (Radiographic Disease Assessments) 
Imaging scans, or radiographic evaluations (computed tomography [CT]/magnetic resonance 
imaging [MRI] of chest, abdomen, and pelvis or other regions known to have disease 
involvement) will be used to assess extent of disease. Scans will be taken at baseline and will be 
conducted every 8 weeks after the first scan. Additionally, patients will have appropriate testing 
of serum-based tumor markers where applicable (e.g., radiographic assessments. All on-study 
tumor assessments (radiographic and tumor markers) will be performed independent of dose 
delays and/or dose interruptions, and/or at any time when progression of disease is suspected. 
Brain scans will be conducted if clinically indicated; bone scans will be conducted per standard 
of care. After 1 year, patients who remain on treatment will have imaging performed every 12 
weeks (84 ±7 days). If a patient discontinues treatment for a reason other than progression or 
death, withdrawal of consent, or loss to follow-up, radiographic scans and appropriate testing of 
serum tumor markers should continue at the specified intervals. All radiographic images/scans 
will be sent to a central imaging vendor upon acquisition and archived for potential future 
evaluation.  
Per RECIST v1.1, patients who achieve CR or PR should have the response confirmed; tumor 
imaging for confirmation of response may be performed at the earliest 4 weeks after the first 
indication of response, or at the next scheduled scan (e.g., 8 weeks after the previous scan), 
whichever is clinically indicated. In addition, PD should be confirmed a minimum of 4 weeks but 
within 6 weeks after the first PD assessment. Based on a recognized phenomenon of transient 
tumor flare in the first few months after the start of immunotherapy with subsequent disease 
response, patients treated with study treatment will be permitted to continue treatment beyond 
initial RECIST v1.1-defined PD while awaiting confirmation of PD. Treatment may continue 
based on Investigator judgement if the patient is clinically stable (i.e., no signs or symptoms of 
clinically significant or rapid progression of disease, including worsening of laboratory values or 
decline in performance status; no progressive tumor at critical anatomical sites [e.g., cord 
compression, intracranial tumor hemorrhage, etc.] requiring urgent medical intervention). 
Clinically stable patients should not be discontinued until progression is confirmed. 


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6.1.6 
Stool Analyses 
Stool samples will be collected before, during, and at the end of VE800 administration according 
to the schedule in Table 1 for metagenomic analysis to determine VE800 components’ detection, 
colonization degree and duration, determination of global changes in microbiome composition, 
metabolomic analysis, and culture and recovery of live bacteria. In addition to this, the Sponsor 
may analyze stool samples from patients for possible exploratory purposes and biomarkers. 
Whenever possible, stool sample collection should occur at the study site. However, because it is 
important to collect a stool sample at scheduled time points, patients may be provided with a kit 
and instructions for stool sample collection at home, if necessary. Applicable instructions will be 
provided with the Laboratory Manual. 
6.1.7 
Survival Follow-up 
In this study, survival is an important endpoint. Post-treatment follow-up is of critical importance 
and is essential to preserving patient safety and the integrity of the study. Patients who 
discontinue study treatment must continue to be followed for collection of outcome and/or 
survival follow-up data as required and in line with Table 1 until death or the conclusion of the 
study, unless the patient has withdrawn consent for all contacts or is lost to follow-up. Patients 
are to return for a clinic visit for the first survival follow-up assessment and subsequent 
assessments are via phone contact. If the patient is unable to return to the clinic for the first 
follow-up visit, assessment via phone call is allowed. 
6.2 
Discontinuation or Withdrawal 
6.2.1 
Individual Patients 
Patients may withdraw their consent at any time for any reason without prejudice to their future 
medical care by the physician or at the institution. If a patient withdraws consent, the date and 
stated reason for consent withdrawal will be documented. Patient data, including samples 
(e.g., blood, serum), collected up to the date of consent withdrawal (i.e., early termination) will 
be included in the analyses. 
Wherever possible, the tests and evaluations listed for the EOT visit will be carried out within 
7 days of the decision to discontinue study treatment. Patients who:  
• discontinue VE800 but continue with nivolumab treatment will have an end of VE800 
visit within 7 days after the decision to discontinue VE800 and an EOT visit 7 days after 
the decision to discontinue nivolumab. 
• discontinue nivolumab but continue with VE800 treatment will have an end of 
nivolumab visit within 7 days after the decision to discontinue nivolumab and an EOT 
visit 7 days after the decision to discontinue VE800. 
• discontinue VE800 and nivolumab at the same time will have only one EOT visit. 
Patients who discontinue study drug prematurely for reasons other than withdrawal of consent, 
lost to follow-up, or AEs with an outcome of death will continue to be followed for the intended 
duration of the study as outlined in the schedule of events. Further attempts to contact the patient 
are allowed if safety findings require communicating or follow-up. The Sponsor will be notified 
of all study withdrawals. 


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Patients meeting any of the following criteria will discontinue study drug dosing: 
• Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity prior to next scheduled 
nivolumab treatment OR requires systemic treatment 
• Any Grade 3 non-skin, drug-related AE lasting >7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, 
bronchospasm, neurologic toxicity, hypersensitivity reactions, infusion reactions, and 
endocrinopathies: 
− Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation 
− Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Grade 3 adrenal insufficiency 
requires discontinuation regardless of control with hormone replacement.  
− Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
o Grade 3 drug-related thrombocytopenia >7 days or associated with bleeding 
requires discontinuation 
o Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation* 
o Concurrent AST or ALT >3 × ULN and total bilirubin >2 × ULN 
*In most cases of Grade 3 AST or ALT elevation, study treatment will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study treatment, a discussion between the Investigator and 
Sponsor/Medical Monitor must occur. 
• Any allergic reaction during study drug administration, regardless of grade, should 
prompt study drug discontinuation unless there is a clear alternative etiology for the 
event. The study drug may be restarted if a clear alternative etiology for the event is 
identified. 
• Disease progression as determined by Investigator, as defined in the Section 6.2.2 
• Any other AE, laboratory abnormality, incurrent illness where continued treatment could 
be detrimental to patient’s well-being 
• Withdrawal of consent 
• Pregnancy 
• Lost to follow-up 
• Discretion of the Investigator (e.g., protocol violations, noncompliance, continued study 
drug administration not in the patient’s best interest) 
• Termination of the study or a study site by the Sponsor 
6.2.2 
Nivolumab Treatment Beyond Disease Progression 
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD (Wolchok, 2009). Participants treated with 
nivolumab will be permitted to continue nivolumab treatment beyond initial RECIST 1.1 defined 


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PD, assessed by the investigator up to a maximum of 24 months from date of first dose as long as 
they meet the following criteria: 
• Investigator-assessed clinical benefit 
• Tolerance of study treatment 
• Stable performance status 
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases) 
• Participant provides written informed consent prior to receiving additional nivolumab 
treatment. All other elements of the main consent including description of reasonably 
foreseeable risks or discomforts, or other alternative treatment options will still apply. 
A radiographic assessment/ scan should be performed within 6 weeks of initial investigator 
assessed progression to determine whether there has been a decrease in the tumor size or 
continued PD. The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the participant is clinically deteriorating and unlikely to receive any benefit from 
continued treatment with nivolumab. 
If the investigator feels that the nivolumab participant continues to achieve clinical benefit by 
continuing treatment, the participant should remain on the trial and continue to receive 
monitoring according to Table 1. 
For the participants who continue nivolumab study therapy beyond progression, further 
progression is defined as an additional 10% increase in tumor burden with a minimum 5 mm 
absolute increase from time of initial PD. This includes an increase in the sum of diameters of all 
target lesions and/ or the diameters of new measurable lesions compared to the time of initial PD. 
Nivolumab treatment should be discontinued permanently upon documentation of further 
progression. 
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). Any new lesion considered non-measurable at the time of initial progression may 
become measurable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 
15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm. 
6.2.3 
Replacement of Patients 
After consultation between the Investigators and Sponsor, enrollment may be extended to replace 
patient(s) that become non-evaluable for safety or if there is insufficient PK data. 
6.3 
Study Termination 
This study may be discontinued at any time due to safety concerns, failure to meet expected 
enrollment goals, administrative reasons, or at the discretion of the Sponsor. Should the study be 
terminated prematurely, the Sponsor will provide written notification to the Investigator and 
regulatory authorities and will specify the reason(s) for early termination. The Investigator must 
inform the IRB/EC promptly and provide the reason(s) for the termination as well as patient 
status of all patients at their site. 


