Conditions: Metastatic Melanoma
Keywords: Metastatic Melanoma anti-PD1 Nivolumab Microbiome SER-401
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 14
Healthy volunteers: no

Brief summary:
This study is designed to evaluate the safety and tolerability of treatment with oral microbiome study intervention (SER-401) or matching placebo in combination with anti-programmed cell death 1 (anti-PD-1) therapy (nivolumab) in participants with unresectable or metastatic melanoma. The study also intends to assess clinical outcomes, the impact of microbiome study intervention administration on the microbiome profile, and its association with clinical and immunological outcomes.

Detailed description:
This is a Phase 1b, multicenter, randomized, placebo-controlled, blinded study in adult participants with anti-PD-1 therapy naïve, unresectable or metastatic melanoma to evaluate the safety and tolerability of SER-401, or matching placebo in combination with anti-PD-1 therapy (nivolumab). Prior to initiating microbiome study intervention and nivolumab, participants will undergo an antibiotic or antibiotic placebo treatment lead-in to prime the gut microbiome for engraftment of the oral microbiome study intervention. Study intervention groups will be assessed for safety, changes in the microbiome, changes in the percentage of tumoral CD8 T cells, and antitumor activity. Participants must have measurable disease that can be biopsied and consent to baseline and on-treatment biopsies, as well as stool and blood biomarker collection throughout the study.

Arms:
arm 1: Participants will undergo a 4-day lead-in pretreatment with antibiotic placebo, then matching placebo for SER-401 and nivolumab (480 mg) treatment. arm 2: Participants will undergo a 4-day lead-in pretreatment with antibiotic (vancomycin) to prime the gut microbiome for engraftment of the oral microbiome study intervention, then SER-401 and nivolumab treatment.

Interventions: intervention 1: Placebo for antibiotic intervention 2: Vancomycin pretreatment intervention 3: Nivolumab intervention 4: Matching Placebo for SER-401 intervention 5: SER-401
Intervention descriptions: intervention 1: Placebo for antibiotic will be administered orally four times a day for 4 days, followed by a 2-3 day washout. intervention 2: Vancomycin (125mg) will be administered orally four times a day, followed by a 2-3 day washout. intervention 3: Nivolumab (480 mg) will be administered intravenously (IV) according to institutional guidelines every 4 weeks for up to 12 cycles. A cycle is defined as 4 calendar weeks. intervention 4: Administered once a day for 7 days during the lead-in phase, followed by once a day for 8 weeks during the microbiome/anti-PD-1 treatment phase. intervention 5: Administered once a day for 7 days during the lead-in phase, followed by once a day for 8 weeks during the microbiome/anti-PD-1 treatment phase.

Protocol document:
Prot_000.pdf: 
 
MCGRAW – Parker Institute for Cancer Immunotherapy 
Protocol PICI0014 Amendment 2, 08JAN2020 
1
 
 
Protocol Title:  A Multicenter Phase 1b Randomized, Placebo-controlled, Blinded Study to 
Evaluate the Safety, Tolerability and Efficacy of Microbiome Study Intervention Administration 
in Combination with Anti-PD-1 Therapy in Adult Patients with Unresectable or Metastatic 
Melanoma 
Protocol Number:  PICI0014 
Amendment Number:  Not applicable 
Compound Number:  Microbiome Study Intervention (Oral fecal microbiota transplant [FMT] 
or SER-401) and Anti-PD-1 Monoclonal Antibody (Nivolumab) 
Short Title:  Melanoma Checkpoint and Gut Microbiome Alteration with Microbiome 
Intervention (MCGRAW) 
Sponsor Name and Legal Registered Address:   
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
Tel: 415-985-7311 
Fax: 415-872-5305 
Regulatory Agency Identifying Number(s):  
IND NUMBER: 018517 
EudraCT NUMBER:  Not applicable 
Approval Date:  Final Protocol: 25 Sep 2018 
 
Amendment 1: 14 Nov 2018 
 
Amendment 2: 08 Jan 2020 
 
CONFIDENTIAL 
This document and its contents are the property of and confidential to Parker Institute for Cancer 
Immunotherapy. Any unauthorized copying or use of this document is prohibited. 




 
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3
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with this protocol, any future amendments, and with 
any other study conduct procedures provided by Parker Institute for Cancer 
Immunotherapy. 
• 
Not to implement any changes to the protocol without written agreement from Parker 
Institute for Cancer Immunotherapy and prior review and written approval from the 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) except where 
necessary to eliminate an immediate hazard to patients. 
• 
That I am thoroughly familiar with the appropriate use of the study drug(s), as described 
in this protocol and any other information provided by Parker Institute for Cancer 
Immunotherapy including, but not limited to, the current Investigator’s Brochure(s).  
• 
That I am aware of, and will comply with, the International Conference on 
Harmonisation for Good Clinical Practices (GCP) and all applicable regulatory 
requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about the 
study drugs, the Parker Institute for Cancer Immunotherapy study protocol, and of their 
study-related duties and functions as described in the protocol. 
• 
That I agree that persons debarred from conducting or working on clinical studies by any 
court or regulatory agency will not be allowed to conduct or work on studies for the 
Parker Institute for Cancer Immunotherapy or for a partnership in which the Parker 
Institute for Cancer Immunotherapy is involved, and that I will immediately disclose in 
writing to the Parker Institute for Cancer Immunotherapy if any person who is involved 
in the study is debarred, or if any proceeding for debarment is pending. 
 
 
Signature: 
 
 
Date: 
 
 
Name 
(print): 
 
  
 
Site 
Number: 
Principal Investigator 
 
___________ 
  
 
 
  
 


 
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Amendment 1: 14 Nov 2018 
Text revisions resulting from this amendment are incorporated in the synopsis and body of 
Protocol Amendment 1. Major changes to the protocol are summarized below. 
Key Revisions in Amendment 1 
Section # and Name 
Description of Change 
Safety Assessments 
8.3.1 Time Period and 
Frequency for Collecting 
AE, AESI, SAE, and Other 
Reportable Safety Event 
Information 
Clarified that all SAEs and AEs, including AESIs, will be collected until 90 days 
after the last dose of nivolumab (ie, removed the following text: “or until the 
initiation of a new systemic anticancer therapy, whichever occurs first.”).  
8.3.4 Regulatory Reporting 
Requirements for SAEs 
Added text to address safety reporting to drug manufacturers. 
10.5.3 Recording AEs and 
SAEs 
Updated the definitions for toxicity attribution for AEs, AESIs, and SAEs 
Study Design 
4.1 Overall Design 
Added text to reflect that the first 5 participants in each microbiome study 
intervention group (ie, FMT/matching placebo or SER-401/matching placebo) will 
be contacted twice following the first dose of nivolumab (once between Days 2-4 
and once on Day 7 [± 1 day to accommodate weekends or holidays]) to assess for 
emerging AEs that may require early intervention. 
Study Intervention 
Synopsis 
Added text to reflect staggering administration of study intervention by at least 1 
day for the first 5 participants enrolled in each microbiome study group (ie, 
FMT/matching placebo or SER-401/matching placebo) to monitor for safety.  
6.1 Study Interventions 
Administered 
Added text to reflect staggering administration of study intervention by at least 1 
day for the first 5 participants enrolled in each microbiome study group (ie, 
FMT/matching placebo or SER-401/matching placebo) to monitor for safety. 
6.6.1 Dose Modifications 
with Nivolumab and Oral 
Microbiome Study 
Intervention 
Added new criterion to Table 4 for any infection with an organism acquired from 
FMT or SER-401. 
7.1.1 Study-wide Hold for 
Specified Safety Events 
Added new section to reflect that occurrence of any report of an SAE related to 
FMT or SER-401 or of any infection with an organism acquired from FMT or 
SER-401 will result in a study-wide hold and immediate discontinuation of oral 
microbiome study intervention administration.  
Study Assessments and Procedures 
1.3 Schedule of Activities 
Revised Table 1 as follows: 
• changed window for Cycle 1, Day 1 to ±1 day and the window for the Q3M 
follow up visits to ±14 days; 
• clarified the timing of the baseline disease assessment and revised text to describe 
disease assessment schedule during treatment phase and follow-up to reflect 
schedule of every 12 weeks until radiographic PD or the start of subsequent 
therapy; 


 
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Section # and Name 
Description of Change 
• revised AE collection schedule to reflect continuous nature of this activity and 
added text to reflect that the first 5 participants in each microbiome study 
intervention group (ie, FMT/matching placebo or SER-401/matching placebo) 
will be contacted twice during Cycle 1 (once between Days 2-4 and once on Day 
7 [± 1 day to accommodate weekends or holidays]) to assess for emerging AEs 
that may require early intervention 
Statistical Considerations 
9.5.1 Data Monitoring 
Committee 
Added to text to reflect that it is the responsibility of the Data Monitoring 
Committee (DMC) to adjudicate study-holding criteria per the study-specific DMC 
charter. 
Clarification of Document 
General Revisions 
Document updated to address minor typographical errors and editorial changes for 
clarity. 
Investigator Protocol 
Agreement Page 
Revised as follows: 
• added reference to International Conference on Harmonisation with regard to 
Good Clinical Practices; 
• added bullet addressing requirement to exclude persons who have been debarred 
from conducting or working on clinical studies. 
7.1.1 Temporary 
Discontinuation 
Removed section as it was not applicable to this protocol. 
 
Amendment 2: 08 Jan 2020 
Text revisions resulting from this amendment are incorporated in the synopsis and body of 
Protocol Amendment 2. Major changes to the protocol are summarized below. 
Key Revisions in Amendment 2 
Section # and Name 
Description of Change 
Safety Assessments 
1.3 Schedule of Activities 
4.1 Overall Design 
6.5 Concomitant Therapy 
8.3.1 Time Period and 
Frequency for Collecting 
AE, AESI, SAE, and Other 
Reportable Safety Event 
Information 
8.3.2 Follow-up Event 
Reporting 
Clarified that all adverse events, adverse events of special interest, serious adverse 
events, and concomitant therapies, will now be collected for at least 100 days after 
the last dose of study intervention, instead of at least 90 days. 
1.3 Schedule of Activities 
4.1 Overall Design 
8.2.5 Participant Diary 
8.3 Adverse Events and 
Serious Adverse Events 
Clarified solicited symptoms that are collected on the diary cards, including gas or 
flatulence; abdominal discomfort (distention, bloating, pain or cramping); 
diarrhea; vomiting; constipation, and oral temperature, should be recorded as 
adverse events only if they meet the CTCAE criteria. 


 
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Section # and Name 
Description of Change 
8.3.1 Time Period and 
Frequency for Collecting 
AE, AESI, SAE, and Other 
Reportable Safety Event 
Information 
6.6.4.1 Management of 
Invasive Infections 
7.1.1 Study-wide Hold for 
Specified Safety Events 
Specified which safety events would result in a study-wide hold and will be 
adjudicated by the study Data Monitoring Committee. 
8.3.7 Adverse Events of 
Special Interest 
Identified adverse events of special interest (AESIs) for the trial and clarified that 
serious AESIs will be adjudicated by the Data Monitoring Committee. 
6.6.2 Dose Delays or 
Discontinuations Due to 
Toxicity 
10.6 Contraceptive 
Guidance and Collection of 
Pregnancy Information 
Updated Table 4, Table 6, and Appendix 6 to incorporate current nivolumab 
standards from the manufacturer. 
Study Design 
Synopsis 
3.0 Objectives and 
Endpoints 
9.4.1.2 Secondary 
Endpoints 
9.4.1.3 Exploratory 
Endpoints 
Updated Objectives and Endpoint tables to clarify that progression of disease 
should be documented radiographically and to remove landmark analysis 
timepoints, allowing for greater flexibility of the final survival analysis.  
Synopsis 
1.2 Schema 
1.3 Schedule of Activities 
4.1.1 Cross-over for 
Participants in Group 2 or 3 
4.4 Treatment Beyond 
Disease Progression 
6.3.3 Unblinding 
10.1.4 Informed Consent 
Clarified requirements for participants in Groups 2 and 3 to cross-over to active 
SER-401 and nivolumab as part of Group 5. 
Synopsis 
1.2 Schema 
1.3 Schedule of Activities 
4.1 Overall Design 
4.5 End of Study and End 
of Treatment Definitions 
7.2 Participant 
Discontinuation/Withdrawal 
from Study 
Clarified that individual participants will be active in the study for approximately 
2 years. 
Defined End of Treatment date and End of Treatment visit. 
1.2 Schema 
1.3 Schedule of Activities 
Clarified that the first follow-up visit will occur 100 days after the last dose of 
study intervention to align with standards. 


 
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Section # and Name 
Description of Change 
7.2 Participant 
Discontinuation/Withdrawal 
from Study 
10.6.3 Pregnancy Testing 
6.5.3 Prohibited Therapy 
Clarified that natural remedies may be permitted with Medical Monitor approval. 
Clarified the prohibition of live vaccines during the study. 
Study Population 
Synopsis 
4.1 Overall Design 
5.2 Exclusion Criteria 
Added criterion to allow participants with prior adjuvant anti-PD-1 therapy to 
enter into the study. 
5.1 Inclusion Criteria 
Clarified existing criterion that participants with only one measurable lesion by 
RECIST 1.1 must be discussed with the Medical Monitor prior to enrollment. 
Revised baseline AST and ALT values to < 3 x ULN at study entry. 
5.2 Exclusion Criteria 
Moved existing criterion from inclusion to the exclusion setting to enhance 
grammatical understanding. Continued to allow enrollment of participants who 
have received prior BRAF-targeted therapy and prior anti-CTLA-4. 
Clarified that there are no enrollment restrictions on participants with contrast 
allergies. 
Study Intervention 
1.2 Schema 
1.3 Schedule of Activities 
4.1 Overall Design 
Clarified that the oral FMT and matching placebo will be dispensed at the study 
site.  
1.3 Schedule of Activities 
4.1 Overall Design 
Clarified that participants receiving SER-401 or matching placebo should observe 
at least a 6-hour fast prior to study intervention administration. 
2.2.2 Combination of Oral 
Microbiome and 
Checkpoint Inhibitor 
Therapy 
2.2.3 Background on 
Microbiome Study 
Intervention 
2.3 Benefit/Risk 
Assessment 
4.2 Scientific Rationale 
Updated that the oral FMT used in the study will be from healthy donors whose 
stool has a “favorable” microbiome composition, instead of from donors with a 
response to checkpoint inhibitors.  
2.3 Benefit/Risk 
Assessment 
Updated benefit/risk of nivolumab to include additional approved indications set 
forth by the manufacturer.  
4.1 Overall Design 
Clarified grammar for the administration of SER-401/matching placebo and 
FMT/matching placebo. 
6.6.1 Dose Reductions of 
Study Interventions 
Improved grammar and clarified that no dose escalations or reductions to any 
study intervention are permitted. 
Improved grammar and clarified that no dose modifications for SER-401 or FMT 
are allowed. 