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INVESTIGATIONAL MEDICAL PRODUCT 
7.1 
Description of Products 
7.1.1 
VE800 
7.1.1.1 
Formulation, Storage, Preparation, and Handling 
VE800 is an orally administered LBP consisting of 11 well characterized, clonally-derived 
nonpathogenic, nontoxigenic, commensal bacterial strains. VE800 is formulated as an enteric 
capsule for PO administration and supplied in sealed high-density polyethylene (HDPE) bottles. 
Each capsule contains approximately 400 mg of a mixture of 5 × 107 CFU of lyophilized bacteria 
from each of 11 clonally-derived and distinct bacterial species for a total bacterial content of 
5 × 108 CFU per capsule, respectively. Additionally, the capsule contains sucrose, histidine, 
yeast extract, cysteine, sodium metabisulfite, and microcrystalline cellulose as excipients. 
VE800 is shipped to clinical sites and stored at 5°C ± 3°C. 
7.1.1.2 
Dosing and Administration 
Eligible patients will receive VE800 5 capsules per day for the first 7 days only followed by 
1 capsule per day continuously. 
After the initial loading dose, VE800 will be administered orally QD throughout the study. 
Patients will be instructed to take their dose at the same time of the day, preferably in the 
morning after an overnight fast (i.e., on an empty stomach). Patients must swallow all capsules 
whole and not chew the capsules. The consumption of clear beverages prior to, during, and after 
VE800 administration is permissible. Patients must abstain from solid food, liquids containing 
solid food (e.g., soup, energy drinks, and nutritional supplements) for at least 1 hour before and 
at least 1 hour after VE800 ingestion. Liquids may be warm or cool, but should not be cold or 
hot (e.g., hot liquids such as hot coffee and tea, as well as iced drinks, are discouraged). 
Dose and schedule modifications of VE800 will be allowed, if warranted by the study safety 
findings after consultation with the Sponsor. 
In patients for whom a safety issue arises that is related to VE800, depending on the type and 
severity of the AE, dose of VE800 may be reduced, or treatment with VE800 may be withheld 
permanently or temporarily upon consultation with the Sponsor, while a patient continues on 
nivolumab. 
A patient who becomes unable to ingest VE800 may be allowed to continue single agent 
nivolumab, after discussion between the Sponsor and Investigator. 
If a course of antibiotics listed in Appendix 6 is required for an infection, VE800 administration 
will continue normally during the antibiotic treatment. Upon completion of the course of 
antibiotics, VE800 should be administered at a dose of 5 capsules per day for 7 days only, 
followed by 1 capsule per day (QD) continuously. Nivolumab dosing regimen will remain 
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7.1.2 
Vancomycin 
7.1.2.1 
Dosing and Administration 
Eligible patients will receive vancomycin PO, 125 mg QID for 5 days prior to start of dosing 
with VE800 PO QD. 
7.1.3 
Nivolumab 
7.1.3.1 
Dose Rationale  
A nivolumab dose of 480 mg given every 4 weeks (Q4W) was selected for this study based on 
available PK, safety, and efficacy data.  
Nivolumab PK has been extensively studied in multiple tumor types, including melanoma, 
non-small cell lung cancer (NSCLC), renal cell cancer (RCC), classic Hodgkin lymphoma 
(cHL), squamous cell carcinoma of the head and neck, CRC, and urothelial carcinoma and has 
been safely administered at doses up to 10 mg/kg Q2W. Nivolumab monotherapy was originally 
approved as a body-weight based dose of 3 mg/kg Q2W, and was recently updated to 240 mg 
Q2W or 480 mg Q4W in multiple indications (OPDIVO package insert, 2019; OPDIVO 
Summary of Product Characteristics, 2018). Nivolumab 360 mg Q3W is also under evaluation in 
monotherapy and in combination therapy studies. Less frequent 360 mg Q3W and 480 mg Q4W 
dosing regimens can reduce the burden to patients of frequent, lengthy IV treatments and allow 
combination of nivolumab with other agents using alternative dosing regimens.  
The benefit-risk profiles of nivolumab 240 mg Q2W, 360 mg Q3W and 480 mg Q4W are 
predicted to be comparable to 3 mg/kg Q2W. This assessment is based on a comprehensive 
characterization of nivolumab PK, safety, efficacy, and exposure-response (E-R) relationships 
across indications. Population PK (PPK) analyses have shown that the PK of nivolumab is linear 
with proportional exposures over a dose range of 0.1 to 10 mg/kg; no clinically meaningful 
differences in PK across ethnicities and tumor types were observed. Using the PPK model, the 
exposures following administration of several dosing regimens of nivolumab administered as a 
flat dose were simulated, including 240 mg Q2W, 360 mg Q3W and 480 mg Q4W. The 
simulated average serum concentration at steady state (Cavg) following administration of 
nivolumab 360 mg Q3W and 480 mg Q4W are predicted to be similar to those following 
administration of nivolumab 240 mg Q2W and nivolumab 3 mg/kg Q2W administered to 
participants over a wide body weight range (34-180 kg) across tumor types.  
Extensive E-R analyses of multiple PK measures (maximum serum concentration at 
Day 1[Cmax1], average serum concentration at Day 28 [Cavg28], and trough serum concentration 
at Day 28 [Cmin28]) and efficacy and safety endpoints indicated that the efficacy of the flat-dose 
480 mg IV regimen are similar to that of 3 mg/kg Q2W IV regimen. In E-R efficacy analyses for 
OS and ORR conducted in melanoma, RCC, and NSCLC using Cavg28 as the exposure measure, 
probabilities of achieving a response and survival probabilities at 1 year and 2 years for IV 480 
mg Q4W were similar to that of IV 3 mg/kg Q2W. In E-R safety analyses, it was demonstrated 
that the exposure margins for safety are maintained following nivolumab 480 mg Q4W, and the 
predicted risks of discontinuations due to AEs or death, AE Grade 3+, and imAEs Grade 2+ are 
similar following nivolumab 480 mg Q4W relative to nivolumab 3 mg/kg Q2W across tumor 
types. In addition, nivolumab exposures with 240 mg Q2W, 360 mg Q3W, and 480 mg Q4W 


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flat-dose IV regimens across tumor types are maintained well below the corresponding exposures 
observed with the well-tolerated 10 mg/kg IV nivolumab Q2W dose regimen. 
Additional details on nivolumab and nivolumab risk-benefit can be found in the nivolumab IB. 
7.1.3.2 
Formulation, Storage, Preparation and Handling 
Nivolumab is supplied as 240 mg/24 mL solution in a single-dose vial. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles. 
Care must be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. 
Nivolumab is shipped to clinical sites and stored at 5°C ± 3°C. Nivolumab should be protected 
from light. 
7.1.3.3 
Dosing and Administration 
Nivolumab will be administered at a dose of 480 mg as a 30-minute IV infusion on Day 1 of 
each 4-week treatment cycle until progression, unacceptable toxicity, withdrawal of consent, or 
the study ends, whichever occurs first. Patients may be dosed within a ±3-day window. 
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed. 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding in-line filter at the protocol-specified dose. It is not to be 
administered as an IV push or bolus injection. Nivolumab injection can be infused undiluted or 
diluted so as not to exceed a total infusion volume of 160 mL. Nivolumab infusion must be 
promptly followed by a flush of diluent to clear the line. 
Patients should be carefully monitored for infusion reactions during nivolumab administration. 
No dose and schedule modifications of nivolumab will be allowed, except as noted below. In 
patients for whom a safety issue arises that is related to nivolumab, nivolumab should be 
withheld permanently and/or supportive care measures administered per the Management 
Algorithms for Nivolumab in Appendix 1. Nivolumab dosing delays up to 28 days are permitted 
in case of medical/surgical events or logistical reasons or unrelated to study treatment after 
discussion with the medical monitor. 
Nivolumab administration should be delayed for the following: 
• Grade 2 non-skin, drug-related AE, with the exception of fatigue 
• Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities 
• Grade 3 skin, drug-related AE 
• Grade 3 drug-related laboratory abnormality, with the following exceptions:  
− Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay 
− Grade ≥ 3 AST, ALT, Total Bilirubin will require dose discontinuation  
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication 


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Participants who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.  
If nivolumab is discontinued, continuing VE800 may be allowed upon consultation between 
Investigator and Sponsor.  
7.2 
Dose-limiting Toxicity Criteria 
The following treatment related AEs will be considered dose-limiting if determined to be at least 
possibly related to VE800 or to the combination of VE800 and nivolumab: 
• ≥ Grade 2 uveitis or eye pain, that does not resolve with topical therapy i.e., 
corticosteroids within 2 weeks 
• Grade 4 rash, or Grade 3 if no improvement (i.e., resolution to ≤ Grade 1 after a 1-2 week 
dose delay) 
• Grade ≥ 4 hypersensitivity reaction, or Grade 3 that does not resolve to Grade 1 in <6 hrs 
• Grade 2 or 3 colitis or diarrhea that persists without resolution to ≤ Grade 1 for ≥7 days 
despite adequate immune suppressive and anti-diarrheal therapy 
• Grade 3 or 4 imAE without resolution to Grade ≤ 1 or baseline within 8 days despite 
adequate immune suppressive therapy 
• Any Grade clinically significant imAE (e.g., myocarditis, encephalitis) requiring 
treatment discontinuation 
• Any other ≥ Grade 3 non-hematologic clinical (non-laboratory) toxicity excluding: 
− Nausea and vomiting resolving to ≤ Grade 1 within 48 hours with adequate treatment 
− Grade 3 fatigue with duration <7 days 
− Grade 3 or Grade 4 electrolyte abnormalities that last less than 48 h with adequate 
treatment 
− Grade 3 fever not associated with hemodynamic compromise 
− Grade 3 endocrinopathy that is well controlled by hormone replacement 
− Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to sites of known 
or suspected tumor 
• Any clinically-significant Grade ≥ 3 non-hematologic laboratory abnormality, except 
Grade 3 or Grade 4 elevation of amylase or lipase not associated with clinical or 
radiographic evidence of pancreatitis 
• Any clinically-significant hematologic toxicity specifically defined as: 
− Grade 4 thrombocytopenia for ≥7 days, or Grade 3 or 4 associated with bleeding or 
requiring platelet transfusion 
− Grade 4 neutropenia for ≥7 days, or Grade 3 or 4 associated with infection or febrile 
neutropenia 
− Grade 4 anemia, or Grade 3 requiring blood transfusion 
• Any death that is not clearly attributed to the underlying disease or extraneous causes 
Toxicities will be assessed according to CTCAE v5.0. If multiple toxicities occur, the presence 
of DLT will be graded based on the most severe toxicity observed. 


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7.3 
Treatment Assignment and Bias Minimization 
This is an open-label, non-randomized study. 
Patients will be enrolled in cohorts based on cancer type. The study will use a Simon two-stage 
design. 
7.4 
Assessment and Verification of Compliance 
Patients will be instructed to return all study drug supplies (including empty, partially empty, and 
full bottles) at each scheduled clinic visit for accountability and compliance review by study 
personnel. Study personnel will reinforce dosing instructions and answer patient questions at 
each clinic visit and during telephone follow-up. 
7.5 
Prior and Concomitant Therapies 
All medications and supplements administered within 14 days prior to Screening through the last 
follow-up visit will be recorded in the electronic case report forms (eCRFs) using generic drug 
names when possible. All antibiotics used within the 60 days prior to Screening will be recorded 
in the eCRF. 
7.5.1 
Permitted Therapies 
Concomitant medications may be administered at the Investigator’s discretion to conform to 
standard practice, including routine medications a patient will continue during study participation 
as well as newly prescribed medications, except for those excluded medications described in 
Section 7.5.3. Overall, VE800 has a low likelihood for eliciting clinically relevant drug-drug 
interactions (DDI); however, no formal DDI studies have been done and the Investigator will 
need to use caution when prescribing concomitant medications. The Investigator is strongly 
encouraged to contact the Medical Monitor when unsure of a possible DDI. 
Patients are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses >10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions 
(e.g., delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. 
7.5.2 
Concomitant Antacids and Acid Reducers 
Use of medications changing the gastric acidity may potentially reduce the effectiveness of 
VE800. Use of these medications should be restricted to the following: 
• Patients are not to consume food or fast-acting antacids (e.g., calcium-, aluminum-, or 
magnesium-containing products such as TUMS® or Maalox®) for at least 1 hour before 
and at least 1 hour after study drug ingestion 
• Patients are not to receive a histamine2-receptor antagonist (ranitidine, famotidine, etc.) 
within the 12 hours before or 1 hour after study drug ingestion 
• Patients are not to receive a proton-pump inhibitor (omeprazole, pantoprazole, etc.) 
within the 12 hours before or 1 hour after study drug ingestion 