 
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Section # and Name 
Description of Change 
6.6.2 Dose Delays or 
Discontinuations Due to 
Toxicity 
Improved grammar and clarified the circumstances for which dose delays and 
interruptions are allowed. 
Study Assessments and Procedures 
1.3 Schedule of Activities 
4.1 Overall Design 
5.1 Inclusion Criteria 
8.7 Biomarkers 
8.7.3 Exploratory 
Biomarkers 
Added language describing that the on-treatment biopsy should occur ideally from 
the same tumor lesion as the screening biopsy. 
4.4 Treatment Beyond 
Disease Progression 
Improved grammar and clarified the process for treating participants beyond 
disease progression and provided guidance for when treatment should be 
discontinued upon evidence of further progression. 
8.2.5 Participant Diary 
Clarified that the paper diary will be used as a tool to track solicited symptoms, 
not adverse events. 
10.1.4 Informed Consent  
Clarified circumstances when the participant will be asked to complete a new 
informed consent form. 
Clarification of Document 
General Revisions 
Document updated to address minor typographical errors and editorial changes for 
clarity. 
Provided updated references for USPIs, nivolumab immune-mediated adverse 
reactions management guide, and the CTCAE. 
Removed reference to IVRS throughout the document. 
Replaced acronym “SAERF” with “SAE report form” throughout the document. 
Synopsis 
Added table numbers to make navigation easier for the reader. 
8.3.8.1 Emergency Medical 
Contacts 
Updated the study Medical Monitor and contact information 
10.6 Contraceptive 
Guidance and Collection of 
Pregnancy Information 
Updated contraception guidance to align with current manufacturer standards 
 


 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................9 
LIST OF TABLES .........................................................................................................................15 
LIST OF FIGURES .......................................................................................................................15 
1 
PROTOCOL SUMMARY .................................................................................................16 
1.1 
Synopsis .................................................................................................................16 
1.2 
Schema ...................................................................................................................20 
1.3 
Schedule of Activities ............................................................................................23 
2 
INTRODUCTION .............................................................................................................28 
2.1 
Study Rationale ......................................................................................................28 
2.2 
Background ............................................................................................................28 
2.2.1 
Microbiome Modulation ..........................................................................29 
2.2.2 
Combination of Oral Microbiome and Checkpoint Inhibitor Therapy ...30 
2.2.3 
Background on Microbiome Study Intervention .....................................33 
2.2.4 
Background on Nivolumab ......................................................................34 
2.3 
Benefit/Risk Assessment .......................................................................................34 
3 
OBJECTIVES AND ENDPOINTS ...................................................................................38 
4 
STUDY DESIGN...............................................................................................................39 
4.1 
Overall Design .......................................................................................................39 
4.1.1 
Cross-over for Participants on Placebo in Groups 2 or 3 ........................42 
4.2 
Scientific Rationale for Study Design....................................................................42 
4.3 
Justification for Dose .............................................................................................43 
4.3.1 
Rationale for Nivolumab Dose and Schedule .........................................43 
4.3.2 
Rationale for Oral FMT Dose and Schedule ...........................................43 
4.3.3 
Rationale for SER-401 Dose and Schedule .............................................43 
4.4 
Treatment Beyond Disease Progression ................................................................44 
4.5 
End of Study and End of Treatment Definitions ...................................................44 
5 
STUDY POPULATION ....................................................................................................45 
5.1 
Inclusion Criteria ...................................................................................................45 
5.2 
Exclusion Criteria ..................................................................................................46 
5.3 
Lifestyle Considerations ........................................................................................48 


 
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5.4 
Screen Failures .......................................................................................................48 
6 
STUDY INTERVENTION ................................................................................................49 
6.1 
Study Interventions Administered .........................................................................49 
6.2 
Preparation/Handling/Storage/Accountability .......................................................50 
6.3 
Measures to Minimize Bias: Randomization and Blinding ...................................51 
6.3.1 
Intervention Assignment .........................................................................51 
6.3.2 
Blinding ...................................................................................................52 
6.3.3 
Unblinding ...............................................................................................52 
6.4 
Study Intervention Compliance .............................................................................52 
6.5 
Concomitant Therapy.............................................................................................53 
6.5.1 
Permitted Therapy ...................................................................................53 
6.5.2 
Cautionary Therapy .................................................................................53 
6.5.3 
Prohibited Therapy ..................................................................................53 
6.6 
Dose Modifications ................................................................................................54 
6.6.1 
Dose Reductions of Study Intervention ...................................................54 
6.6.2 
Dose Delays or Discontinuations Due to Toxicity ..................................55 
6.6.2.1 
Potential for Overlapping Toxicities with Nivolumab and 
Oral Microbiome Study Intervention ....................................56 
6.6.3 
Dose Modifications for Nivolumab .........................................................57 
6.6.3.1 
Dose Modifications and Toxicity Management for Infusion-
related Reaction Associated with Nivolumab .......................59 
6.6.3.2 
Management of Invasive Infections ......................................62 
6.7 
Intervention After the End of the Study .................................................................62 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..........................................................................62 
7.1 
Discontinuation of Study Intervention ...................................................................62 
7.1.1 
Study-wide Hold for Specified Safety Events .........................................63 
7.2 
Participant Discontinuation/Withdrawal from Study.............................................64 
7.3 
Lost to Follow-up ...................................................................................................64 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................................65 
8.1 
Efficacy Assessments.............................................................................................65 
8.2 
Safety Assessments ................................................................................................66 
8.2.1 
Medical History and Demographic Data .................................................67 


 
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8.2.2 
Physical Examinations .............................................................................67 
8.2.3 
Vital Signs ...............................................................................................67 
8.2.4 
Electrocardiograms ..................................................................................67 
8.2.5 
Participant Diary ......................................................................................68 
8.2.6 
Clinical Safety Laboratory Assessments .................................................68 
8.2.6.1 
Local Laboratory Assessments ..............................................69 
8.3 
Adverse Events and Serious Adverse Events ........................................................69 
8.3.1 
Time Period and Frequency for Collecting AE, AESI, SAE, and Other 
Reportable Safety Event Information ......................................................70 
8.3.1.1 
Events Requiring Expedited Reporting to the Sponsor .........71 
8.3.2 
Follow-up Event Reporting .....................................................................71 
8.3.3 
Method of Eliciting Adverse Event Information .....................................72 
8.3.4 
Regulatory Reporting Requirements for SAEs .......................................72 
8.3.5 
Pregnancy ................................................................................................72 
8.3.6 
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs .......................................................................................73 
8.3.7 
Adverse Events of Special Interest ..........................................................73 
8.3.8 
Sponsor Contact Information ..................................................................74 
8.3.8.1 
Emergency Medical Contacts ................................................74 
8.3.8.2 
Safety Reporting Contacts .....................................................74 
8.4 
Treatment of Overdose ..........................................................................................74 
8.5 
Pharmacokinetics ...................................................................................................75 
8.6 
Anti-drug Antibodies .............................................................................................75 
8.7 
Biomarkers .............................................................................................................75 
8.7.1 
Genetics ...................................................................................................77 
8.7.2 
Enrollment Biomarker .............................................................................77 
8.7.3 
Exploratory Biomarkers ..........................................................................77 
8.7.4 
Sample Collection for Long-term Future Biomedical Research .............78 
8.7.4.1 
Overview of Long-term Future Biomedical Research ..........78 
8.7.4.2 
Sample Collection .................................................................78 
8.7.4.3 
Withdrawal from Long-term Sample Storage .......................79 
8.7.4.4 
Protection of Data Privacy and Data Generation ..................79 
8.8 
Medical Resource Utilization and Health Economics ...........................................79 


 
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9 
STATISTICAL CONSIDERATIONS...............................................................................79 
9.1 
Statistical Hypothesis .............................................................................................79 
9.2 
Sample Size Determination....................................................................................80 
9.3 
Populations for Analysis ........................................................................................80 
9.4 
Statistical Analyses ................................................................................................81 
9.4.1 
Efficacy Analyses ....................................................................................81 
9.4.1.1 
Primary Efficacy Endpoints ..................................................82 
9.4.1.2 
Secondary Efficacy Endpoints ..............................................82 
9.4.1.3 
Exploratory Efficacy Endpoints ............................................82 
9.4.2 
Safety Analyses .......................................................................................83 
9.4.3 
Other Analyses ........................................................................................83 
9.4.3.1 
Biomarker Analyses ..............................................................84 
9.5 
Interim Analyses ....................................................................................................84 
9.5.1 
Data Monitoring Committee ....................................................................84 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....86 
10.1 
Appendix 1: Regulatory, Ethical and Study Oversight Considerations .................86 
10.1.1 
Compliance with Laws and Regulations .................................................86 
10.1.2 
Institutional Review Board or Independent Ethics Committee ...............86 
10.1.3 
Financial Disclosure ................................................................................87 
10.1.4 
Informed Consent ....................................................................................87 
10.1.5 
Data Protection ........................................................................................88 
10.1.6 
Dissemination of Clinical Study Data .....................................................88 
10.1.7 
Administrative Structure .........................................................................89 
10.1.8 
Data Quality Assurance ...........................................................................89 
10.1.9 
Source Documentation ............................................................................89 
10.1.10 Study and Site Closure ............................................................................90 
10.1.11 Site Inspections ........................................................................................91 
10.1.12 Retention of Records ...............................................................................91 
10.1.13 Publication Policy and Protection of Trade Secrets ................................91 
10.2 
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status
................................................................................................................................93 
10.3 
Appendix 3: RECIST Criteria (Version 1.1) .........................................................94 
10.3.1 
Measurability of Tumor at Baseline ........................................................94 


 
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10.3.2 
Tumor Response Evaluation ....................................................................95 
10.3.2.1 
Baseline Documentation of Target and Nontarget Lesions ...95 
10.3.2.2 
Evaluation of Target Lesions .................................................95 
10.3.2.3 
Evaluation of Nontarget Lesions ...........................................96 
10.3.2.4 
New Lesions ..........................................................................96 
10.3.2.5 
Evaluation of Overall Response ............................................96 
10.4 
Appendix 4: Clinical Laboratory Tests ..................................................................98 
10.5 
Appendix 5: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ...................................................................99 
10.5.1 
Definitions ...............................................................................................99 
10.5.1.1 
Definition of AE ....................................................................99 
10.5.1.2 
Definition of SAE ................................................................100 
10.5.1.3 
Definition of Unexpected AE ..............................................101 
10.5.1.4 
Definition of Treatment-emergent AE ................................102 
10.5.2 
Additional Events Reported in the Same Manner as an SAE ...............102 
10.5.3 
Recording AEs and SAEs ......................................................................102 
10.5.4 
Reporting of AEs, AESIs, SAEs, and Other Reportable Safety Events to 
the Sponsor ............................................................................................106 
10.5.5 
Additional Reporting Considerations ....................................................107 
10.6 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy Information
..............................................................................................................................111 
10.6.1 
Definitions .............................................................................................111 
10.6.1.1 
Woman of Childbearing Potential (WOCBP) .....................111 
10.6.2 
Contraception Guidance: .......................................................................111 
10.6.2.1 
Male Participants .................................................................111 
10.6.2.2 
Female Participants .............................................................112 
10.6.3 
Pregnancy Testing .................................................................................113 
10.6.4 
Collection of Pregnancy Information ....................................................114 
10.6.4.1 
Male Participants with Partners who Become Pregnant ......114 
10.6.4.2 
Female Participants who Become Pregnant ........................114 
10.7 
Appendix 7: Genetics ...........................................................................................115 
10.8 
Appendix 8: Participant Diary .............................................................................116 
10.9 
Appendix 9: List of Abbreviations ......................................................................126 


 
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10.10 Appendix 10: Protocol Amendment History .......................................................129 
11 
REFERENCES ................................................................................................................130 
 


 
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LIST OF TABLES 
 
Table 1: 
Schedule of Activities ............................................................................................23 
Table 2: 
Objectives and Corresponding Endpoints ..............................................................38 
Table 3: 
Study Intervention ..................................................................................................49 
Table 4: 
Toxicity Criteria Requiring Permanent Treatment Discontinuation From 
Nivolumab or Microbiome Interventions ..............................................................56 
Table 5: 
Dose Modifications and Toxicity Management Guidelines for Adverse Events 
Specific to Nivolumab ...........................................................................................58 
Table 6:  
Dose Modification and Toxicity Management Guidelines for Infusion-related 
Reaction Associated with Nivolumab ....................................................................60 
Table 7: 
Laboratory Tests Sent to the Study Site Local Laboratory for Analysis ...............69 
Table 8: 
Confidence Intervals for the True Proportion of Responders ................................80 
Table 9: 
Populations for Analysis ........................................................................................80 
Table 10: 
Stopping Rules for Trial-limiting Toxicity Rate Greater Than 30% .....................85 
 
 
LIST OF FIGURES 
 
Figure 1: 
Study Schema.........................................................................................................21 
Figure 2: 
Differential Gut Microbiota in Responders (R) and Non-responders (NR) to Anti-
PD-1 Therapy are Associated with Differential Immune Infiltrates ......................32 
 
 


 
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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Protocol Title:  A Multicenter Phase 1b Randomized, Placebo-controlled, Blinded Study to 
Evaluate the Safety, Tolerability and Efficacy of Microbiome Study Intervention Administration 
in Combination with Anti-PD-1 Therapy in Adult Patients with Unresectable or Metastatic 
Melanoma 
Short Title:  Melanoma Checkpoint and Gut Microbiome Alteration with Microbiome 
Intervention (MCGRAW) 
Rationale: 
This study is designed to evaluate the safety and tolerability of treatment with oral microbiome 
study interventions (fecal microbiota transplant [FMT] or SER-401) or matching placebo in 
combination with anti-programmed cell death 1 (anti-PD-1) therapy (nivolumab) in participants 
with unresectable or metastatic melanoma. The study also intends to assess clinical outcomes, 
the impact of microbiome study intervention administration on the microbiome profile, and its 
association with clinical and immunological outcomes. 
Synopsis Table 1: Key Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
• To determine the safety of microbiome study 
intervention administration with anti-PD-1 therapy. 
• 
Incidence and severity of AEs 
• 
Change from baseline in vital signs, clinical 
laboratory tests, electrocardiograms, and ECOG 
performance status. 
Secondary 
 
• To evaluate the engraftment of FMT and SER-401 
bacteria into the intestinal microbiome community 
in stool samples. 
• To assess the association of microbiome study 
intervention administration with clinical outcomes 
(objective response rate [ORR], disease control rate 
[DCR], progression-free survival [PFS] rate, overall 
survival [OS], and duration of response). 
• To assess the change in percentage of tumoral CD8 
cells in tumor samples in response to anti-PD-1 
therapy with or without microbiome study 
intervention administration. 
• Determination of the engraftment of FMT or 
SER-401 bacteria into each of the microbiome study 
intervention groups relative to placebo. 
• ORR: Defined as CR or PR as best response by 
Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 assessment. Participants who 
do not have RECIST assessment for any reason will 
be counted as not responding. 
• DCR: Defined as CR, PR, or stable disease (SD) for 
≥ 24 weeks as best response by RECIST v1.1. 
Participants who do not have RECIST assessment 
for any reason will be counted as not responding. 
• PFS: Defined as the time from randomization to date 
of first documented radiographic progression of 


 
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Objectives 
Endpoints 
disease or date of death due to any cause, whichever 
occurs first. 
• PFS rate at 1 year: Defined as the proportion of 
participants without documented progression of 
disease or death due to any cause at 1 year. 
• OS: Defined as the time from randomization until 
death due to any cause. 
• OS rate at 1 year: Defined as the proportion of 
participants alive at 1 year. 
• Duration of response: Defined as time from date of 
documented CR or PR to date of first documented 
radiographic progression of disease or date of death 
due to any cause, whichever occurs first. 
• Change in the percentage of CD8 cells in tumor 
tissue from baseline at Cycle 2. 
AE = adverse event; CR = complete response; CTCAE = Common Terminology for Adverse Events; DCR = disease 
control rate; ECOG = Eastern Cooperative Oncology Group; ORR = objective response rate; OS = overall survival; 
PD-1 = programmed cell death-1; PFS = progression-free survival; PR = partial response; RECIST = Response 
Evaluation Criteria in Solid Tumors; SD = stable disease; TOX = trial-limiting toxicities 
 
Overall Design: 
This is a Phase 1b, multicenter, randomized, placebo-controlled, blinded study in adult 
participants with unresectable or metastatic melanoma to evaluate the safety and tolerability of 
FMT, SER-401, or matching placebo in combination with anti-PD-1 therapy (nivolumab). Prior 
to initiating microbiome study intervention and nivolumab, participants will undergo an 
antibiotic or antibiotic placebo treatment lead-in to prime the gut microbiome for engraftment of 
the oral microbiome study intervention. Study intervention groups will be assessed for safety, 
changes in the microbiome, changes in percentage of tumoral CD8 T cells, and antitumor 
activity. Participants must have measurable disease that can be biopsied and consent to baseline 
and on-treatment biopsies, as well as stool and blood biomarker collection throughout the study. 
Participants will be assigned to 1 of the 2 oral microbiome study interventions and randomized 
within each microbiome study intervention to the following groups: 
• FMT: Group 1 (FMT) or Group 2 (FMT matching placebo) 
• SER-401: Group 3 (SER-401 matching placebo) or Group 4 (SER-401) 
 
Participants randomly assigned to receive placebo in Groups 2 or 3 and who have progression of 
disease while on study will be offered the option of receiving active SER-401 and nivolumab 
treatment as part of a cross-over to Group 5.  