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7.5.3 
Prohibited Therapies 
The following therapies are prohibited during the study, unless necessary for management of a 
medical condition. If any of the following are medically indicated and prescribed, these should 
be entered in the eCRF as concomitant medications: 
• Any live/attenuated vaccine (e.g., varicella, zoster, yellow fever, rotavirus, oral polio and 
MMR) within the last 30 days. Vaccines are permitted after the first 28 days of study 
treatment. 
• Immunosuppressive agents 
• Immunosuppressive doses of systemic corticosteroids (i.e., daily doses higher than 10 mg 
of prednisone equivalent) 
• Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, extensive, non-palliative radiation therapy) 
• Any botanical preparation (e.g., herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study or provide supportive care. Use of marijuana and 
its derivatives for treatment of symptoms related to cancer or cancer treatment are 
permitted if obtained by medical prescription or if its use (even without a medical 
prescription) has been legalized locally. 
• Drugs that alter gut motility (e.g., loperamide, diphenoxylate, or opium tincture) 
• Fecal microbial products or fecally-derived products (e.g., fecal matter delivered by 
capsules, enemas, or endoscopic placement), or any other live bacterial products, with the 
exception of live-bacteria-containing food products (such as yogurt) or over the counter 
probiotics 
• Other investigational products 
7.5.4 
Antibiotic Use During the Study 
Beyond the initial study-specific 5-day course of oral vancomycin, use of oral or parenteral 
antibiotics during the study treatment is not allowed, unless clinically indicated. Should 
antibiotic be used, VE800 administration may continue during the course of the antibiotic as long 
as discontinuation is considered unnecessary by the investigator. If discontinuation of VE800 is 
necessary, this should be discussed with Medical Monitor. If one or more of antibiotics listed in 
Appendix 6 was used, upon completion of the course of antibiotic, VE800 should be 
administered at a dose of 5 capsules per day for 7 days only followed by 1 capsule QD 
continuously. Infection-required antibiotic use should be reported as an AE and the antibiotic(s) 
used should be reported in the CRF.  
An unscheduled visit(s) should be scheduled at the end of their antibiotic course to ensure 
patients have enough VE800 until their next cycle. At this unscheduled visit, a stool sample 
(microbiota composition/VE800 detection) will be collected upon completion of the antibiotic 
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8 
SAFETY MONITORING 
8.1 
Definitions 
• Adverse event – An AE is any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related 
• Serious adverse event – An event is considered “serious” if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
− Death 
− A life-threatening AE (An event is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more 
severe form, might have caused death)  
− Inpatient hospitalization or prolongation of existing hospitalization 
− A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
− A congenital anomaly/birth defect 
− Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
• Adverse reaction – An adverse reaction is any AE caused by a drug 
• Suspected adverse reaction (SAR) – An SAR is any AE for which there is a reasonable 
possibility that the drug caused the AE. For the purposes of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between 
the drug and the AE. SAR implies a lesser degree of certainty about causality than AR. 
• Treatment-emergent adverse event (TEAE) – A TEAE is an undesirable event not 
present prior to medical treatment, or an already present event that worsens either in 
intensity or frequency following study treatment.  
• Immune-mediated adverse event – An imAEs is an AE consistent with an 
immune-mediated mechanism or immune-mediated component for which 
non-inflammatory etiologies (e.g., infection or tumor progression) have been ruled out. 
ImAEs can include events with an alternate etiology which were exacerbated by the 
induction of autoimmunity 
• Unexpected adverse event – An event is considered unexpected if it is not listed in the 
IB, is not listed at the specificity or severity that has been observed, or is not consistent 
with the risk information described in the General Investigational Plan. Unexpected also 


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refers to events that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug but are not specifically 
mentioned as occurring with the particular drug under investigation. 
8.2 
Documenting Adverse Events 
Adverse events will be assessed by direct observation and patient assessments/interviews. 
Abnormal clinical laboratory values and vital sign and ECG measurements will be recorded as 
AEs only if they are considered to be clinically significant by the Investigator. If a laboratory 
abnormality is the sole potential AE, the abnormality must be confirmed (if possible) with a 
repeat laboratory test performed as soon as possible. 
8.2.1 Timeframe for Collection 
All AEs and SAEs will be collected and recorded for each patient from the day of signing the 
ICF until 100 days after the last dose of the study treatment or until alternate anticancer therapy 
is initiated, whichever occurs first. Thereafter, only SAEs will be collected and recorded during 
the survival follow-up period or until alternate anticancer therapy is initiated. Any SAE 
occurring after the start of a new treatment that is considered to be related to study treatment by 
the investigator will be reported. 
All AEs and SAEs experienced by a study patient, irrespective of the suspected causality, will be 
monitored until the AE or SAE has resolved or stabilized (e.g., until abnormal laboratory values 
have returned to baseline or normalized, until there is a satisfactory explanation for the changes 
observed), until the patient is lost to follow-up, or until the patient has died, whichever is earlier. 
8.2.2 
Classification of Events 
8.2.2.1 
Assessment of Toxicity Grade 
The toxicity grade of an AE refers to its severity. The severity of AEs will be categorized using 
the National Cancer Institute (NCI) CTCAE, version 5.0 (CTCAE, 2017), which is appropriate 
for grading and assessing the range of potential AEs that may be observed in the targeted study 
population. For any term that is not specifically listed in the CTCAE scale, severity must be 
assigned a grade of 1 through 5 using the following CTCAE guidelines: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living 
Grade 4: Life-threatening consequences; urgent intervention indicated 
Grade 5: Death related to AE 


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8.2.2.2 
Assessment of Causality 
Medical judgment will be used to determine the cause of the AE, considering all relevant facts 
such as (but not limited to) the underlying study indication, comorbidities, concomitant 
medication(s), medical history, pattern of the AE (e.g., continuous, intermittent), temporal 
relationship to the study drug, and de challenge or re-challenge. 
The Investigator will be responsible for selecting “Yes” or “No” as detailed below for the 
relationship of each AE to the study drug. 
Yes: there is a reasonable possibility that there is a causal relationship to the study drug and one 
or more of the following criteria apply: 
• The event follows a reasonable temporal sequence from the time of administration of the 
study drug 
• The event could not be reasonably attributed to the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered to 
the patient 
• The event follows a known pattern of response to the study drug 
• The event disappears or decreases on cessation or reduction in dose. (It should be noted 
that in some situations an AE will not disappear or decrease in intensity upon 
discontinuation of study dosing despite other clear indications of relatedness). 
No: there is no reasonable possibility that the study drug caused the event; one or more of the 
following criteria apply: 
• The event does not follow a reasonable temporal sequence from administration of the 
study drug to the time of the AE 
• The event could be reasonably attributed to the known characteristics of the patient’s 
clinical state, concurrent illness, environmental or toxic factors, or other modes of 
therapy administered to the patient 
• The event does not follow a known pattern of response to the study drug 
• The event does not disappear or decrease on cessation, and it does not reappear or worsen 
when dosing is resumed 
8.2.2.3 
Action Taken with Study Drug(s) 
For each AE reported, the action taken with the study drug as a result of the AE will be recorded 
as one of the following: 
• None 
• Dose reduced 
• Dose delayed 
• Drug interrupted 
• Drug discontinued 


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8.2.2.4 
Outcome of Adverse Event 
The outcome of each AE at the time of last observation will be reported as one of the following: 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved/ongoing (e.g., for irreversible congenital anomalies) 
• Recovered/resolved with sequelae (e.g., for other irreversible medical conditions) 
• Fatal (i.e., death is at least possibly related to the AE) 
• Unknown 
8.3 
Reporting Serious Adverse Events 
All SAEs, regardless of relationship to study drug, must be reported to the clinical research 
organization (CRO) within 24 hours of site personnel knowledge. This will be done by faxing or 
emailing the completed SAE Report Form to the CRO at the number provided on the SAE 
Report Form. 
Contact information for safety reporting is as follows: 
Safety Reporting 
Fax: +1-888-772-6919 
E-mail: CHOSafety@prahs.com 
Investigators must follow patients with SAEs until event resolution or stabilization, withdrawal 
of consent, patient is lost to follow-up, or death, whichever occurs first. 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB. For fatal or life-threatening SAEs for which important or 
relevant information is missing, active follow-up must be undertaken immediately. 
The Sponsor, or their representatives, will provide the health authority; IRB, as appropriate; and 
participating investigators with clinical safety updates/IND safety reports according to local 
requirements. 
Any SAEs considered to have at least a possible relationship to the study drug and discovered by 
the Investigator at any time period after the patient’s study treatment has ended should be 
reported according to the timeframe described above. 
8.3.1 Submission and Distribution of Serious Unexpected Suspected Adverse Reaction 
Reports 
Per regulatory requirements, if an SAE is assessed by the Sponsor as a serious unexpected 
suspected adverse reaction (SUSAR), it will be submitted to the Regulatory Authorities. In 
addition to this, a copy of the report (CIOMS or MedWatch 3500A) will be distributed to the 
Investigators/site. A copy of the report will be submitted to the respective IRB/EC and 
Investigators as per local regulation. Reporting will be conducted in compliance with 
21 CFR 312.32. 


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8.4 
Adverse Events of Special Interest  
The following are considered AEs of special interest due to the indications under study and the 
nature of the investigational product (live bacteria) and potential for gastrointestinal or 
extraintestinal AEs: 
• Any clinically significant (Grade 2 or higher) gastrointestinal AE considered related to 
study drug 
• Any clinically significant (Grade 2 or higher) bacterial infection considered related to 
study drug 
• Immune-mediated AEs, i.e., events consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (e.g., infection or 
tumor progression) have been ruled out. Immune-mediated AEs can include events with 
an alternate etiology which were exacerbated by the induction of autoimmunity. 
These AEs will be tabulated and analyzed separately from other AEs. 
8.5 
Clinical Laboratory Findings 
It is the responsibility of the Investigator to assess the clinical significance of all abnormal 
laboratory values as defined by the appropriate reference range(s). All abnormal values assessed 
to be of clinical concern and at least possibly related to the study drug or of uncertain causality 
will be repeated. Persistent abnormal values or changes of possible clinical concern that remain 
within the normal range will be followed up and further evaluated at the discretion of the 
Investigator. 
An abnormal laboratory value that is not already associated with an AE is to be recorded as an 
AE if: 
• A repeat test is performed when possible to confirm the abnormality 
• An action on study drug dosing is made as a result of the abnormality 
• An intervention for management of the abnormality is required 
• The Investigator considers the abnormality to be an AE 
Abnormal test results must not be recorded as AEs unless they fulfill the aforementioned criteria. 
All abnormal laboratory values, even if reported as an AE, will be categorized by the 
Investigator as not clinically significant (NCS) or clinically significant (CS) and a severity grade 
will be included in the eCRF. 
8.6 
Pregnancy 
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at 
Screening, prior to dosing in Cycle 2 and each subsequent 28-day dosing cycle, and at EOT. 
Definitions of WOCBP and methods of contraception are provided in Appendix 5. Men must use 
contraception for 7 months following the last dose of study drug (nivolumab or VE800). 
Pregnancies occurring on study that involve a study patient must be brought to the attention of 
the treating physician immediately, and pregnant patients must discontinue study dosing. Site 
personnel will notify the Sponsor within 24 hours of the Investigator’s knowledge of the 


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pregnancy using a Pregnancy Notification Form per contact details noted in Section 8.3. Such 
pregnancies will be followed to outcome, as possible. 
The outcome of all pregnancies that occur from the date of the first dose until 5 months after the 
last dose of study treatment should, if possible, be followed up and documented. When a report 
of pregnancy is received, the Investigator must obtain the consent of the patient’s partner prior to 
obtaining information about the pregnancy (using a suitably approved consent form in accord 
with local procedures). 
Pregnancy in a female patient or female partner of a male patient is neither an AE nor an SAE, 
unless a complication relating to the pregnancy occurs (e.g., spontaneous abortion, which may 
qualify as an SAE). 
8.7 
Overdose or Misuse 
Overage in dosing of either the study drug or a concomitant medication without overdose signs 
or symptoms unless the event meets SAE criteria (e.g., hospitalization) are excluded from SAE 
reporting; however, dosing that is not within 95-105% of a planned dose should be recorded on 
the appropriate eCRF page. 


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9 
ANALYSIS 
An overview of planned analyses is presented in this section. Details will be provided in the 
statistical analysis plan (SAP). 
Data from 3 cohorts will be analyzed and reported separately by cohort. 
9.1 
Sample Size Determination 
The study will use a Simon two-stage design. In each disease-specific expansion cohort, a Simon 
two-stage design will be used to provide an initial assessment of the clinical activity at Stage 1 
for continuation to Stage 2. ORR will be evaluated using RECIST 1.1. 
In the melanoma and the gastric/GEJ adenocarcinoma cohorts, with an undesirable ORR of 10% 
or less, a desirable ORR of 25% or more, and Type 1 error rate of 10%, 42 patients give 85% 
power to detect the minimal desirable or indecision ORR of 25%. After the first stage 
(enrollment of 14 patients), enrollment (of another 28 patients) maybe discontinued to the second 
stage if less than 2 patients achieve objective response. The cohort will be declared a success at 
the end of the second stage if more than 6 patients achieve objective response.  
Similarly, in the CRC-MSS cohort, with an undesirable ORR of 2% or less, a desirable ORR of 
15% or more, and Type 1 error rate of 10%, 27 patients give 85% power to detect the minimal 
desirable or indecision ORR of 15%. After the first stage (enrollment of 13 patients), enrollment 
(of another 14 patients) maybe discontinued to the second stage if no patients achieve objective 
response. The cohort will be declared a success at the end of the second stage if more than 1 
patient achieves objective response. 
9.2 
Analysis Sets 
The following patient populations (i.e., analysis sets) will be evaluated and used for presentation 
of the data: 
• Full Analysis Set: All patients who were enrolled and received any dose of any study 
drug (vancomycin, VE800, or nivolumab). The Full Analysis Set will be the default 
analysis set for all analyses, unless otherwise specified. 
• Safety Analysis Set: All patients who were enrolled and received at least 1 dose of any 
study drug (VE800 or nivolumab). The Safety Analysis Set will be the primary set for the 
analysis of safety data. 
• DLT-evaluable population: The first 12 patients to complete the first 28 days of 
combination treatment of VE800 and nivolumab administration or experience a DLT 
• PK population: All patients who receive at least 1 dose of VE800 and have at least 1 PK 
sample. 
• Efficacy Population: all patients who receive one dose of the combination treatment of 
VE800 and nivolumab and have a valid baseline and post baseline tumor assessment 
(death or documented clinical progression without imaging may be considered a valid 
post-baseline assessment). 
9.3 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint is the ORR defined as the proportion of patients achieving a best 
overall response of CR or PR evaluated using RECIST 1.1. 


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Objective responses will be confirmed no less than 4 weeks after the criteria for response are first 
met (if possible, 4 – 6 weeks). 
All efficacy endpoints will be summarized on the data from patients by tumor cohort. The 
primary efficacy analysis is based on the Efficacy Population defined in Section 9.2. All analyses 
will include summary statistics, including number of patients (n) and percentage (%) for 
categorical variables and number of patients, mean, standard deviation, median, minimum, and 
maximum for continuous variables. Time-to-event analyses will be performed using 
Kaplan-Meier (KM) methods. Totality of data will be taken into account for transition to Stage 2.  
9.4 
Analysis of Secondary Efficacy Endpoints 
Additional measures of ORR will be evaluated using RECIST 1.1, including the following  
• Antitumor response based on change in measurable tumor burden 
• Time-point response assessment: percentage changes in tumor burden per assessment 
time point 
• Best overall response assessment (CR, PR, SD, PD) 
• DCR, defined as CR+PR+SD 
• DOR, defined as the time from first documentation of CR or PR until the time of first 
documentation of PD 
PFS according to RECIST (v1.1) is defined as the time from enrollment to the earlier date of 
assessment of progression or death by any cause in the absence of progression. PFS will be 
assessed at 2 months and every 2 months thereafter until 1 year, and then every 12 weeks after 1 
year. Landmark PFS at 6 and 12 months will be measured. 
OS as measured from the date of start of treatment to the date of death by any cause will also be 
evaluated. 
9.5 
Analysis of Exploratory Efficacy Endpoints 
Exploratory endpoints will be analyzed, including: 
• Measures of clinical benefit, including ORR, DOR, and PFS according to iRECIST 
• Changes in stool composition, peripheral blood and/or tumor tissue; e.g., circulating and 
intra-tumoral changes in immune cells 
• Measures of clinical benefit in subsets of patients based on biomarkers 
• Global changes in microbiome composition and metabolomics 
9.6 
Population Analysis 
9.6.1 
Disposition 
A tabulation of the disposition of patients will be presented, including the number of patients 
who fail Screening after signing informed consent, receive study drug, and complete or 
prematurely discontinue, and the reasons for study discontinuation. Entry criteria eligibility and 
protocol deviations will be listed. 