 
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Number of Participants: 
Approximately 60 participants will be treated. Since the primary objective is safety, no formal 
power/sample size computation is performed. 
Enrollment caps will be utilized to ensure adequate representation of participants with low (ie, 
“unfavorable”) fecal microbiome composition of the Ruminococcaceae abundance-based metric 
at screening. Each study intervention (FMT or SER-401) will enroll a minimum of 18 
participants (60%) with low Ruminococcaceae (see Section 2.2.2). 
Intervention Groups and Duration: 
Participants will be assigned to 1 of the 2 oral microbiome study interventions (FMT or 
SER-401) by the Investigator based on clinical judgment and availability or feasibility of the 
interventions. Within each microbiome study intervention, participants will be randomized in a 
2:1 ratio to the oral microbiome study intervention or matching placebo. 
Prior to initiating the microbiome study intervention, participants will undergo a 4-day lead-in 
pretreatment with either antibiotic (vancomycin) or antibiotic placebo to prime the gut 
microbiome for engraftment of the oral microbiome study intervention, which will be 
administered following a 2-3 day washout. 
Synopsis Table 2: Antibiotic/Microbiome Study Intervention Lead-in Doses and Schedule 
Group 
Antibiotic/Microbiome 
Study Intervention 
Assignment 
Number of 
Participants 
Antibiotic/Washout/Microbiome Lead-in (Dosing 
Schedule) 
Antibiotic or 
PBO 
(Start Day -14) 
ABX 
Washout 
(Day -10) 
Microbiome Study 
Intervention 
(Day -7) 
1 
Vancomycin/ 
FMT Capsules 
20 
125 mg 
QID x 4 days 
2 (+ 1) 
daysa 
FMT 
10 capsules 
(≥ 109 CFU) 
QOD x 3b 
2c 
Placebo for Antibiotic/ 
FMT Matching Placebo 
10 
ABX PBO 
QID x 4 days 
2 (+ 1) 
daysa 
FMT PBO 
10 capsules 
QOD x 3b 
3c 
Placebo for 
Antibiotic/SER-401 
Matching Placebo 
10 
ABX PBO 
QID x 4 days 
2 (+ 1) 
daysa 
SER-401 PBO 
2 capsules 
QD x 7 
4 
Vancomycin/SER-401 
20 
125 mg 
QID x 4 days 
2 (+ 1) 
daysa 
SER-401 
2 capsules  
(5 x 106 SCFU) 
QD x 7 
ABX = antibiotic; CFU = colony forming units; FMT = fecal microbiota transplant; PBO = placebo; QD = every 
day; QID = 4 times daily; QOD = every other day; SCFU = spore colony forming units 


 
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a The washout duration will be a minimum of 2 days (48 hours), with a window of 1 additional day (24 hours), if 
needed to accommodate scheduling. Microbiome study intervention should be initiated no more than 3 days 
(72 hours) after stopping the antibiotic or antibiotic placebo. 
b FMT or matching placebo will be administered QOD for 3 doses. If needed to accommodate scheduling, no more 
than 1 of the 3 doses may be administered with a window of 1 additional day (ie, dosing interval of up to 3 days 
instead of 2 days). 
c Participants randomly assigned to receive placebo in Groups 2 or 3 and who have radiographic evidence of 
progression of disease while on study will be offered the option of receiving active SER-401 and nivolumab 
treatment as part of a cross-over to Group 5. Participants who agree to this option will follow the 
antibiotic/microbiome study intervention lead-in dose and schedule as shown for Group 4. 
 
The protocol active treatment with anti-PD-1 therapy (nivolumab, 480 mg) will be administered 
intravenously (IV) according to institutional guidelines Q4W for up 12 cycles, unless the 
participant experiences confirmed disease progression or unacceptable toxicity in the judgment 
of the treating physician. A cycle is defined as 4 calendar weeks. Participants will be followed 
for approximately of 2 years from the time of the initiation of study intervention. 
Synopsis Table 3: Microbiome Study Intervention/Anti-PD-1 Doses and Schedules 
Group 
Intervention 
Assignment 
Number of 
Participants 
Microbiome Study Intervention/ 
Anti-PD-1 (Dosing Schedule) 
Anti-PD-1 
(Dosing 
Schedule) 
Microbiome Study 
Interventiona 
Anti-PD-1 
1 
FMT Capsules/ 
Nivolumab 
20 
FMT 
10 capsules 
(≥ 109 CFU) 
QW x 8 weeks 
Nivolumab 
480 mg 
Q4W 
Nivolumab 
480 mg 
Q4W 
2b 
FMT Matching 
Placebo/ Nivolumab 
10 
FMT PBO 
10 capsules 
QW x 8 weeks 
Nivolumab 
480 mg 
Q4W 
Nivolumab 
480 mg 
Q4W 
3b 
SER-401 Matching 
Placebo/ Nivolumab 
10 
SER-401 PBO 
2 capsules 
QD x 8 weeks 
Nivolumab 
480 mg 
Q4W 
Nivolumab 
480 mg 
Q4W 
4 
SER-401/ Nivolumab 
20 
SER-401 
2 capsules 
(5 × 106 SCFU) 
QD x 8 weeks 
Nivolumab 
480 mg 
Q4W 
Nivolumab 
480 mg 
Q4W 
CFU = colony forming units; PBO = placebo; PD-1 = programmed cell death-1; QD = every day; QID = 4 times 
daily; QOD = every other day; QW = every week; Q4W = every 4 weeks; SCFU = spore colony forming units 
a Total duration of microbiome study intervention is 9 weeks (1-week lead-in + 8 weeks with anti-PD-1). 
b Participants randomly assigned to receive placebo in Groups 2 or 3 and who have radiographic evidence of 
progression of disease while on study will be offered the option of receiving active SER-401 and nivolumab 
treatment as part of a cross-over to Group 5. Participants who agree to this option will follow the microbiome 
study intervention/anti-PD-1 dose and schedule as shown for Group 4. 
 


 
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Administration of study intervention will be staggered by at least 1 day for the first 5 participants 
enrolled in each microbiome study intervention group (ie, FMT/matching placebo or 
SER-401/matching placebo) to monitor for safety.  
Data Monitoring Committee: Yes (see Section 9.5.1) 
1.2 
SCHEMA 
The study schema is depicted in Figure 1. 


 
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Figure 1: 
Study Schema 
 
 
ABX = antibiotic (vancomycin); FMT = fecal microbiota transplant; Hx = history; N = number; PBO = placebo; PD-1 = programmed cell death-1 (nivolumab 
[Nivo]); PE = physical exam; QD = every day; QID = 4 times daily; Q3M = every 3 months; QOD = every other day; QW = every week; Q4W = every 4 weeks; 
wks = weeks 
The protocol active treatment phase ends after up to 12 cycles of anti-PD-1 treatment (nivolumab), unless the participant experiences confirmed disease 
progression or unacceptable toxicity in the judgment of the treating physician. A cycle is defined as 4 calendar weeks. Participants will be followed for 
approximately 2 years from the time of the initiation of study intervention. 
FMT requires frozen storage (≤ -65°C). FMT doses will be dispensed for administration at the study site. Participants in Groups 1 and 2 will come to the 
investigative site QOD for 3 doses during Week -1 and weekly for first 8 weeks of administration with nivolumab (Cycles 1 and 2). 
SER-401 requires refrigerated storage (2° to 8°C). The first dose of SER-401 will be dispensed for administration in the clinic; subsequent doses will be self-
administered by the participant at home. Participants in Groups 3, 4, and 5 will receive enough capsules to cover administration until the next clinic visit. 


 
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a The washout duration will be a minimum of 2 days (48 hours), with a window of 1 additional day (24 hours), if needed to accommodate scheduling. 
Microbiome study intervention should be initiated no more than 3 days (72 hours) after stopping the antibiotic or antibiotic placebo. 
b FMT or matching placebo will be administered QOD for 3 doses. If needed to accommodate scheduling, either the second or third dose (but not both), may be 
administered with a window of 1 additional day (ie, dosing interval of up to 3 days instead of 2 days). 
c Participants randomly assigned to receive placebo in Groups 2 or 3 and who have radiographic evidence of progression of disease while on study will be 
offered the option of receiving active SER-401 and nivolumab treatment as part of a cross-over to Group 5. 
 


 
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1.3 
SCHEDULE OF ACTIVITIES 
Table 1: 
Schedule of Activities 
Tests & Procedures 
Pre-Study 
Evaluations 
for 
Screening/ 
Enrollmenta 
On-Treatment Evaluation 
End of 
Treatmentb 
Follow-upc 
ABX/Microbiome 
Lead-in 
Microbiome/ 
Anti-PD-1 Treatment 
Anti-PD-1 
Treatment 
ABX Rx 
and 
Washout 
Microbiome 
Study 
Intervention 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles 
4 – 12 
30 days 
after last 
dose 
First visit 
(100 days 
after last 
dose)c 
Q3M for up to 
2 years from 
initiation of 
study 
interventiond 
Day 
-43 to -15 
-14 
-7 
Day 1 
Day 1 
Day 1 
Day 1 
Window (days) 
 
Refer to footnote m 
± 1 
± 3 
± 3 
± 3 
+ 5 
 
± 14 
Informed consente 
X 
 
 
 
 
 
 
 
 
 
Review of I/E criteria 
X 
 
 
 
 
 
 
 
 
 
Medical, cancer history 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Pregnancy test (serum or 
urine) 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs (see Section 
8.2.3) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology (see Table 7) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry (see 
Table 7) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
 
X 
 
X 
 
 
 
 
cfDNA (blood)f 
X 
 
 
 
X 
 
Xf 
X 
 
 
Circulating soluble 
analytesg 
X 
 
X 
X 
X 
X 
Xg 
X 
 
 
Blood immune biomarkersg 
X 
 
X 
X 
X 
X 
Xg 
X 
 
 


 
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Tests & Procedures 
Pre-Study 
Evaluations 
for 
Screening/ 
Enrollmenta 
On-Treatment Evaluation 
End of 
Treatmentb 
Follow-upc 
ABX/Microbiome 
Lead-in 
Microbiome/ 
Anti-PD-1 Treatment 
Anti-PD-1 
Treatment 
ABX Rx 
and 
Washout 
Microbiome 
Study 
Intervention 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles 
4 – 12 
30 days 
after last 
dose 
First visit 
(100 days 
after last 
dose)c 
Q3M for up to 
2 years from 
initiation of 
study 
interventiond 
Day 
-43 to -15 
-14 
-7 
Day 1 
Day 1 
Day 1 
Day 1 
Window (days) 
 
Refer to footnote m 
± 1 
± 3 
± 3 
± 3 
+ 5 
 
± 14 
Stool collection 
Xh 
Xi (to be collected 
following completion of 
ABX or ABX placebo 
and prior to starting 
microbiome study 
intervention) 
Xh 
(Day 1 
and 
Day 8) 
X 
X 
Xh 
(Cycle 4 
and 
Cycle 7) 
Xh 
 
 
Tumor biopsyi 
X 
 
 
 
X 
(Cycle 2, 
Days 2-12) 
 
 
Xi (at PD) 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
All AEs, AESIs, and SAEs will be collected for at least 100 days after the last dose of study intervention.b,j 
The first 5 participants enrolled in each microbiome study intervention group (ie, FMT/matching placebo or 
SER-401/matching placebo) will be contacted twice during Cycle 1 (once between Days 2-4 and once on Day 7 
[± 1 day to accommodate weekends or holidays]) to assess for emerging AEs that may require early intervention. 
 
Randomization 
 
Xk 
 
 
 
 
 
 
 
 
Participant-reported diary 
for: 
• solicited symptoms 
• recording body 
temperature 
• tracking study 
intervention compliance 
 
Participants will: 
• record safety events commonly associated with 
microbiome study intervention on a daily basis 
from Day -7 through the end of Cycle 1 
• measure and record body temperature on a daily 
basis from Day -7 through Day 1 
• track compliance to the self-administered oral 
antibiotic and SER-401 from Day -14 through 
the end of Cycle 2 
 
 
 
 
 
Collection of participant-
reported diaryl 
 
X 
X 
X 
X 
X 
 
 
 
 


 
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Tests & Procedures 
Pre-Study 
Evaluations 
for 
Screening/ 
Enrollmenta 
On-Treatment Evaluation 
End of 
Treatmentb 
Follow-upc 
ABX/Microbiome 
Lead-in 
Microbiome/ 
Anti-PD-1 Treatment 
Anti-PD-1 
Treatment 
ABX Rx 
and 
Washout 
Microbiome 
Study 
Intervention 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles 
4 – 12 
30 days 
after last 
dose 
First visit 
(100 days 
after last 
dose)c 
Q3M for up to 
2 years from 
initiation of 
study 
interventiond 
Day 
-43 to -15 
-14 
-7 
Day 1 
Day 1 
Day 1 
Day 1 
Window (days) 
 
Refer to footnote m 
± 1 
± 3 
± 3 
± 3 
+ 5 
 
± 14 
Oral vancomycin/placebo 
pretreatmentm  
 
X 
 
 
 
 
 
 
 
 
Oral microbiome 
administration (based on 
randomization) 
 
 
 
 
 
 
 
 
 
 
Groups 1 and 2: 
FMT capsules or 
matching placebon 
 
 
QOD x 
3 dosesn 
QW x 8 weeks 
(ie, Cycles 1 and 2) 
 
 
 
 
 
Groups 3 and 4 (and 5): 
SER-401 or SER-401 
matching placeboo 
 
 
QD x 
7 doses 
QD x 8 weeks 
(ie, Cycles 1 and 2) 
 
 
 
 
 
Nivolumab administrationp 
 
 
 
X 
X 
X 
X 
 
 
 
Disease assessmentq 
X 
(Day -29 to 
Day -15) 
 
 
Repeat every 12 weeks (± 1 week) from Cycle 1, Day 1 
until radiographic PD or the start of subsequent therapy 
Follow-up for overall 
survival 
 
 
 
 
 
 
 
 
X 
X 
ABX = antibiotic; AE(s) = adverse event(s); AESI(s) = adverse event(s) of special interest; cfDNA = cell-free deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; ED = early discontinuation; EOT = end of treatment; FMT = fecal microbiota transplant; I/E = inclusion/exclusion; LDH = lactate dehydrogenase; 
PD = progressive disease; PD-1 = programmed cell death-1; QD = every day; QID = 4 times daily; Q3M = every 3 months; QOD = every other day; QW = every week; 
Q4W = every 4 weeks; SAE(s) = serious adverse event(s) 
a Tests/procedures performed as standard of care prior to obtaining informed consent and within 28 days prior to randomization do not have to be repeated at screening. 
b The End of Treatment Visit will be completed following the last dose of study intervention (ie, after 12 cycles of study intervention or at early discontinuation). All participants, 
including those who discontinue early after receiving any study intervention, should have the End of Treatment visit to complete the visit procedures. The visit at which disease 
assessment shows progressive disease may be used as the End of Treatment visit if it occurs 30 (+5) days after the last dose of nivolumab. Every effort should be made to 
complete the visit within the 30 (+5) day window; however, the visit should be conducted even if outside the window. Participants who have received any microbiome study 
intervention should continue to be followed for SAEs and AESIs up to 26 weeks after the last dose of microbiome study intervention (see Section 8.3.1). 


 
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c At least one hundred (100) days after the last dose there is a visit with assessments if no alternative therapy has started (continued administration of monotherapy nivolumab 
beyond the 12 cycles administered in this clinical trial will not be considered alternative therapy). If the participant has started alternative therapy within that 100 days after the 
last dose, the first follow up visit will be contact by telephone only. AEs, concomitant medications, or other assessments are reported up to the date of start of alternative therapy. 
d For approximately 2 years from the initiation of study intervention, participants will be contacted by telephone every 3 months to determine their survival status. 
e Participants randomly assigned to receive placebo in Groups 2 or 3 and who have radiographic evidence of progression of disease while on study will be offered the option of 
receiving active SER-401 and nivolumab treatment as part of a cross-over to Group 5. Participants who agree to this option will provide informed consent and will enter 
Group 5. 
f cfDNA (blood) will be assessed at screening, Cycle 2 Day 1, Cycle 4 Day 1, and EOT. 
g Circulating soluble analytes and blood immune biomarkers will be assessed at screening, Microbiome Lead-in (Day -7), Cycle 1 Day 1, Cycles 2-4 Day 1, and EOT. 
h Stool will be collected at screening for assessment of the fecal microbiome composition of the Ruminococcaceae abundance-based metric for stratification and other microbiome 
assessments. A second screening collection will be allowed if the results of the initial screening collection are indeterminate. Following randomization, stool will be collected 
with a window of up to 2 days prior to the following timepoints, when feasible: start of microbiome study intervention (ie, collected after completion of ABX or ABX placebo 
and prior to the start microbiome study intervention) and Cycle 1 Day 1 (ie, 7 days after start of microbiome study intervention). Thereafter, stool will be collected with a 
window of ± 3 days of the following timepoints, when feasible: Cycle 1 Day 8 (ie, 7 days after first dose of nivolumab); Cycle 2 Day 1; Cycle 3 Day 1; Cycle 4 Day 1 (ie, 4 
weeks after last dose of microbiome study intervention); Cycle 7 Day 1; and at EOT. 
i Participants will undergo 2-3 tumor biopsies: prior to beginning any protocol therapy including antibiotic treatment (ie, baseline biopsy, mandatory), and during treatment (ie, 
on-treatment biopsy during Cycle 2, if medically feasible). On-treatment biopsy should occur as early as possible after the second dose of nivolumab (ie, Cycle 2, Day 2 – 
Day 12); however, any on-treatment biopsy after Day 1 of Cycle 2 will be accepted. An optional biopsy may be obtained during the course of the study or at the time of disease 
progression, including  from participants who respond and subsequently progress. 
j All SAEs will be collected from the time the participant signs informed consent. All AEs, including AESIs, will be collected from the start of study intervention.  
k Randomization occurs prior to ABX administration. 
l Participants will be asked to bring the participant diary to each clinical visit so that the clinical staff can record the compliance and safety information on an ongoing basis. 
m Four days of oral QID vancomycin (125 mg) or placebo pretreatment, which can be self-administered at home, followed by a washout prior to starting microbiome study 
intervention. The washout duration will be a minimum of 2 days (48 hours), with a window of 1 additional day (24 hours), if needed to accommodate scheduling. Microbiome 
study intervention should be initiated no more than 3 days (72 hours) after stopping the antibiotic or antibiotic placebo. 
n The first dose of FMT or matching placebo will be administered in the clinic and will be followed by a 1-hour observation period after dosing. The participant should have 
nothing by mouth for 4 hours prior to and 45 minutes following FMT administration. Subsequent doses of FMT or matching placebo will be dispensed for administration at the 
study site. FMT or matching placebo will be administered QOD for 3 doses for the first week. If needed to accommodate scheduling, no more than 1 of the 3 doses may be 
administered with a window of 1 additional day (ie, dosing interval of up to 3 days instead of 2 days). Tests and procedures as indicated are required at the time of the first dose 
(Day -7) only and do not need to be repeated at the visits for the second and third doses. Starting on Cycle 1 Day 1, FMT or matching placebo will be administered QW for 8 
weeks.  
o The first dose of SER-401 or matching placebo will be administered in the clinic and will be followed by a 1-hour observation period after dosing. SER-401 should be taken at 
approximately the same time on each day. The participant should observe an overnight or at least a 6-hour fast (no food or drink except for small amounts of water) prior to 
SER-401 administration. Subsequent doses of SER-401 or matching placebo will be dispensed to the participant for self-administration QD at home. Compliance will be 
recorded on the participant-reported diary.  
p Nivolumab will be administered at a dose of 480 mg IV over 30 minutes Q4W starting on Day 1 of Cycle 1 and will continue for up to 12 cycles, unless the participant 
experiences confirmed disease progression or unacceptable toxicity in the judgment of the treating physician. A cycle is defined as 4 calendar weeks. The time between 
nivolumab doses should not be less than 25 days. 


 
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q Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to randomization do not have to be repeated at screening. Tumor 
assessments should be performed every 12 weeks until radiographic PD or the start of subsequent therapy.  
 


 
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2 
INTRODUCTION 
2.1 
STUDY RATIONALE 
This study is designed to evaluate the safety and tolerability of treatment with oral microbiome 
study interventions (fecal microbiota transplant [FMT] or SER-401) or matching placebo in 
combination with anti-programmed cell death 1 (anti-PD-1) therapy (nivolumab) in participants 
with unresectable or metastatic melanoma. The study also intends to assess clinical outcomes, 
the impact of microbiome study intervention administration on the microbiome profile, and its 
association with clinical and immunological outcomes. 
2.2 
BACKGROUND 
Melanoma is a deadly form of skin cancer with an incidence that is rising rapidly (Tripp et al., 
2016). It was estimated that 80,000 patients would be diagnosed with melanoma in 2017 in the 
United States, with over 10,000 patients dying of metastatic disease (Siegel et al., 2017). 
Melanoma disproportionately causes a significant number of life years lost per cancer-related 
death, resulting in substantial financial burden (US $3.5 billion per year) (Ekwueme et al., 2011). 
Historically, < 10% of patients with stage IV melanoma achieve long-term (> 5 years) survival 
(Balch et al., 2010). 
Four immune checkpoint inhibitor (CPI) monotherapy or combination regimens, each of which 
can produce long-term clinical benefit, have been approved since 2011 for the treatment of 
patients with stage IV melanoma. Ipilimumab, a humanized antibody that blocks cytotoxic T-
lymphocyte-associated protein 4 (CTLA-4) on the surface of T cells, approved in 2011, achieves 
clinical responses in ~10% of patients, but results in 3 year overall survival (OS) rates of ~22% 
with many durable responses (Hodi et al., 2010; Balch et al., 2010; Schadendorf et al., 2015). 
Nivolumab and pembrolizumab, approved in 2014, are antibodies against PD-1 on the surface of 
T cells; both achieve clinical responses in 35-45% of treatment-naïve patients, with most 
responses lasting >2 years (Hodi et al., 2010; Ribas et al., 2016). Importantly, high-grade toxicity 
rates are much lower for the more active anti-PD-1 therapies (8%) compared with ipilimumab 
(27%) (Robert et al., 2015a). While the results with single-agent anti-PD-1 therapy are 
impressive, combined treatment with ipilimumab and nivolumab (FDA-approved 2015) produces 
clinical responses in 55-60% of metastatic melanoma patients (Ribas et al., 2017; Larkin et al., 
2015). The increased activity of ipilimumab/nivolumab, however, is accompanied by increased 
side effects; 55% of patients experience significant toxicities, some long lasting or lethal, and 
~30% of patients have to stop treatment due to toxicity. Thus, there is a critical need to develop 
new approaches that are safer, and which may also overcome resistance in patients who fail this 
treatment. 


 
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2.2.1 
Microbiome Modulation 
The microbiome is the collection of microbes – bacteria, viruses and fungi – that live on and in 
the human body. The composition of the gut microbiome has received particular scientific 
attention due to its correlation with various disease processes. Our understanding of the bacterial 
component of the gut microbiome in particular has been advanced in the last decade due to the 
use of next generation sequencing to elucidate the complex and variable ecology of commensal 
species and pathobionts (commensal species that, under certain circumstances can play a role in 
disease). The gut microbiome is thought to play a role in health in the following broad ways:  
promoting resistance to colonization and infection by pathogenic bacteria; educating and 
regulating the immune system; maintaining gut epithelial barrier integrity; modulating host 
metabolism; and potentially altering the function of the central nervous system (Lynch and 
Pedersen, 2016). 
Fecal microbiota transplant (FMT) is a procedure where minimally processed stool is transferred 
from a donor to a person with disease. FMT can be administered via oral capsules (Youngster et 
al., 2016), nasogastric or nasoduodenal tube, colonoscopy or enema. FMT has been shown to 
prevent recurrence of Clostridium difficile infection (CDI), and reported rates of efficacy vary 
from 50% to 90+%. However, the largest blinded, randomized, placebo-controlled study using 
enema delivery suggested prevention of recurrence in 63.9% of subjects receiving FMT 
compared to 45.5% for placebo (p = 0.046, Dubberke et al., 2016). The other indication in which 
FMT has shown efficacy in blinded, randomized, placebo-controlled setting is active, mild-to-
moderate ulcerative colitis with remission rates of ~20% above placebo (Moayyedi et al., 2015; 
Paramsothy et al., 2017). Unlike CDI, efficacy in treating active ulcerative colitis requires 
repetitive FMT, for instance weekly or daily over a 6-8 week period. FMT is generally regarded 
as well tolerated with adverse events (AEs) limited to nausea, vomiting, fever, abdominal pain, 
and diarrhea (Vermeire et al., 2016; Pigneur and Sokol, 2016). While FMT has been evaluated in 
other disease conditions, there is as yet no compelling evidence for clinical utility for indications 
other than CDI. 
The activity of repetitive FMT in the setting of ulcerative colitis demonstrates the causal 
relationship between microbiome composition and immune tone. In animal models and studies in 
human cohorts, bacterial genera such as Bacteroides, Clostridium, and Faecalibacterium have 
been reported to modulate antitumor immunity via expansion of T-regulatory cells, activation of 
dendritic cells or secretion of anti-inflammatory cytokines (Gopalakrishnan et al., 2018, Sivan et 
al., 2015; Routy et al., 2018; Matson et al., 2018). The link between gut microbiota composition 
and immune state has prompted an evaluation in cancer and particularly, in regard to treatment 
with immunotherapy such as CPI (NCT03353402; NCT03341143; NCT03637803).  


 
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SER-401 is a spore preparation made from the stool of a healthy donor whose fecal microbiome 
embodies characteristics of the “favorable” microbiome profile identified by Gopalakrishnan et 
al. (Gopalakrishnan et al., 2018) as discussed in Section 2.2.3. Spore preparations from healthy 
donors that embody characteristics of the “favorable” microbiome have been shown to be 
efficacious in improving response to anti-PD-1 treatment in several mouse models of cancer 
(SER-TSC-18-002 Report, 2018; SER-TSC-18-003 Report, 2018; SER-TSC-18-006 Report, 
2018). 
2.2.2 
Combination of Oral Microbiome and Checkpoint Inhibitor 
Therapy 
Despite the impressive benefits of single-agent CPI in patients with Stage IV melanoma, less 
than 10% of patients achieve complete response to therapy (Robert et al., 2015a; Robert et al., 
2015b; Ribas et al., 2016). While CPI is now standard-of-care for the treatment of advanced 
metastatic melanoma patients, there is a global effort to improve response to these therapies in 
order to extend this benefit to the majority of patients, most of whom will die as a result of their 
cancer. 
The microbiome of metastatic melanoma patients prior to treatment with anti-PD-1 monoclonal 
antibody has been studied by investigators at the University of Texas MD Anderson Cancer 
Center (MDACC). These findings, which were recently published (Gopalakrishnan et al., 2018), 
demonstrate that the pretreatment composition of the fecal microbiome in patients who respond 
to anti-PD-1 therapy (responder [R]) has a distinct bacterial signature compared to patients who 
do not respond to anti-PD-1 therapy (non-responder [NR]). Specifically, higher alpha-diversity 
(ie, a higher number of different species) and relative abundance of the bacterial genus 
Faecalibacterium (within the order Clostridiales and Family Ruminococcaceae) was associated 
with better treatment response and prolonged progression-free survival (PFS) (Figure 2A-C). 
Conversely, lower alpha-diversity and higher abundance of the bacterial order Bacteriodales was 
associated with lack of treatment response and shorter PFS (Figure 2A-B, D). The bacterial 
signature in patients who achieved a response to anti-PD-1 treatment was also associated with a 
more favorable tumor immune profile in a subset of melanoma patients with available tumor 
samples (Figure 2E-F). Analysis of the stool microbiome and clinical response to anti-PD-1 
treatment from an additional cohort of metastatic melanoma patients also supported the use of a 
Ruminococcaceae abundance-based metric (unpublished data). Across the Gopalakrishnan study 
(43 patients), the additional cohort (69 patients), and the combined dataset (112 melanoma 
patients), Ruminococcaceae family abundance, and the higher order taxa containing 
Ruminococcaceae, were the only common statistically significant enrichment in Responders vs 
Non-responders.  


 
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In order to evaluate causality in a preclinical model, the MDACC team transplanted the fecal 
microbiota (FMT) from human melanoma patients who either responded to CPI (Rs) or failed to 
respond to CPI (NRs) into germ free mice via oral gavage. After several weeks for microbiome 
equilibration, syngeneic murine tumors were implanted, and mice were treated with CPI 
(anti-programmed cell death ligand 1 [PD-L1] antibody). Mice who received FMT from R 
patients experienced a significantly lower tumor burden and improved responses to PD-L1-based 
therapy compared to mice who received NR FMT (n = 6, Figure 2G). The differences in tumor 
size (expressed as a fold change relative to control) were computed using the Mann-Whitney test 
(p < 0.01). Fecal microbiota transplant alone was not evaluated in these preclinical studies as it 
has been reported to have minimal antitumor activity as a single agent treatment (Matson et al., 
2018). 


 
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Figure 2: 
Differential Gut Microbiota in Responders (R) and Non-responders (NR) to 
Anti-PD-1 Therapy are Associated with Differential Immune Infiltrates 
 
A) Linear discriminant analysis (LDA) scores computed for differentially-abundant taxa in the fecal 
microbiomes of R (blue) and NR (red). Length indicates effect size associated with a taxon. p=0.05 for the 
Kruskal-Wallis test; LDA score > 3. B) Taxonomic cladogram from LEfSe showing differences in fecal 
taxa. Dot size is proportional to the abundance of the taxon. Letters correspond to the following taxa: (a) 
Gardnerella vaginalis (b) Gardnerella (c) Rothia (d) Micrococcaceae (e) Collinsella stercoris (f) 
Bacteroides mediterraneensis (g) Porphyromonas pasteri (h) Prevotella histicola (i) Faecalibacterium 
prausnitzii (j) Faecalibacterium (k) Clostridium hungatei (l) Ruminococcus bromii (m) Ruminococcaceae 
(n) Phascolarctobacterium faecium (o) Phascolarctobacterium (p) Veilonellaceae (q) Peptoniphilus (r) 
Desulfovbrio alaskensis. Comparison Kaplan Meier (KM) PFS curves by long-rank test in patients with C) 
high (dark blue, n=19, median PFS=undefined) or low (light blue, n=20, median PFS=242 days) abundance 
of Faecalibacterium (top) or D) high (dark red, n=20, median PFS=188 days) or low (light red, n=19, 
median PFS=393 days) abundance of Bacteroidales (bottom). E) Pairwise Spearman rank correlation 
heatmap of significantly different taxa in fecal samples (n=15) at baseline and CD3, CD8, PD-1, FoxP3, 
GzmB and RORγT density and PD-L1 by H-score in matched tumors. (F) Representative multiplex IHC 


 
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images and (G) Difference in size by MW test of tumors at day 14, implanted in R-FMT (blue) and NR-
FMT mice (red) expressed as fold change (FC) relative to average tumor volume of Control GF mice. Data 
from 2 independent FMT experiments (R-FMT, n=5, median FC=0.18; NR-FMT, n=6, median FC=1.52).  
 