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9.6.2 
Demographics and Baseline Characteristics 
Descriptive summaries of demographic and baseline disease characteristic will be generated. 
Data to be tabulated will include sex, age, race, and ethnicity, as well as cancer history and prior 
treatments. 
9.6.3 
Disease History 
For disease history the following will be documented: 
• Date of first diagnosis 
• Cancer diagnosis and Stage at the time initial diagnosis 
• Histology and grade of disease at diagnosis and most recent biopsy if additional biopsy 
performed 
• For patients with CRC: microsatellite stability status (MSS or microsatellite instable 
[MSI] high) 
• Information on first anticancer treatment: 
− Intent (adjuvant, neoadjuvant, curative, palliative) 
− Date of start of first treatment 
− Agents used in first treatment 
− Date of last dose of first treatment 
• Information on second and subsequent anticancer treatments: 
− Intent (adjuvant, neoadjuvant, curative, palliative) 
− Dates of start of all subsequent treatments 
− Agents in all subsequent treatments 
− Dates of last dose of all subsequent treatments 
• Best response to prior anticancer treatment  
• (For melanoma only) best response to iCPI 
• Date of recurrence for each prior anticancer treatment 
9.7 
Safety Analysis 
9.7.1 
Adverse Events 
Adverse events will be coded using the most current version of Medical Dictionary for 
Regulatory Activities (MedDRA®) at the time of study initiation. A by-patient AE data listing, 
including verbatim term, preferred term, system organ class, study drug arm, severity, and 
relationship to study drug, will be provided. The number of patients experiencing a DLT will be 
summarized by study cohort, system organ class, and preferred term. Additionally, the number of 
patients experiencing TEAEs and the number of individual TEAEs will be summarized by study 
cohort, system organ class, and preferred term. TEAEs will also be summarized by severity and 
by relationship to study drug. 


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9.7.2 
Clinical Laboratory Analysis 
Changes in clinical laboratory parameters (hematology, chemistry) will be summarized by 
protocol-specified collection time point. A summary of changes from baseline will also be 
presented for each protocol-specified time point. 
9.7.3 
Other Safety Endpoint 
Vital signs, ECG parameters, ECOG performance status, and physical examinations be 
summarized by protocol-specified collection time point. A summary of changes from baseline 
will also be presented for each protocol-specified time point. 
9.8 
Pharmacokinetics Analysis 
Results from stool microbiota composition and VE800 detection analyses will be presented in 
by-patient listings and summarized by cohort and study day, including absolute values and 
changes from baseline. 
Tabular and/or graphical summaries for the microbiome and VE800 detection analyses will be 
produced for VE800 strain presence, community composition (relative abundance of the top 10 
species and VE800 strain abundance), community diversity (Shannon Index, Simpson Index, and 
Species Richness calculations), and relative abundance of all species detected in the sample. In 
addition, an analysis will be performed to evaluate the longitudinal microbiome composition and 
VE800 strains within each patient and within each study arm, including changes in diversity over 
time, changes in microbiome species over time, and changes in VE800 strains over time (both 
presence/absence and relative abundance). 
The Sponsor will also collect serum and stool samples from clinical study patients and may 
analyze them for possible exploratory purposes and biomarkers. 
9.9 
Pharmacodynamics and Biomarker Analysis 
A biomarker analysis will be conducted on fresh and/or archival tumor tissue samples, and stool 
samples to correlate with the clinical outcome to identify the biomarker signature of treatment 
outcomes to the combination treatment. Stool samples will be collected for VE800 bacterial 
components detection, colonization duration, and evaluation of other microbiome components 
such as overall diversity. 
9.10 
Specified Analyses for Safety Committee Review 
The safety committee will meet on a bi-weekly basis to oversee emerging safety data until the 
first 12 patients have completed the first cycle of combination treatment of vancomycin, 
followed by VE800 and nivolumab administration or have experienced a DLT. As described in 
Section 4.2, patients will be evaluated for safety, PK and pharmacodynamics for 28 days of a 
DLT period, encompassing 5 days of vancomycin followed by 28 days of VE800 dosing with 
nivolumab on Day 1. 
The committee may pause enrollment at any time, if warranted, based on incidence of DLTs 
(e.g., if DLTs are observed in >33% of at least 6 patients, as defined in the safety committee 
charter). The study will be stopped if the DLT rate exceeds 33% or if Grade 4 SAEs that are at 
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study patients. A decision to re-open enrollment at the current or reduced dose of VE800 will be 
made based on the overall safety profile of combination treatment. 
The committee may modify the frequency of meetings as deemed appropriate during the course 
of the trial. 
9.11 
Procedures for Reporting Changes to the Planned Analysis 
All deviations from the SAP will be provided in the clinical study report. 


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10 
ETHICAL CONSIDERATIONS 
10.1 
Good Clinical Practice 
The study will be performed in accordance with the protocol, guidelines for GCP established by 
the International Council for Harmonisation (ICH), and applicable local regulatory requirements 
and laws. 
The Sponsor is committed to designing, implementing, conducting, analyzing, and reporting this 
trial in compliance with the highest ethical and scientific standards. Protection of patient safety is 
the overriding concern in the design of clinical trials. In all cases, Vedanta clinical trials will be 
conducted in compliance with local and/or national regulations and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki. 
10.2 
Ethics Review 
The Investigator must inform and obtain approval from the IRB/EC for study conduct at named 
sites, the protocol, informed consent documents, and any other written information that will be 
provided to the patients and any advertisements that will be used. Written approval must be 
obtained prior to recruitment of patients and shipment of study drugs. 
Proposed amendments to the protocol and aforementioned documents must be submitted to the 
Sponsor for review and approval, then to the IRB/EC. Amendments may be implemented only 
after a copy of the approval letter from the IRB/EC has been transmitted to the Sponsor. 
Per GCP guidelines, the Investigator will be responsible for ensuring that an annual update is 
provided to the IRB/EC until the study is completed (i.e., finalization of the clinical study report) 
to facilitate continuing review of study conduct and that the IRB/EC is informed about the end of 
the study. Copies of the update, subsequent approvals, and final letter must be sent to the 
Sponsor. 
In addition to IRB/EC and regulatory authority approval, all other required approvals 
(e.g., approval from the local research and development board or scientific advisory committee) 
will be obtained prior to recruitment of patients and shipment of study drugs. 
10.3 
Informed Consent 
Informed consent is a process that is initiated prior to the patient’s agreeing to participate and 
continues throughout the patient’s participation. It is the Investigator’s (or designee’s) 
responsibility to obtain written informed consent from each patient after adequate explanation of 
the aims, methods, anticipated benefits, and potential hazards before any study procedures are 
initiated. Each patient must be given a copy of the signed informed consent documents and 
associated materials. The original copy of the signed and dated informed consent documents 
must be retained at the site and is subject to inspection by representatives of the Sponsor or 
regulatory authorities. If any amendments affect the ICF (e.g., when new study procedures or 
assessments have been added), all active patients must be reconsented using the same process for 
the initial consent. 