Based on these analyses, healthy donors whose stool has a “favorable” microbiome composition 
of high Ruminococcaceae, similar to that of melanoma patients who achieved a response to anti-
PD-1 treatment, will be enrolled in a stool donor collection protocol for the oral FMT 
manufacturing to be used in this study. Ruminococcaceae abundance for an “unfavorable” 
microbiome will be used as a stratification metric for this study. 
2.2.3 
Background on Microbiome Study Intervention 
Support for the use of microbiome study intervention is provided in Section 2.2.1. 
Two investigational microbiome products will be used in this program. The FMT investigational 
product will be collected and processed from qualified healthy donors according to established 
FMT procedures described by Massachusetts General Hospital (MGH) Investigational New Drug 
(IND) 16011. The FMT will be delivered in capsule form. This group is intended to test the 
safety of an intervention whose composition is enriched in the family Ruminococcaceae that is 
characterized as a “favorable” microbiome (Gopalakrishnan et al., 2018). By virtue of possessing 
spore formers and non-spore formers, the FMT investigational product represents a broader set 
of bacterial taxa. It will be administered at a dose and regimen consistent with a prior study of 
FMT in chronic disease settings (NCT02530385). 
SER-401 is an investigational product containing microbial spores purified from the stool of 
qualified healthy donors and delivered in capsule form. This group is intended to test the safety 
of an intervention whose composition is enriched in spore-forming members of the family 
Ruminococcaceae that is characterized as a “favorable” microbiome (Gopalakrishnan et al., 
2018). It will be administered at a dose and regimen similar to that used in prior studies of spore-
based products for the treatment of active mild-to-moderate ulcerative colitis (NCT02618187). 
The study design, evaluating FMT and SER-401 in the same clinical study, provides the 
opportunity to define how the participant’s microbiome influences CPI therapy outcomes by 
including a wide range of bacterial species from 2 microbiologically-diverse investigational drug 
products. The aim of this clinical study is to determine: 
(1) safety and tolerability of each study intervention group (microbiome study interventions 
or matched placebo, each combined with anti-PD-1 therapy). 
(2) whether microbiome administration increases the percentage of tumoral CD8 cells and 
enhances response to anti-PD-1 therapy as determined by clinical endpoints of ORR, 
DCR, PFS, and OS; and if so, 


 
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(3) the changes in the fecal microbiome as a result of administration of microbiome study 
intervention, and, in an exploratory setting, to identify species and metabolites that 
correlate with clinical and immunological outcomes. 
 
2.2.4 
Background on Nivolumab 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 
receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated 
inhibition of the immune response, including the antitumor immune response. Opdivo® 
(nivolumab) is approved in the US for the treatment of several cancer types, including 
unresectable or metastatic melanoma (as monotherapy or in combination with ipilimumab) and 
as monotherapy in previously-treated metastatic non-small cell lung cancer (NSCLC), advanced 
renal cell carcinoma (RCC), relapsed or refractory classical Hodgkin lymphoma (cHL), locally 
advanced or metastatic urothelial carcinoma; recurrent or metastatic squamous cell carcinoma of 
the head and neck (SCCHN), microsatellite instability-high (MSI-H) or mismatch repair 
deficient (dMMR) metastatic colorectal cancer (CRC), and hepatocellular carcinoma (HCC). 
Refer to the approved prescribing information (Opdivo USPI, 2019) for detailed background 
information on nivolumab. 
2.3 
BENEFIT/RISK ASSESSMENT 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types, including NSCLC, melanoma, RCC, cHL, small cell lung cancer, SCCHN, 
urothelial cancer, HCC, and MSI-H or dMMR CRC. In confirmatory trials, nivolumab 
demonstrated a statistically significant improvement in OS as compared with the current standard 
of care in subjects with unresectable or metastatic melanoma, advanced or metastatic NSCLC, 
advanced RCC, or SCCHN. 
The safety profile of nivolumab monotherapy is similar across tumor types. There is no pattern in 
the incidence, severity, or causality of AEs to nivolumab dose level. In Phase 3 controlled 
studies, the safety profile of nivolumab monotherapy is acceptable in the context of the observed 
clinical efficacy, and manageable using established safety guidelines. Clinically relevant AEs 
typical of stimulation of the immune system were infrequent and manageable by delaying or 
stopping nivolumab treatment and timely immunosuppressive therapy or other supportive care 
(Opdivo USPI, 2019). 
Overall, these findings support a favorable benefit-risk profile for nivolumab across various 
tumor types. More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of nivolumab may be found in the prescribing information (Opdivo 
USPI, 2019). 


 
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Fecal microbiota transplantation (FMT) has emerged as an important tool for investigating the 
role of the microbiome in humans. FMT is most commonly used for preventing Clostridium 
difficile recurrence in patients with multiple recurrent infections and is considered standard of 
care (McDonald et al., 2018). Due to its reported safety profile (see below), the experimental use 
of FMT has expanded to include indications as diverse as inflammatory bowel disease (IBD), 
hepatic encephalopathy, autism spectrum disorder, metabolic syndrome and Parkinson’s disease 
(reviewed in Choi and Cho, 2016). Indeed, there are now studies in patients with refractory 
melanoma evaluating FMT derived from stool donor(s) who were responders to CPI treatment 
(NCT03353402) or FMT derived from stool donors who were complete responders to CPI in 
combination with anti-PD-1 treatment (NCT03341143). A third study is evaluating microbiome 
drug product in combination with anti-PD-1 treatment in patients with solid tumors 
(NCT03637803).  
Short-term reported adverse events following FMT include abdominal discomfort, bloating, 
flatulence, diarrhea, vomiting, fever, and constipation (Choi and Cho, 2016). IBD flares have 
been reported in patients with a history of IBD in multiple studies, including those not being 
actively treated for IBD (Qazi et al., 2017). Procedural complications, including perforations and 
bleeding following endoscopy or pulmonary aspiration following naso-duodenal administration, 
have also been reported (Choi and Cho, 2016). The long-term evaluation of FMT safety has been 
limited since most CDI studies are IND-exempt and conducted by individual investigators or 
physicians. Potential serious adverse events (SAEs) include infection by undetected or 
unscreened enteric pathogens (bacteria, viruses, fungi and protists) present in the FMT product 
(Wang et al., 2016), and mortality (Lee et al., 2016; Dubberke et al., 2018). In addition to the risk 
of transfer of infectious agents, additional potential concerns include increased frequency of 
metabolic disorders such as diabetes, obesity or liver disease including non-alcoholic 
steatohepatitis, irritable bowel syndrome (IBS), immunological/inflammatory disorders such as 
IBD, asthma and autoimmune conditions. Most of these long-term concerns have not been 
reported but have a scientific basis due to the association of the microbiome in humans with 
many of these diseases. There is one case report suggesting the transmission of obesity from 
stool donor to the FMT patient in the setting of CDI (Alang and Kelley, 2015).  
Several studies have shown that following FMT delivered via colonoscopy or enema, the 
recipient microbiome changes within days and tends to be more similar to the donor than the pre-
FMT baseline (Hamilton et al., 2013; Weingarden et al., 2015; Khanna et al., 2017). There can 
be variation in the recipient’s microbiome composition over time. The donor-recipient similarity 
is strongest immediately following FMT; as time progresses, the patient tends to diverge from 
the donor microbiome profile, and the patient’s microbiome assumes a unique composition, 
distinct from either the donor or the starting state post-antibiotics (Hamilton et al., 2013; 
Weingarden et al., 2015; Khanna et al., 2017). 


 
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Frozen oral formulations of FMT have been reported in the literature for patients with recurrent 
CDI (Youngster et al., 2016). Participants with CDI received a regimen of 15 FMT capsules 
orally per day for 2 days. Resolution of diarrhea was observed in 14/20 (70%) patients after a 
single regimen with no serious adverse events attributed to the treatment. Of the 6 non-
responders, 4 responded to a subsequent treatment (Youngster et al., 2016), demonstrating that 
oral administration of frozen FMT capsules can be effective in the treatment of CDI and 
restructures the gut microbiome. 
SER-401 is a purified suspension of Firmicute spores derived from a donor whose microbiome 
meets the Ruminococcaceae metric characterized as favorable (Gopalakrishnan et al., 2018). 
While SER-401 has not been evaluated in humans, related donor-derived spore products, 
SER-109 and SER-287, have been evaluated in clinical studies in subjects with recurrent CDI 
and ulcerative colitis ([UC]; NCT02437487; NCT02618187) at a dose of 1 x 108 SporQs (“spore 
equivalents”, a biochemical measure of spore content equivalent to approximately 1 x 107 spore 
colony-forming units [SCFUs]) in 1 or 2 doses (SER-109) or a weekly or daily dose for up to 
8 weeks (SER-287). 
Subjects with multiply recurrent CDI or with mild-to-moderate UC may differ from individuals 
considering a study of SER-401. In Seres’ studies of SER-109, the average age of subjects who 
received SER-109 was ~ 65 years, whereas in studies with SER-287, the average age of subjects 
was 47 years. This difference may influence the AEs that may be anticipated in subjects 
administered SER-401. 
In 3 completed clinical studies (SERES-001, SERES-004, and SERES-005) a total of 141 
subjects received 1 or 2 doses of SER-109. The available safety data from these 3 studies, 
including 2 open-label studies and 1 placebo-controlled study, suggest that SER-109 is safe and 
well-tolerated in subjects with multiply recurrent CDI, although in these subjects SER-109 is 
associated with a slight increase in gastrointestinal (GI) AEs, particularly diarrhea, compared 
with placebo (25% vs. 14%, respectively). 
Across completed studies of SER-109 as of April 19, 2017, 87% of the subjects (123/141) who 
had received 1 or 2 doses of SER-109 had experienced at least one AE. Most adverse events 
were mild to moderate in intensity, and the most common events (ie, incidence ≥ 5% in either 
study) were GI disorders. Overall, 24% (34/141) of subjects had an AE reported to be related to 
SER-109 (ie, probably or likely due to SER-109). In total, 15% of subjects who had received 
SER-109 (21/141) had experienced at least 1 SAE; however, no SAEs were reported to be 
related to SER-109. There have been 6 deaths in subjects who received SER-109, all of which 
were unrelated to SER-109 and 1 of which occurred after the subject left the study. 
Clinical experience with SER-287 includes a completed Phase 1b study (SERES-101), a 
multicenter, randomized, double-blind, placebo-controlled, multiple dose study that evaluated 


 
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the safety and tolerability of SER-287, in addition to the microbiome alterations and 
pharmacodynamics associated with 2 dosing regimens of SER-287 in adult subjects with active 
mild-to-moderate UC. The study enrolled a total of 58 subjects who were randomized into 1 of 4 
treatment groups; endpoints were assessed following a 6-day pretreatment period (vancomycin 
or placebo) followed by an 8-week induction treatment period (SER-287 or matching placebo). 
This regimen is similar to the proposed use of SER-401. 
As of September 19, 2017, safety information was available for all subjects who were followed 
for up to 92 days (11.5 weeks), including subjects who withdrew from the study at an earlier 
time point. Forty-seven subjects received SER-287; 15 subjects received daily SER-287 and 32 
subjects received weekly SER-287. The available safety data from this study suggest that SER-
287 is safe and well-tolerated in subjects with UC, with a safety profile similar to placebo. 
Among the 47 subjects who received SER-287:  
• Overall, there were a total of 91 treatment-emergent adverse events (TEAEs) reported in 
subjects who received SER-287; all were considered to be mild to moderate in intensity. 
A total of 66% of subjects (31/47) who received SER-287 experienced at least 1 TEAE. 
• 27.7% of subjects (13/47) had a least 1 TEAE reported to be related to SER-287, the most 
common being abdominal pain (8.5% compared with 0% in the placebo group) and 
diarrhea (6.4% compared with 9.1% in the placebo group).  
• There was one SAE (worsening depression in a subject with a history of depression), 
which was considered not to be related to study drug by the investigator. 
• There were no deaths in the study. 
 
One of the primary objectives of the SER-287 Phase 1b UC trial was to determine the 
engraftment of SER-287 bacteria in each of the treatment groups relative to placebo. The data 
support oral administration of a spore-based microbiome drug product following vancomycin 
pretreatment and demonstrate conversion to the Ruminococcaceae metric characterized as a 
favorable in the majority of the UC participants (SER-DSC-0043 Report, 2018). In the absence 
of antibiotic pretreatment, engraftment of SER-287 was neither robust nor durable. SER-287 
given daily after vancomycin led to rapid engraftment which reached a maximum by Day 10. 
Engraftment did not change between Day 56, the last day of treatment, and 4 weeks thereafter, 
consistent with properties expected of a living drug. 
In addition, clinical remission and endoscopic improvement were improved with daily dosing 
compared with weekly dosing of SER-287.  


 
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Overall, these findings support a favorable benefit-risk profile for FMT and SER-401 in humans 
across a range of diseases. The treatment of participants with metastatic melanoma with oral 
FMT or SER-401 in combination with anti-PD-1 therapy is expected to be safe and tolerable. 
Additionally, we postulate that treatment with oral FMT or SER-401 will favorably impact the 
microbiome profile of participants treated with the combination and correlate with clinical 
outcomes. 
3 
OBJECTIVES AND ENDPOINTS 
The study objectives and endpoints are listed in Table 2. 
Table 2: 
Objectives and Corresponding Endpoints 
Objectives 
Endpoints 
Primary 
 
• To determine the safety of microbiome study 
intervention administration with anti-PD-1 therapy. 
• Incidence and severity of AEs 
• Change from baseline in vital signs, clinical 
laboratory tests, electrocardiograms, and ECOG 
performance status. 
Secondary 
 
• To evaluate the engraftment of FMT and SER-401 
bacteria into the intestinal microbiome community 
in stool samples. 
• To assess the association of microbiome study 
intervention administration with clinical outcomes 
(objective response rate [ORR], disease control rate 
[DCR], progression-free survival [PFS] rate, overall 
survival [OS], and duration of response). 
• To assess the change in percentage of tumoral CD8 
cells in tumor samples in response to anti-PD-1 
therapy with or without microbiome study 
intervention administration. 
• Determination of the engraftment of FMT or 
SER-401 bacteria into each of the microbiome study 
intervention groups relative to placebo. 
• ORR: Defined as CR or PR as best response by 
Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 assessment. Participants who 
do not have RECIST assessment for any reason will 
be counted as not responding. 
• DCR: Defined as CR, PR, or stable disease (SD) for 
≥ 24 weeks as best response by RECIST v1.1. 
Participants who do not have RECIST assessment 
for any reason will be counted as not responding. 
• PFS: Defined as the time from randomization to date 
of first documented radiographic progression of 
disease or date of death due to any cause, whichever 
occurs first. 
• PFS rate at 1 year: Defined as the proportion of 
participants without documented progression of 
disease or death due to any cause at 1 year. 
• OS: Defined as the time from randomization until 
death. 
• OS rate at 1 year: Defined as the proportion of 
participants alive at 1 year. 
• Duration of response: Defined as time from date of 
documented CR or PR to date of first documented 
radiographic progression of disease or date of death 
due to any cause, whichever occurs first. 


 
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Objectives 
Endpoints 
• Change in the percentage of CD8 cells in tumor 
tissue from baseline at Cycle 2. 
Exploratory 
 
• To assess the safety and efficacy of SER-401 
administration with anti-PD-1 therapy in participants 
who receive SER-401 after progressing while on 
placebo. 
• To evaluate changes in the composition of the fecal 
microbiome. 
• To evaluate changes in signatures of host and 
microbial functional responses in stool and blood. 
• To explore the association of microbiome, tumor 
and immune biomarkers in blood, tumor, and stool 
samples with clinical endpoints and/or AE. 
• Incidence and severity of AEs and changes from 
baseline in vital signs, clinical laboratory tests, 
electrocardiograms, and ECOG performance status 
in participants who receive SER-401 after 
progressing while on placebo. 
• ORR in participants who receive SER-401 after 
progressing while on placebo. 
• DCR in participants who receive SER-401 after 
progressing while on placebo. 
• PFS rate at 1 year in participants who receive SER-
401 after progressing while on placebo. 
• OS rate at 1 year in participants who receive SER-
401 after progressing while on placebo. 
• Changes in the composition of the fecal microbiome 
from baseline to on treatment following 
administration of FMT, SER-401, or placebo. 
• Functional changes in transcriptomic, metabolomic, 
and/or proteomic profiles from baseline to on 
treatment. 
• Association of T-cell phenotypic characteristics and 
immune characteristics in the tumor with clinical 
outcomes (eg, ORR, DCR, PFS, OS) and/or AEs. 
• Molecular (genomic, metabolic, and/or proteomic) 
or microbial biomarkers that may be indicative of 
clinical response/resistance, safety, 
pharmacodynamic activity, and/or mechanism of 
action of anti-PD-1 therapy and their relationship to 
microbiome study intervention administration. 
AE(s) = adverse event(s); CR = complete response; CTCAE = Common Terminology for Adverse Events; 
DCR = disease control rate; ECOG = Eastern Cooperative Oncology Group; FMT = fecal microbiota transplant; 
ORR = objective response rate; OS = overall survival; PD-1 = programmed cell death-1; PFS = progression-free 
survival; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This is a Phase 1b, multicenter, randomized, placebo-controlled, blinded study in adult 
participants with unresectable or metastatic melanoma to evaluate the safety and tolerability of 
FMT, SER-401, or matching placebo in combination with anti-PD-1 therapy. Participants must 
have measurable disease that can be biopsied and consent to baseline and on-treatment biopsies. 


 
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Approximately 60 participants will be treated with microbiome study intervention or placebo in 
combination with nivolumab. Enrollment caps will be utilized to ensure adequate representation 
of participants with low (ie, “unfavorable”) fecal microbiome composition of the 
Ruminococcaceae abundance-based metric at screening. Each study intervention (FMT or 
SER-401) will enroll a minimum of 18 participants (60%) with low Ruminococcaceae. 
After consenting to participate in this clinical trial, participants will undergo screening for 
eligibility, including blood and stool biomarker sampling, assessment of stool for the 
Ruminococcaceae abundance-based metric for stratification, and tumor biopsies (baseline and 
on-treatment core needle or incisional biopsies are required; fine needle aspiration is not 
acceptable). Participants will be assigned to 1 of the 2 oral microbiome study interventions (FMT 
or SER-401) by the Investigator based on clinical judgment and availability or feasibility of the 
interventions. Within each study intervention, participants will be randomized in a 2:1 ratio to 
the oral microbiome study intervention or matching placebo (Figure 1). 
The 2-week antibiotic/microbiome study intervention lead-in phase of the study will consist of 4 
days of pretreatment with oral vancomycin (125 mg) or placebo administered 4 times daily 
(QID), starting on Day -14, followed by a 2 (+1) day washout. The washout may be extended by 
the additional day, as indicated, if needed to accommodate scheduling. Participants unable to 
tolerate the antibiotic pretreatment will be discontinued from the study and replaced prior to 
administration of the microbiome/anti-PD-1 combination. 
A 1-week loading regimen of the microbiome study intervention will be performed 2-3 days 
following antibiotic/placebo administration. Participants assigned to the FMT arm will receive 3 
doses of FMT investigational intervention or placebo administered every other day (QOD). If 
needed to accommodate scheduling, either the second or third dose of FMT (but not both), may 
be administered with a window of 1 additional day (ie, dosing interval of up to 3 days instead of 
2 days). All FMT doses will be dispensed for administration at the study site. The participant 
should observe a fast of at least 4 hours (no food or drink except for small amounts of water) 
prior to and 45 minutes after FMT administration. 
Participants in the SER-401/placebo arm will receive 7 doses of SER-401 investigational 
intervention or placebo administered every day (QD) for one week. The first dose of SER-401 or 
matching placebo will be administered in the clinic and will be followed by a 1-hour observation 
period after dosing. SER-401 should be taken at approximately the same time on each day and 
the administration date recorded on the diary card. The participant should observe an overnight 
or at least a 6-hour fast (no food or drink except for small amounts of water) prior to SER-401 
administration. Subsequent doses of SER-401 or matching placebo will be dispensed to the 
participant for self-administration QD at home. 


 
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During the antibiotic/microbiome lead-in phase, participants will use a participant-reported diary 
to track compliance to the oral antibiotic and SER-401, as well as to record, on a daily basis 
during administration, the occurrence of solicited symptoms commonly associated with 
microbiome study intervention (see Section 8.2.5). 
Nivolumab therapy will begin on Cycle 1 Day 1, which is approximately one day following the 
7-days of lead-in with the microbiome intervention. An anti-PD-1 study intervention cycle will 
be defined as 4 calendar weeks, starting on the day of each anti-PD-1 infusion. The protocol 
active treatment phase with anti-PD-1 therapy (nivolumab) will continue for up to 12 cycles, 
unless the participant experiences confirmed disease progression or unacceptable toxicity in the 
judgment of the treating physician. Participants will be followed for approximately 2 years from 
the time of the initiation of study intervention. 
Participants assigned to blinded FMT (Group 1) or matching placebo (Group 2) will have 3 
clinic visits (QOD) during the antibiotic/microbiome lead-in phase and weekly clinic visits 
during the microbiome/anti-PD-1 treatment phase for administration of the blinded microbiome 
study intervention. 
Participants assigned to blinded SER-401 (Group 4) or matching placebo (Group 3) will receive 
enough capsules of the blinded microbiome study intervention to cover administration until the 
next clinic visit. 
Participants will be monitored for safety and will report solicited symptoms using a diary card 
during the antibiotic and microbiome dosing portions of the trial. Adverse events, including 
adverse events of special interest (AESIs), will be collected from the start of study intervention 
until at least 100 days after the last dose of study intervention. 
In addition, the first 5 participants enrolled in each microbiome study intervention group (ie, 
FMT/matching placebo or SER-401/matching placebo) will be contacted twice following the 
first dose of nivolumab, as follows: once between Days 2 – 4 and once on Day 7 [± 1 day to 
accommodate weekends or holidays]). The intent of these phone calls is to assess for emerging 
AEs that may require early intervention. 
Blood and stool biomarkers will be collected throughout the study. Participants will be supplied 
with home fecal collection kits to obtain stool samples for metagenomic and metabolomic 
analyses. Following randomization, stool will be collected with a window of up to 2 days prior to 
the following timepoints, when feasible: start of microbiome study intervention (ie, collected 
after completion of antibiotic/placebo and prior to the start microbiome study intervention) and 
Cycle 1 Day 1 (ie, 7 days after start of microbiome study intervention). Thereafter, stool will be 
collected with a window of ± 3 days of the following timepoints, when feasible: Cycle 1 Day 8 
(ie, 7 days after first dose of nivolumab); Cycle 2 Day 1; Cycle 3 Day 1; Cycle 4 Day 1 (ie, 4 


 
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weeks after last dose of microbiome study intervention); Cycle 7 Day 1; and at the End of 
Treatment visit. 
A screening biopsy is required. An on-treatment tumor biopsy is required when medically 
feasible. The on-treatment biopsy should occur ideally from the same tumor lesion and after the 
second dose of anti-PD-1 therapy (ie, Cycle 2, Days 2 – 12); however, any on treatment biopsy 
will be accepted. 
An optional biopsy may be obtained during the course of the study or at the time of disease 
progression, including from participants who respond and subsequently progress. Participants 
must provide additional consent for this procedure. 
4.1.1 
Cross-over for Participants on Placebo in Groups 2 or 3 
Participants who were randomly allocated to receive placebo in Groups 2 or 3 and who have 
radiographic evidence of progression of disease while on study (as described in Section 4.4) will 
be offered the option to receive active SER-401 and nivolumab treatment as part of a cross-over 
to Group 5. Participants who agree to this option will provide informed consent and will enter 
Group 5 following unblinding in the Interactive Web Response System (IWRS). The procedures 
in Group 5 will be identical to those in Group 4 and need to be repeated according to the 
Schedule of Activities beginning with the antibiotic administration 14 days prior to Cycle 1. 
To be eligible for treatment in Group 5, participants must be unblinded and found to have been 
assigned to the placebo microbiome intervention arm. Participants must continue to meet all 
safety-related eligibility criteria described in Section 5.1 and Section 5.2. Additionally, 
participants must have tolerated nivolumab therapy without unresolved toxicity or toxicity 
requiring permanent treatment discontinuation as defined in Table 4. A new baseline biopsy is 
optional and not required for entry into Group 5. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This study is designed to assess the safety and tolerability of treatment with oral microbiome 
study interventions or matching placebo in enhancing the response to anti-PD-1 therapy in 
participants with advanced melanoma. The study uses 2 complex, donor-derived products to be 
tested in combination with anti-PD-1 treatment in adult patients with advanced metastatic 
melanoma: FMT formulated for oral delivery (Youngster et al., 2016) derived from healthy 
donors and SER-401, a healthy donor-derived spore composition formulated in capsules for oral 
administration. The justification for evaluating FMT and SER-401 in separate groups of the same 
clinical study is that this approach enhances the opportunity to define how the participant 
microbiome influences CPI therapy by including a wide range of bacterial species from two 
diverse products. Based on the mechanism of action of improving immune responsiveness to 
immunotherapy and the lack of antitumor activity of single agent FMT in preclinical tumor 


 
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models (Matson et al., 2018), this first in man study is evaluating FMT or SER-401 
administration in combination with anti-PD-1 therapy. Donors for each of these products have 
been selected to have a “favorable” microbiome profile (see Section 2.2.2 and Section 2.2.3) 
based on the findings of Gopalakrishnan et al. (Gopalakrishnan et al., 2018). In addition to 
evaluating the safety of these compositions in combination with anti-PD-1 treatment, this study 
will evaluate the mechanisms by which the microbiome influences immune response and clinical 
outcomes to CPI treatment. 
The study population rationale is provided in Section 2. 
4.3 
JUSTIFICATION FOR DOSE 
Nivolumab will be administered using the established dosing regimen for metastatic melanoma 
(Section 4.3.1). The dose and schedule proposed for oral FMT (Section 4.3.2) and SER-401 
(Section 4.3.3) are based on precedents in other indications and experiences with other bacterial 
spore products in other clinical trials, respectively. 
4.3.1 
Rationale for Nivolumab Dose and Schedule 
Nivolumab will be administered at a dose of 480 mg Q4W, as approved by the FDA in March 
2018 for the treatment of metastatic melanoma (Opdivo USPI, 2019).  
4.3.2 
Rationale for Oral FMT Dose and Schedule 
Oral FMT dose and schedule is guided by historical precedent in other indications; a dose of 
10 – 15 capsules is typical in CDI, delivered over 2 consecutive days. As the capsules are large 
(Size 00, about the size of a multi-vitamin), larger numbers are not considered generally 
tolerable, and thus, a dose of 10 capsules was selected. Additionally, this dose level (ie, capsule 
number) and frequency has precedent for chronic oral FMT administration in a clinical trial at 
Massachusetts General Hospital studying patients with metabolic syndrome (NCT02530385). 
4.3.3 
Rationale for SER-401 Dose and Schedule 
SER-401 dose and schedule are guided by recent experience with another bacterial spore 
product, SER-287, in a setting of mild-to-moderate ulcerative colitis. In the SERES-101 trial, a 
6-day pretreatment antibiotic lead-in with vancomycin 125 mg QID followed by a daily dose of 
1 x 108 SporQs (equivalent to approximately 1 x 107SCFUs) for 8 weeks resulted in significant 
engraftment of spore species (NCT02618187). Clinical remission, endoscopic improvement, and 
engraftment was improved with daily dosing compared with weekly dosing. There were no 
treatment-related drug discontinuations in the SER-287 daily study intervention group, and all 
treatment-emergent AEs were mild or moderate with no drug-related SAEs. Thus, a similar 
regimen, 4-day vancomycin 125 mg QID pretreatment antibiotic lead-in followed by daily 


 
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SER-401 5×106 SCFU for 9 weeks, is proposed for participants with unresectable or metastatic 
melanoma in the current study. 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION 
Accumulating evidence indicates that a minority of patients treated with immunotherapy may 
derive clinical benefit from continued treatment despite initial evidence of disease progression 
(Wolchok et al., 2009). Therefore, participants will be permitted to continue study intervention 
beyond initial RECIST v1.1-defined disease progression (PD) assessed by the Investigator, 
provided they meet the following criteria: 
• Investigator-assessed clinical benefit 
• Participant is tolerating study intervention and has no unresolved toxicity (ie, has 
returned to baseline grade/severity) 
• Participant has a stable performance status 
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, central nervous system metastases) 
• Participant agrees to continue treatment beyond progression and has been informed of 
alternate treatment options as part of the documented informed consent process 
 
All decisions to continue treatment beyond initial progression must be discussed with and agreed 
upon by the Sponsor and documented in the study records. 
A follow-up scan should be performed at the next scheduled imaging evaluation (no sooner than 
4 weeks) following initial investigator-assessed progression to determine whether there is 
evidence of further progressive disease.  
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant may remain on the trial and continue to receive study intervention(s) 
and undergo monitoring according to the Schedule of Activities (Section 1.3). Participants 
should discontinue study intervention upon evidence of further progression, defined as an 
additional ≥ 10% increase in tumor burden from the time of initial progression (including all 
target lesions and new measurable lesions). 
4.5 
END OF STUDY AND END OF TREATMENT DEFINITIONS 
Each participant will have an End of Treatment date and an End of Treatment visit. The End of 
Treatment date is the calendar date when all study interventions are discontinued. The End of 
Treatment visit is the date that a clinic visit was completed following the last dose of study 
intervention (ie, after 12 cycles of study intervention or at early discontinuation). All 


 
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participants, including those who discontinue early after receiving any study intervention, should 
have the End of Treatment visit and date to complete the visit procedures. The clinic visit at 
which disease assessment shows progressive disease may be used as the End of Treatment visit if 
it occurs 30 (+5) days after the last dose of nivolumab. Every effort should be made to complete 
the End of Treatment visit within the window; however, the visit should be conducted even if 
outside the window. 
For each participant, the End of Study time point is defined as the date when the last study visit 
or procedure for that participant occurs. 
The End of Study for the study is the date at which the last data point required for statistical 
analysis or safety follow-up is received from the last participant, whichever occurs later.  
5 
STUDY POPULATION 
Prospective requests for approval of protocol deviations to recruitment and enrollment criteria, 
also known as waivers or exemptions, are not allowed. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Men and women, ≥ 18 years of age at the time the informed consent is signed. 
2. Participant must be willing to provide a baseline stool sample (see Section 8.7.2).  
3. Male or female participants of child-producing potential must agree to use contraception 
or avoidance of pregnancy measures as detailed in Appendix 6 of this protocol during the 
treatment period and for at least 7 and 5 months, respectively, after the last dose of 
nivolumab. 
4. Women of childbearing potential (as defined in Appendix 6) must have a negative serum 
pregnancy test within 24 hours prior to the start of study intervention. 
5. Participants must be able and willing to comply with the study visit schedule and study 
procedures and requirements, including the ability to take oral drugs. 
6. Histologically-confirmed Stage IV cutaneous melanoma or Stage III cutaneous, acral or 
mucosal melanoma that is judged inoperable. Participants with a history of uveal 
melanoma are not eligible.  
7. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST v1.1; ie, defined as at least 1 lesion that can be accurately measured 
in at least 1 dimension [longest diameter to be recorded] with a minimum size of ≥ 10 
mm by computerized tomography [CT] scan or caliper measurement on clinical exam or 
≥ 20 mm by chest X-ray). 
a. Malignant lymph nodes must be ≥ 15 mm in short axis when assessed by CT scan to 
be considered pathologically enlarged and measurable. 