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10.4 
Data Privacy 
The Investigator must ensure that the patient’s privacy is maintained. On eCRFs and other 
documents submitted to the Sponsor, patients will be identified by their assigned patient number 
only and any other information that may reveal the patient’s identity must be redacted (e.g., first 
and last name). Documents that are not submitted to the Sponsor (e.g., signed informed consent 
documents) must be kept in a confidential file by the Investigator. 
The Investigator shall permit authorized representatives of the Sponsor, regulatory authorities, 
and IRBs/ECs to review the portion of the patient’s medical record that is directly related to the 
study. As part of the required content of informed consent documents, patients must be informed 
that their medical records will be reviewed in this manner. 
10.5 
Disclosure 
Information concerning the study, patent applications, processes, scientific data, or other 
pertinent information is confidential and remains the property of the Sponsor. The Investigator 
may only use this information for the purposes of the study. 
It is understood by the Investigator that the Sponsor will use information obtained in this study in 
connection with the clinical development program, and therefore may disclose it as required to 
other clinical Investigators and to regulatory authorities. In order to allow the use of the 
information derived from this study, the Investigator understands the obligation to provide 
complete test results and all data obtained to the Sponsor. 
Verbal or written discussion of results prior to study completion and full reporting must be 
undertaken only with written consent from the Sponsor. 
10.6 
Biological Specimens and Data 
Following the conclusion of the study, patient samples that have not been depleted may be stored 
and used for additional future research. This research will help understand disease subtypes, drug 
response, and toxicity, and possibly to identify new biomarkers that predict patient response to 
treatment. 
This use of the samples for internal research will be done in accordance with the guidelines 
defined by the FDA document “Guidance on Informed Consent for In Vitro Diagnostic Device 
Studies Using Leftover Human Specimens that are Not Individual Identifiable” (issued 25 April 
2006) and European Medicines Agency’s (EMEA’s) Reflection Paper on Pharmacogenetic 
Samples, Testing, and Data Handling (EMEA, April 2008). If a patient requests destruction of 
their tissue and blood samples and the samples have not yet been de-identified, the Sponsor (or 
central laboratory) will destroy the samples as described in this FDA guidance. The Sponsor (or 
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11 
OVERSIGHT 
11.1 
Quality Control and Assurance 
Quality control procedures will be conducted according to the Sponsor and CRO’s internal 
procedures. The study site may be audited by a quality assurance representative of the Sponsor. 
All necessary data and documents will be made available for inspection along with any required 
study staff. 
11.1.1 
Monitoring 
This study will be closely monitored by representatives of the Sponsor or designee throughout its 
duration. Monitoring will include personal visits with the Investigator and study staff as well as 
appropriate communications by telephone, fax, mail, email, or use of the electronic data capture 
(EDC) system, as applicable. It is the monitor’s responsibility to inspect all eCRFs at regular 
intervals throughout the study to verify the completeness, accuracy, and consistency of the data 
and to confirm adherence to the study protocol and to GCP guidelines. The Investigator agrees to 
cooperate with the monitor to ensure that any problems detected are resolved promptly. The 
Investigator and site will permit study-related monitoring, audits, IRB/EC review, and regulatory 
inspection, including direct access to source documents. 
It is understood that study monitors and any other personnel authorized by the Sponsor may 
contact and visit the Investigator and will be permitted to inspect all study records (including 
eCRFs and other pertinent data) on request, provided that patient confidentiality is maintained, 
and that the inspection is conducted in accordance with local regulations. 
Every effort will be made to maintain the anonymity and confidentiality of patients. However, 
because of the experimental nature of the investigational product, the Investigator agrees to allow 
representatives of the Sponsor and authorized representatives of regulatory authorities to inspect 
the facilities used in the conduct of this study and to inspect, for purposes of verification, all 
hospital or clinic records of all enrolled patients relevant to study participation. 
11.1.2 
Audits 
Regulatory authorities, the IRB/EC, and/or the Sponsor’s clinical quality assurance group, or its 
designee, may request access to all source documents, eCRFs, and other study documentation for 
on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. 
11.1.3 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or ICH GCP 
requirements. The noncompliance may be either on the part of the patient, the Investigator, or the 
study site staff. Deviations must be reviewed by the site, clinical research associate (CRA), 
Sponsor and designee, as appropriate for potential corrective actions development. Corrective 
actions will be implemented promptly. 
These practices are consistent with ICH GCP: 
• 4.5 Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3; 
• 5.1 Quality Assurance and Quality Control, Section 5.1.1; and 
• 5.20 Noncompliance, Sections 5.20.1, and 5.20.2. 


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It is the responsibility of the Investigator to use continuous vigilance to identify and promptly 
report deviations. All deviations must be addressed in study source documents. Protocol 
deviations must be sent to the reviewing IRB/EC per their policies. The Investigator is 
responsible for knowing and adhering to IRB/EC requirements. 
11.1.4 
Records 
11.1.4.1 
Data Capture and Management 
Medical records and/or study visit worksheets will be used by the Investigator or designee as 
source documents for recording data specified in the protocol for each patient enrolled. Data 
recorded in the eCRF derived from source documents must be consistent with the data recorded 
on the source documents. All source documents must be completed in a neat, legible manner to 
ensure accurate interpretation of data. Additional data will be collected through clinical 
laboratories. 
Clinical data derived from source documents will be entered into a 21 CFR Part 11-compliant 
EDC system at the clinical sites. The data system will include password access, consistent 
backup, and an audit trail. Internal and external quality checks will be applied to identify data 
that appear inconsistent, incomplete, or inaccurate. Data not captured on eCRFs will be received 
and stored as external files by the Sponsor or designee. 
Study plans will describe internal and external quality checks and cross functional data 
monitoring to identify and address data issues via a risk-based approach. Needed queries will be 
issued by the system (some fields may require immediate correction for form submission), CRO, 
or authorized Sponsor staff in an attempt to clarify and/or correct missing, incomplete, or 
illogical data. Changes or corrections to eCRFs will be made by the Investigator or an authorized 
member of the study staff. 
Data entered and compiled for interim analysis and/or DMC review will be monitored as closely 
as possible for accuracy and quality but may not undergo final data cleaning and verification. 
It is the Investigator’s responsibility to ensure eCRFs are complete and accurate, regardless of 
whether this responsibility has been delegated in whole or in part. Following review and 
approval, the Investigator or designee will electronically sign and date the pages, which certifies 
that the Investigator has thoroughly reviewed and confirmed all data on the eCRF. 
A read-only copy of the eCRFs will be provided to study sites after the study has ended and the 
EDC system has been locked. 
11.1.4.2 
Records Retention 
Data retention practices will follow ICH guidelines, which note that essential documents must be 
retained for a minimum of 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH region or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. However, these documents must be retained for a longer period if 
required by the applicable local requirements. 


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12 
PUBLICATION POLICY 
The Sponsor encourages the scientific publication of data from clinical research studies. 
However, an Investigator(s) may not present or publish partial or complete study results without 
participation and written agreement of the Sponsor. The Investigator and the Sponsor may 
propose appropriate scientific manuscripts or abstracts from the study data. All proposed 
publications must be reviewed and commented on by the Sponsor before submission for 
publication. The detailed procedures for the review of publications are set out in the clinical trial 
agreement entered into with the Sponsor in connection with this study. These procedures are in 
place to ensure coordination of study data publication and adequate review of data for 
publication against the validated study database for accuracy. 