 
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b. Participants must have at least one measurable lesion by RECIST and a separate 
lesion amenable to biopsy that has not been previously irradiated. 
i. 
Participants must be willing to undergo a newly-obtained core needle or 
incisional biopsy at baseline (prior to antibiotic or antibiotic placebo 
administration). Fine needle aspiration is not acceptable. 
ii. 
Participants who have only one measurable lesion per RECIST 1.1 criteria at 
baseline and no other lesions amendable to biopsy must be discussed with the 
Medical Monitor prior to enrollment. 
8. Participants must be willing to undergo tumor biopsy, ideally from the same tumor 
location, while on treatment. 
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
10. Prior radiotherapy must have been completed at least 2 weeks prior to study intervention 
administration. 
11. Screening laboratory values (within 14 days of randomization): 
a. Absolute neutrophil count ≥ 1.0 x 109/L 
b. Platelets ≥ 100 x 109/L 
c. Hemoglobin ≥ 9 g/dL 
d. Serum creatinine < 1.5x OR creatinine clearance of at least 40 mL/min 
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper 
limit of normal (ULN) 
f. Total bilirubin ≤ 1.5 × ULN 
i. 
Participants with liver lesions may be eligible if they have total bilirubin 
≤ 2.0 x ULN 
ii. 
Participants with Gilbert’s syndrome must have total bilirubin ≤ 3 x ULN and no 
liver lesions 
12. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol, prior to the performance of any protocol-related procedures 
that are not part of normal care. 
 
5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
1. Had a surgical procedure requiring general anesthesia less than 2 weeks prior to 
beginning protocol therapy. 
2. Is pregnant, lactating or breastfeeding. 
3. Participants who require hemodialysis. 


 
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4. Participants with a history of another cancer in the last 5 years, except for: a) curatively 
resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; c) 
localized prostate cancer not requiring systemic therapy; and c) other primary tumors 
with no known active disease present that, in the opinion of the Investigator and the 
Sponsor, will not affect participant outcome in the setting of the current diagnosis. 
5. Any known, untreated brain metastases. Participants with brain metastases are eligible if 
these have been treated, and provided: 
a. Brain metastases must be stable (image-documented) 4 weeks after completion of 
treatment for brain metastases and require treatment with less than 10 mg/day 
prednisone equivalent for at least 2 weeks prior to study intervention administration. 
b. Neurological symptoms should be absent or returned to baseline. 
6. Prior checkpoint inhibitor therapy with anti-PD-1 or anti-PD-L1. 
a. Exception: Participants with stage 3 or 4 cutaneous melanoma status post-resection 
who have received up to one year of adjuvant anti-PD-1 therapy who have recurred 
> 6 months after their last dose of anti-PD-1 therapy are eligible. 
7. Other prior systemic treatment (ie, anticancer chemotherapy, immunotherapy, or 
investigational agents) for unresectable or metastatic melanoma EXCEPT: 
a. Participants who received prior BRAF-targeted therapy (ie, BRAF or BRAF-MEK) in 
the metastatic setting is allowed if the therapy was completed at least 4 weeks prior to 
the first dose of anti-PD-1. 
b. Participants who received prior anti-CTLA 4 therapy in the adjuvant setting are 
allowed if completed at least 12 weeks prior to the first dose of anti-PD-1. 
8. History of active inflammatory bowel disease (eg, active Crohn’s disease or ulcerative 
colitis) with diarrhea OR major gastrointestinal surgery (not including appendectomy or 
cholecystectomy) within 3 months of enrollment (ie, signed informed consent for the 
study), OR any history of total colectomy or bariatric surgery (bariatric surgery which 
does not disrupt the gastrointestinal lumen, ie, restrictive procedures such as banding, are 
permitted). 
9. Any diagnosis of autoimmune disease. Participants with Type I diabetes mellitus, 
hypothyroidism only requiring hormone replacement, adrenal insufficiency on 
replacement dose steroids, skin disorders (such as vitiligo, psoriasis or alopecia) not 
requiring systemic treatment, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll. 
a. Participants with controlled Type 1 diabetes mellitus on a stable insulin regimen may 
be eligible. 
10. Participants with eczema, psoriasis, lichen simplex chronicus or vitiligo except those with 
dermatologic manifestations only (eg, participants with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions: 
a. Participants with psoriasis must have a baseline ophthalmologic exam to rule out 
ocular manifestations. 


 
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b. Rash must cover less than 10% of body surface area. 
c. Disease is well controlled at baseline and only requiring low potency topical steroids 
(eg, hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 
0.05%, aclometasone dipropionate 0.05%). 
d. No acute exacerbations of underlying condition within the last 12 months (not 
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors; high potency or oral steroids). 
11. Has a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of study 
intervention administration. Inhaled or topical steroids, and adrenal replacement doses 
> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune 
disease. 
12. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (ie, bronchiolitis obliterans, cryptogenic organizing pneumonia, 
etc.), or evidence of active pneumonitis on screening chest CT scan. 
a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
13. Has a transplanted organ or has undergone allogeneic bone marrow transplant. 
14. Has received a live vaccine within 30 days prior to first dose. Participants must not 
receive live, attenuated influenza vaccine (eg, FluMist®) within 30 days prior to Cycle 1, 
Day 1 or at any time during the study and 100 days after last dose of nivolumab. 
15. Has used antibiotics within 30 days prior to randomization or has planned or required 
need for antibiotic prophylaxis for more than 24 consecutive hours during the course of 
the study. 
16. Participants with a history of allergy to study intervention components or history of a 
severe hypersensitivity reaction to any monoclonal antibody.  
17. Known allergy or intolerance to oral vancomycin. 
18. Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, 
clinically significant non-healing or healing wounds, symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia, significant pulmonary disease 
(shortness of breath at rest or on mild exertion), uncontrolled infection or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
No restrictions are required. 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 


 
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participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
In this study, stool will be collected at screening for assessment of the fecal microbiome 
composition of the Ruminococcaceae abundance-based metric for stratification. A second 
screening collection will be allowed if the results of the initial screening collection are 
indeterminate. 
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to a study participant according to the study protocol. 
6.1 
STUDY INTERVENTIONS ADMINISTERED 
The study interventions to be administered in this study are summarized in Table 3. 
Table 3: 
Study Intervention 
Study 
Intervention Name 
 
Dosage 
Formulation 
 
Unit Dose 
Strength(s) 
 
Dosage 
Level(s) 
 
Route of 
Administration 
 
 
Sourcing 
Antibiotic 
(Vancomycin) 
Tablet with 
microcrystalline 
cellulose in 
blinding capsule 
125 mg 
125 mg 
PO 
Seres 
Therapeutics 
Matching Placebo 
for Antibiotic  
Microcrystalline 
cellulose in 
blinding capsule 
0 mg 
0 mg 
PO 
Seres 
Therapeutics 
FMT Capsules 
Active glycerol 
suspension in 
capsule 
≥ 109 CFU/ 
10 capsules 
10 capsules 
PO 
MGH IND 16011 
Matching Placebo 
for FMT Capsules 
Placebo glycerol 
suspension in 
capsule 
0 CFU/ 
10 capsules 
10 capsules 
PO 
MGH IND 16011 
SER-401 
Capsules 
Active glycerol 
suspension in 
capsule 
5 x 106 SCFU/ 
2 capsules 
2 capsules 
PO 
Seres 
Therapeutics 
Matching Placebo 
for SER-401 
Capsules 
Placebo glycerol 
suspension in 
capsule 
0 SCFU/ 
2 capsules 
2 capsules 
PO 
Seres 
Therapeutics 
Nivolumab 
Aqueous solution 
10 mg/mL 
480 mg 
IV infusion 
Sourced 
commercially 
CFU = colony-forming units; FMT = fecal microbiota transplant; IV = intravenous; MGH = Massachusetts General Hospital; 
PO = orally; SCFU = spore colony-forming units 
 


 
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Participants will be assigned to receive 1 of the following oral microbiome study interventions 
(FMT or SER-401) in combination with anti-PD-1 therapy. Within each study intervention, 
participants will be randomized in a 2:1 ratio to the oral microbiome study intervention or 
matching placebo:  
• FMT or matching placebo will be administered QOD x 3 days during the lead-in phase, 
followed by QW x 8 weeks during the microbiome/anti-PD-1 treatment phase. The dose 
of FMT product will be 10 capsules given 3 times for the first week (3 doses), followed 1 
time per week for the next 8 weeks (1 dose). This roughly corresponds to 109 or more 
colony forming units (CFU) per 10 capsule dose. 
• SER-401 or matching placebo will be administered QD x 7 days during the lead-in phase, 
followed by QD x 8 weeks during the microbiome/anti-PD-1 treatment phase. The dose 
per day of SER-401 will be 5 x 106 SCFU or 2 capsules.  
 
Prior to initiating the microbiome study intervention, participants will undergo a 4-day lead-in 
pretreatment with either antibiotic (vancomycin) or antibiotic placebo, depending on group 
randomization assignment, to prime the gut microbiome for engraftment of the oral microbiome 
study intervention, which will be administered following a 2-3 day washout. Participants unable 
to tolerate the antibiotic pretreatment will be discontinued from the study and replaced. 
Administration of study intervention will be staggered by at least 1 day for the first 5 participants 
enrolled in each microbiome study intervention group (ie, FMT/matching placebo or SER-
401/matching placebo) to monitor for safety.  
The protocol active treatment with anti-PD-1 therapy (nivolumab, 480 mg) will be administered 
intravenously (IV) according to institutional guidelines Q4W for up to 12 cycles, unless the 
participant experiences confirmed disease progression or unacceptable toxicity in the judgment 
of the treating physician. A cycle is defined as 4 calendar weeks. 
Study intervention administered by site personnel will be performed in a monitored setting in 
which there is immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
The study intervention administered in this protocol is for investigational use only. 
All study intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the Investigator and authorized site staff. Storage requirements for the study intervention are 
as follows: 
• Vancomycin study intervention and matching placebo should be stored at room 
temperature for both clinical site storage, as well as at-home use. 


 
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• FMT study intervention and matching placebo must be stored at ≤ -65°C at the clinical 
site. 
• SER-401 study intervention and matching placebo must be stored at ≤ -15 °C at the 
clinical site and refrigerated at 2°C to 8°C during at-home use. 
• Nivolumab must be stored at 2°C to 8°C (36°F to 46°F) and protected from light and 
freezing.  
 
The Investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may dispense and/or administer study intervention. In this study, oral study intervention, 
including vancomycin and oral microbiome study intervention, will be dispensed to the 
participant for self-administration. 
Participants should return any unused study drug to the site at their next study visit. Returned 
study intervention should not be re-dispensed to other participants. The Investigator, institution, 
or the head of the medical institution (where applicable) is responsible for study intervention 
accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records). 
Further guidance and information for the final disposition of unused or returned study 
interventions are provided in the Pharmacy Manual. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING 
6.3.1 
Intervention Assignment 
Assignment to 1 of the 2 microbiome study interventions will be made by the Investigator based 
on clinical judgment and availability or feasibility of the interventions. All participants will be 
randomly allocated (in a 2:1 ratio) to the oral microbiome study intervention or placebo within 
the 2 microbiome study interventions using an Interactive Web Response System (IWRS). 
Before the study is initiated, log in information and directions for the IWRS will be provided to 
each site. 
Randomization will be stratified by fecal microbiome composition of Ruminococcaceae at 
screening (see Section 2.2.2): high (ie, “favorable”) vs low (ie, “unfavorable”). Each study 
intervention (FMT or SER-401) will enroll a minimum of 18 participants (60%) with low 
Ruminococcaceae. 


 
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6.3.2 
Blinding 
Within the 2 microbiome study interventions, participants will be randomly assigned in a 2:1 
ratio to the oral microbiome study intervention or matching placebo. Nivolumab will be 
administered open-label as standard of care to all groups. Investigators, site personnel, and 
participants will remain blinded to the assignment of microbiome study intervention throughout 
the course of the study. Select Sponsor personnel, including but not limited to the Medical 
Monitor, Clinical Scientists, Biostatistician, and Patient Safety, will be unblinded to treatment 
assignment for ongoing safety monitoring. 
6.3.3 
Unblinding 
The IWRS will be programmed to accommodate unblinding and cross-over cases. In case of an 
emergency, the Investigator has the sole responsibility for determining if unblinding of a 
participant’s intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the Investigator decides that unblinding is 
warranted, the Investigator should make every effort to contact the Medical Monitor prior to 
unblinding a participant’s intervention assignment unless this could delay emergency treatment 
of the participant. If a participant’s intervention assignment is unblinded, the Sponsor must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was broken 
must be recorded in the source documentation and case report form, as applicable. 
If a participant has radiographic evidence of progression of disease while on study (see 
Section 4.4), the Investigator will be able to unblind the participant’s intervention assignment. If 
the participant was allocated to one of the placebo groups (Group 2 or Group 3), the participant 
will be offered the option to receive active SER-401 and nivolumab treatment (Group 5). The 
study intervention (active SER-401 and nivolumab) will be offered open label; Investigators, site 
personnel, and participants will be unblinded to study intervention administered in Group 5. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Participant compliance with study intervention will be assessed at each visit. Compliance for 
study intervention administered by site personnel will be assessed using site drug accountability 
records. Study intervention that is self-administered by the participant will be tracked by the 
participant using a participant-reported diary and reconciled with any returned study 
intervention. 
For study medication self-administered by the participant at home, missed doses should be taken 
as soon as the participant remembers the missed dose. However, if it is almost time for the next 
dose, the missed dose should be skipped, and the regular dosing schedule should be followed. 
The participant should not take a double dose to make up for a missed dose. 


 
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Deviation(s) from the prescribed dosage regimen should be recorded in the electronic case report 
form (eCRF). 
6.5 
CONCOMITANT THERAPY 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
probiotics, and/or herbal supplements) that the participant is receiving at the time of enrollment 
through at least 100 days post last dose of study intervention must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1 
Permitted Therapy 
Concomitant medications or treatments (eg, acetaminophen/paracetamol, diphenhydramine) may 
be prescribed if considered necessary for adequate prophylactic or supportive care except for 
those medications identified as “excluded” in Section 5.2. 
6.5.2 
Cautionary Therapy 
Participants with planned or required antibiotic prophylaxis for more than 24 consecutive hours 
during the course of the study should not be enrolled. Once enrolled, if the need for antibiotic 
treatment arises, the decision to continue the participant will be at the discretion of the 
Investigator, after discussion and agreement with the Medical Monitor. 
6.5.3 
Prohibited Therapy 
The medications listed below are prohibited during the study. The Sponsor must be notified if a 
participant receives any of these during the study. 
• Any concurrent investigational anticancer therapy. 
• Immunosuppressive medications, including chronic systemic steroids at physiologic 
doses (equivalent to a dose > 10 mg oral prednisone), 14 days prior to the first dose of 
antibiotic treatment (except for participants who require hormone replacement therapy 
[HRT] such as hydrocortisone). A temporary course of steroids (ie, contrast allergy, 
chronic obstructive pulmonary disease) may be permitted, depending on the duration and 
dose, after discussion and agreement with the Medical Monitor. 
• Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic, or hormonal treatment. 


 
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• Any live attenuated vaccine therapies used for the prevention of infectious diseases (for 
up to 30 days prior to the first dose of antibiotic treatment and 100 days after the last dose 
of study intervention), including for influenza (eg, FluMist), for up to 30 days prior to the 
first dose of nivolumab and 100 days after the last dose of study intervention.  
• Herbal and natural remedies, including probiotics, unless discussed and agreed with the 
Medical Monitor. 
 