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APPENDICES 


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APPENDIX 1 
NIVOLUMAB MANAGEMENT ALGORITHMS 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens. 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used. 


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APPENDIX 2 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST), V1.1 
Response Criteria by RECIST v1.1 (Eisenhauer, 2009) 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 


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RECIST Response for Patients with Measurable Disease (i.e., Target Disease)  
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Requireda 
CR 
CR 
No 
CR 
>4 wks. Confirmationb 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmationb 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baselineb 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PDc 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease 
a 
See RECIST v1.1 publication for further details on what is evidence of a new lesion. 
b 
Only for non-randomized trials with response as primary endpoint. 
c 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort 
should be made to document the objective progression even after discontinuation of treatment. 
 


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APPENDIX 3 
iRECIST: GUIDELINES FOR RESPONSE CRITERIA IN SOLID 
TUMORS IN TRIALS TESTING IMMUNOTHERAPUETICS 
Response Criteria by iRECIST (Seymour, 2017) 
During the study treatment, a patient with initial evidence of radiological PD may continue on 
study treatment until repeat imaging is obtained at least 4 weeks and up to 8 weeks later. The 
decision to continue treatment past PD only be considered if patient is clinically stable. First 
RECIST PD is immune-unconfirmed progressive disease (iUPD). 
Assignment of timepoint response using iRECIST 
 
Timepoint response 
with no previous 
iUPD in any category 
Timepoint response with previous iUPD in 
any category* 
Target lesions: iCR; non-target lesions: 
iCR; new lesions: no 
iCR 
iCR 
Target lesions: iCR; non-target lesions: 
non-iCR/non-iUPD; new lesions: no 
iPR 
iPR 
Target lesions: iPR; non-target lesions: 
non-iCR/non-iUPD; new lesions: no 
iPR 
iPR 
Target lesions: iSD; non-target lesions: 
non-iCR/non-iUPD; new lesions: no 
iSD 
iSD 
Target lesions: iUPD with no change, 
or with a decrease from last timepoint; 
non-target lesions: iUPD with no 
change, or decrease from last 
timepoint; new lesions: yes 
Not applicable 
New lesions confirm iCPD if new lesions were 
previously identified and they have increased in 
size (≥5 mm in sum of measures for new lesion 
target or any increase for new lesion non-target) 
or number; if no change is seen in new lesions 
(size or number) from last timepoint, 
assignment remains iUPD 
Target lesions: iSD, iPR, iCR; non-
target lesions: iUPD; new lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed on the 
basis of a further increase in the size of non-
target disease (does not need to meet RECIST 
1.1 criteria for unequivocal progression) 
Target lesions: iUPD; non-target 
lesions: non-iCR/non-iUPD, or iCR; 
new lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed on the 
basis of a further increase in sum of measures 
≥5 mm; otherwise, assignment remains iUPD 
Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: no 
iUPD 
Remains iUPD unless iCPD is confirmed based 
on a further increase in previously identified 
target lesion iUPD in sum of measures >5 mm 
or non-target lesion iUPD (previous assessment 
need not have shown unequivocal progression) 
Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: yes 
iUPD 
Remains iUPD unless iCPD is confirmed on the 
basis of a further increase in previously 
identified target lesion iUPD sum of measures 
≥5 mm, previously identified non-target lesion 
iUPD (does not need to be unequivocal), or an 
increase in the size or number of new lesions 
previously identified 
Target lesions: non-iUPD or 
progression; non-target lesions: non-
iUPD or progression; new lesions: yes 
iUPD 
Remains iUPD unless iCPD is confirmed on the 
basis of an increase in the size or number of 
new lesions previously identified 
*Previously identified in assessment immediately before this timepoint. “ ” indicates immune responses assigned using iRECIST. 
iCR=complete response. iPR=partial response. iSD=stable disease. iUPD=unconfirmed progression. non-iCR/non-iUPD=criteria 
for neither CR nor PD have been met. iCPD=confirmed progression. RECIST=Response Evaluation Criteria in Solid Tumors. 


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APPENDIX 4 
ECOG PERFORMANCE STATUS 
 
ECOG PERFORMANCE STATUS 
Grade 
 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5 
Dead 
Source: Oken (1982) 
 


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APPENDIX 5 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION 
DEFINITIONS 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP 
• Premenarchal 
• Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the patient’s medical records, 
medical examination, or medical history interview. 
• Postmenopausal female 
− A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level >40 mIU/mL to confirm menopause. 
 
CONTRACEPTION GUIDANCE FOR FEMALE PATIENTS OF CHILDBEARING 
POTENTIAL 
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as 5 months after the end of 
study treatment.* 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationb 
− oral 
− intravaginal 
− transdermal 
• Progesterone-only hormonal contraception associated with inhibition of ovulationb 
− oral 
− injectable 


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Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb 
• Intrauterine hormone-releasing system (IUS)c 
• Intrauterine device (IUD)c 
• Bilateral tubal occlusion 
• Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
• Sexual abstinence 
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 drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the patient. 
• It is not necessary to use any other method of contraception when complete abstinence 
is elected. 
• WOCBP patients who choose complete abstinence must continue to have pregnancy 
tests, as specified in the protocol. 
• Acceptable alternate methods of highly effective contraception must be discussed in 
the event that the WOCBP patient chooses to forego complete abstinence. 
NOTES: 
a. Typical use failure rates may differ from those when used consistently and correctly. 
Use should be consistent with local regulations regarding the use of contraceptive 
methods for patients participating in clinical studies. 
b. Hormonal contraception may be susceptible to interaction with the study drug, which 
may reduce the efficacy of the contraceptive method. Hormonal contraception is 
permissible only when there is sufficient evidence that the IMP and other study 
medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous. In this 
case, alternative methods of contraception should be utilized. 
c. Intrauterine devices and intrauterine hormone releasing systems are acceptable 
methods of contraception in the absence of definitive drug interaction. 
 


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Unacceptable Methods of Contraception 
• Male or female condom with or without spermicide. Male and female condoms cannot 
be used simultaneously 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal Sponge with spermicide 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action 
• Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• Withdrawal (coitus interruptus) 
• Spermicide only 
• Lactation amenorrhea method (LAM) 
* Local laws and regulations may require use of alternative and/or additional 
contraception methods. 
 
CONTRACEPTION GUIDANCE FOR MALE PATIENTS WITH PARTNER(S) OF 
CHILDBEARING POTENTIAL 
Male patients with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure. 
• Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator. 
• Male patients are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment. 
• Female partners of males participating in the study to consider use of effective methods 
of contraception until the end of relevant systemic exposure, defined as 7 months after 
the end of treatment in the male patient. 
• Male patients with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment and until 7 months after the end of study treatment. 
• Refrain from donating sperm for the duration of the study treatment and until 7 months 
after the end of study treatment. 


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APPENDIX 6 
MICROBIOTA-PERTURBING ANTIBIOTICS 
Antibiotics with significant impact on the intestinal microbiota should be avoided during the study 
period unless clinically indicated. These antibiotics are specified below and include:  
• Beta-lactam antibiotics including Piperacillin-tazobactam, Cefepime, Ceftazidime, 
Ceftriaxone, Cefoxitin, Oxacillin, Etrapenem, Imipenem, Meropenem, Amoxicillin-
Clavulanate, Ampicillin-sulbactam 
• Vancomycin (oral only) 
• Metronidazole 
• Clindamycin 
• Tigecycline 
• Linezolid 
• Daptomycin 
• Ciprofloxacin, Levofloxacin  
• Doxycycline