6.6 
DOSE MODIFICATIONS 
Immuno-oncology agents are associated with AEs that can differ in severity and duration from 
AEs caused by other therapeutic classes. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management algorithms (Opdivo 
Immune-Mediated Adverse Reactions Management Guide, 2019) have been developed to assist 
Investigators in assessing and managing the following groups of drug-related AEs: 
• 
Immune-mediated colitis 
• 
Immune-mediated hepatitis 
• 
Immune-mediated endocrinopathies (hypophysitis, adrenal insufficiency, 
hypothyroidism and hyperthyroidism, Type 1 diabetes mellitus) 
• 
Immune-mediated skin adverse reactions 
• 
Immune-mediated encephalitis 
• 
Immune-mediated pneumonitis 
• 
Immune-mediated nephritis and renal dysfunction 
• 
Other immune-mediated AEs 
 
Based on the available characterization of the mechanism of action, and preliminary data from 
ongoing studies, nivolumab may cause AEs similar to, but independent of, concurrent therapy, 
may exacerbate the frequency or severity, or may have non-overlapping toxicities. The 
anticipated important safety risks are outlined below. Refer to the approved prescribing 
information for nivolumab for a complete summary of safety information (Opdivo USPI, 2019).  
6.6.1 
Dose Reductions of Study Intervention 
There will be no dose escalations or dose reductions to any of the study interventions.  
Dose administration timing may be held or delayed according to Section 6.6.2. 


 
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6.6.2 
Dose Delays or Discontinuations Due to Toxicity 
Participants who experience an AE described in Table 4 will be discontinued from all study 
interventions and should continue follow-up assessments as outlined in the Schedule of 
Activities. 
Grade 3 and 4 toxicities are observed in all trials of nivolumab in multiple tumor types. As such 
toxicities are anticipated; monitoring for AEs described in Table 4 will continue throughout the 
study. 
The Investigator may attribute each AE to the antibiotic, combination of nivolumab and oral 
microbiome study intervention, or to nivolumab or oral microbiome study intervention alone. 
Study participants may not have any dose reductions of vancomycin, nivolumab or oral 
microbiome study intervention in this study. If toxicity does not resolve or the criteria for 
resuming study intervention are not met, the participant must be discontinued from the study 
intervention. 
Holding of 1 study intervention and not the other study intervention(s) is appropriate if, in the 
opinion of the Investigator, the toxicity is clearly related to 1 of the study interventions. 
Appropriate documentation is required regarding the drug to which study intervention the 
Investigator is attributing the AE. If, in the opinion of the Investigator, the toxicity is related to a 
combination of 2 study interventions, then all drugs should be held according to recommended 
dose modifications. 
Specific anticipated or potential toxicities associated with the administration of nivolumab or 
oral microbiome study intervention, as well as the measures intended to avoid or minimize such 
toxicity in this trial, are described in the following sections. Guidance with respect to the 
individual study intervention is provided in Section 6.6.3 and Section 6.6.1, respectively. 
Dose delays and interruptions are permitted for toxicity reasons (see Section 6.6.1 and 
Section 6.6.3). Dose delays and interruptions for reasons other than toxicity, such as surgical 
procedures, may be allowed with Medical Monitor approval. The acceptable length of 
interruption will depend on agreement between Investigator and Medical Monitor, but in general 
should not exceed 6 weeks. 
Refer to the approved prescribing information nivolumab (Opdivo USPI, 2019), vancomycin 
(Vancocin USPI, 2018), and the Investigator’s Brochures for FMT and SER-401 for complete 
summaries of safety information. 


 
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Table 4: 
Toxicity Criteria Requiring Permanent Treatment Discontinuation From 
Nivolumab or Microbiome Interventions 
Participants should be monitored for the occurrence of any of the following AEs that are considered by the 
Investigator to be related (ie, possibly, probably, or definitely related) to nivolumab, microbiome study 
intervention, or the combination of nivolumab and microbiome study intervention. Treatment with all study 
intervention should be permanently discontinued for the following:  
• 
Any Grade 2 uveitis or eye pain or blurred vision related to study intervention that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 
• 
Any Grade 3 non-skin AE related to study intervention lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, study intervention-related uveitis, pneumonitis, bronchospasm, 
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies: 
o 
Grade 3 study intervention-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires discontinuation 
o 
Grade 3 study intervention-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires discontinuation 
regardless of control with hormone replacement. 
o 
Grade 3 laboratory abnormalities related to study intervention do not require discontinuation, except: 
 
Grade 3 thrombocytopenia related to study intervention lasting > 7 days or associated with 
bleeding requires discontinuation 
 
Any liver function test abnormality related to study intervention meeting the following criteria 
requires discontinuation: 
­ 
Grade ≥ 3 AST or ALT (> 5 x ULN), unless a possible favorable benefit/risk warrants 
continuation and a discussion between the Investigator and Medical Monitor occurs 
­ 
Grade ≥ 3 total bilirubin (> 3 x ULN), unless a possible favorable benefit/risk warrants 
continuation and a discussion between the Investigator and Medical Monitor occurs 
­ 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• 
Any Grade 4 AEs or laboratory abnormalities (including but not limited to creatinine, AST, ALT, or total 
bilirubin) related to study intervention, except for the following events that do not require discontinuation: 
o 
Grade 4 neutropenia ≤ 7 days 
o 
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase 
o 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical sequelae and 
are corrected with supplementation/appropriate management within 72 hours of their onset 
o 
Grade 4 endocrinopathy AEs related to study intervention, such as, hyper- or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with physiologic hormone replacement 
(corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the Medical Monitor. 
• 
Any AE, laboratory abnormality, or intercurrent illness, which in the judgment of the Investigator presents 
a substantial clinical risk to the participant with continued administration of study intervention 
• 
Any infection with an organism acquired from FMT or SER-401. 
AE(s) = adverse event(s); ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of 
normal 
 
6.6.2.1 
Potential for Overlapping Toxicities with Nivolumab and Oral 
Microbiome Study Intervention 
Adverse events commonly associated with microbiome study intervention include: fever; nausea, 
diarrhea, vomiting, abdominal discomfort, constipation, and flatulence. Among these AEs, 
diarrhea and nausea have been reported in ≥ 10% of patients receiving nivolumab monotherapy 


 
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and are most likely to have the potential to overlap when nivolumab and oral microbiome study 
intervention are administered together. The remaining AEs have been reported with nivolumab 
monotherapy, but at a lower incidence (ie, < 10%), and thus, are less likely to overlap.  
6.6.3 
Dose Modifications for Nivolumab 
Specific anticipated or potential toxicities associated with the administration of nivolumab, as 
well as the measures taken intended to avoid or minimize such toxicity in this trial, are described 
in the following table and sections. 
This study will include set dosing for nivolumab (480 mg Q4W). No dose escalations or 
reductions of nivolumab are allowed. If toxicity does not resolve or the criteria for resuming 
study intervention are not met within 6 weeks (ie, 42 days), the participant must discontinue 
nivolumab. 
Specific anticipated or potential toxicities associated with the administration of nivolumab, as 
well as the measures to be taken to avoid or minimize such toxicity in this trial, are described in 
Table 5. 
AEs associated with nivolumab exposure may represent an immunologic etiology. These 
immune-related adverse events (irAEs) may occur shortly after the first dose or several months 
after the last dose of treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. Based 
on existing clinical study data, drug-related AEs have included pulmonary toxicity, renal toxicity 
(including acute renal failure), endocrine abnormalities, GI toxicity, dermatologic toxicity 
(including rash), and hepatotoxicity. For nivolumab monotherapy, as well as when administered 
in combination, the majority of these AEs have been managed successfully with supportive care 
and, in more severe cases, a combination of dose delay, permanent discontinuation, and/or use of 
corticosteroids or hormone replacement therapy (endocrinopathies). For suspected irAEs, ensure 
adequate evaluation to confirm etiology or exclude other causes. Additional procedures or tests 
such as bronchoscopy, endoscopy, and skin biopsy may be included as part of the evaluation. 
Dose modification and toxicity management guidelines for irAEs associated with nivolumab are 
provided in Table 5. 


 
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Table 5: 
Dose Modifications and Toxicity Management Guidelines for Adverse Events 
Specific to Nivolumab 
Adverse Reaction 
Severitya 
Dose Modifications 
Colitis 
Grade 2 diarrhea or colitis 
Withhold doseb 
Grade 3 diarrhea or colitis 
Withhold doseb when administered 
as a single agent 
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis 
Grade 2 pneumonitis 
Withhold doseb 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
Hepatitis/non-HCC 
AST or ALT more than 3 and up to 5 times 
the ULN or total bilirubin more than 1.5 and 
up to 3 times the ULN 
Withhold doseb 
AST or ALT more than 5 times the ULN or 
total bilirubin more than 3 times the ULN 
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 hypophysitis 
Withhold doseb 
Grade 4 hypophysitis 
Permanently discontinue 
Adrenal insufficiency 
Grade 2 adrenal insufficiency 
Withhold doseb 
Grade 3 or 4 adrenal insufficiency 
Permanently discontinue 
Type 1 diabetes mellitus 
Grade 3 hyperglycemia 
Withhold doseb 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and renal 
dysfunction 
Serum creatinine more than 1.5 and up to 6 
times the ULN 
Withhold doseb 
Serum creatinine more than 6 times the 
ULN 
Permanently discontinue 
Skin 
Grade 3 rash or suspected Stevens-Johnson 
syndrome (SJS) or toxic epidermal 
necrolysis (TEN) 
Withhold doseb 
Grade 4 rash or confirmed SJS or TEN 
Permanently discontinue 
Encephalitis 
New onset moderate or severe neurologic 
signs or symptoms 
Withhold doseb 
Immune-mediated encephalitis 
Permanently discontinue 
Other 
Other Grade 3 adverse reaction 
• First occurrence 
• Recurrence of the same Grade 3 adverse 
reaction 
 
Withhold doseb 
Permanently discontinue 
Life-threatening or Grade 4 adverse reaction 
Permanently discontinue 
Grade 3 myocarditis 
Permanently discontinue 
Requirement for 10 mg per day or greater 
prednisone or equivalent for more than 12 
weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions 
lasting 12 weeks or longer 
Permanently discontinue 
Source: Opdivo USPI, 2019 


 
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ALT = alanine aminotransferase; AST = aspartate aminotransferase; HCC = hepatocellular carcinoma; 
SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; ULN = upper limit of normal 
a Guidelines based on toxicity graded per National Cancer Institute Common Terminology Criteria for Adverse 
Events version 4 (NCI CTCAE v4). 
b Resume treatment when adverse reaction improves to Grade 0 or 1. 
c Resume treatment when AST/ALT return(s) to baseline. 
 
6.6.3.1 
Dose Modifications and Toxicity Management for Infusion-
related Reaction Associated with Nivolumab 
Interrupt or slow the rate of infusion in participants with mild or moderate infusion reactions. 
Discontinue nivolumab in participants with severe or life-threatening infusion reactions. 
All Grade 3 or 4 infusion reactions must be reported within 24 hours to the study Medical 
Monitor and reported as an SAE if it meets the criteria. Infusion reactions should be graded as 
described in Section 10.5.3. 
Dose modification and toxicity management guidelines for infusion-related reactions are 
provided in Table 6. 


 
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Table 6:  
Dose Modification and Toxicity Management Guidelines for Infusion-related Reaction Associated with 
Nivolumab 
Grade 
(NCI CTCAE v 5.0) 
 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption not indicated; 
intervention not indicated 
Remain at bedside and monitor participant until recovery from symptoms.  
The following prophylactic 
premedications are 
recommended for future 
infusions: 
diphenhydramine 50 mg (or 
equivalent) and/or 
acetaminophen/paracetamol 325 
to 1000 mg at least 30 minutes 
before additional nivolumab 
administrations 
Grade 2 
Requires therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion 
Begin an IV infusion of normal saline and treat the participant with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 
325 to 1000 mg; remain at bedside and monitor participant until resolution of 
symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the 
infusion at 50% of the original infusion rate when symptoms resolve; if no 
further complications ensue after 30 minutes, the rate may be increased to 100% 
of the original infusion rate. Monitor participant closely. If symptoms recur, 
then no further study medication will be administered at that visit. 
For future infusions, the 
following prophylactic 
premedications are 
recommended: 
diphenhydramine 50 mg (or 
equivalent) and/or 
acetaminophen/paracetamol 325 
to 1000 mg should be 
administered at least 30 minutes 
before nivolumab infusions. If 
necessary, corticosteroids (up to 
25 mg of hydrocortisone or 
equivalent) may be used. 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae (eg, 
renal impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening consequences; urgent intervention 
indicated 
Stop Infusion 
Begin an IV infusion of normal saline and treat the participant as follows: 
Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected 
slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be 
monitored until the Investigator is comfortable that the symptoms will not recur. 
Remain at bedside and monitor participant until recovery of the symptoms. 
Study drug will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. 
No subsequent dosing 
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine or corticosteroids). 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 


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For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 
CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute; NSAIDs = nonsteroidal anti-inflammatory drugs; IV = intravenous 


 
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6.6.3.2 
Management of Invasive Infections 
Potential AESIs include invasive infections (eg, bacteremia, abscess, meningitis). Among 286 
subjects enrolled in completed studies conducted by Seres Therapeutics who have received a 
microbiome investigational drug, a single event of invasive infection (moderate submental 
abscess unrelated to microbiome investigational drug) has been reported. Notable findings of the 
report include: the subject had a prior history of a dental infection; and at the time of the report, 
the subject did not experience fever, swelling, warmth, erythema, or enlarged or tender lymph 
nodes. The submental abscess, diagnosed by an Ear, Nose, and Throat examination, resolved 
following treatment with broad spectrum antibiotics. 
The protocol monitors such toxicities (see Appendix 5). All SAEs and AESIs will be collected 
and reported as described in Section 8.3.1. 
Participants who develop an invasive infection should be managed according to institutional 
guidelines. 
A study-wide hold and evaluation by the DMC will be initiated if, 1) any SAE or AESI 
considered by the Investigator to be related to FMT or SER-401 occurs, or 2) any infection with 
an organism acquired from FMT or SER-401 occurs in any participant during the study. 
Microbiologic testing for both aerobic and anaerobic organisms will be requested to assess 
whether the infection is likely related due to an organism acquired from FMT or SER-401. Any 
isolates obtained should be retained for genomic sequencing. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY 
There will be no study intervention provided following the end of the study. 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Participants must discontinue study intervention if they experience any of the following: 
• Any toxicity described in Table 4 
• Intolerable toxicity related to study intervention, including the development of an AE 
determined by the Investigator to be unacceptable even with the participant’s potential 
response to intervention due to the severity of the event 
• Any dosing interruption lasting > 6 weeks with the following exceptions: 
o Dosing interruptions to allow for prolonged steroid tapers to manage AEs related to 
study intervention 
o Dosing interruptions > 6 weeks for AEs unrelated to study intervention may be 
allowed if approved by the Medical Monitor 


 
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• Any medical condition that may jeopardize participant safety if he or she continues to 
receive study intervention 
• Use of another anticancer therapy 
• Pregnancy (see Appendix 6) 
• Symptomatic deterioration attributed to disease progression 
• Progression of disease: Either unequivocal symptomatic progression necessitating a 
change in therapy in the opinion of the treating physician or confirmed radiographic 
progression as defined by cross-sectional imaging utilizing RECIST v1.1 criteria (see 
Appendix 3) 
 
Participants have the right to voluntarily withdraw from study intervention at any time for any 
reason. In addition, the Investigator has the right to withdraw a participant from study 
intervention at any time. Reasons for withdrawal from the study may include, but are not limited 
to, the following: 
• Investigator or Sponsor determines it is in the best interest of the participant 
• Participant noncompliance 
 
The primary reason for study intervention discontinuation should be documented on the 
appropriate eCRF page. 
The visit at which disease assessment shows progressive disease may be used as the treatment 
discontinuation visit if it occurs 30 (+5) days after the last dose of nivolumab; participants who 
discontinue study intervention for any reason other than PD or loss of clinical benefit should 
have an end of treatment discontinuation assessment as outlined in the Schedule of Activities 
(SOA; see Section 1.3). All participants should to continue follow-up assessments as outlined in 
the SOA (Section 1.3). Additionally, participants who have received any microbiome study 
intervention should continue to be followed for SAEs and AESIs up to 26 weeks after the last 
dose of microbiome study intervention (see Section 8.3.1). 
7.1.1 
Study-wide Hold for Specified Safety Events 
A study-wide hold and evaluation by the study DMC will be initiated if, 1) any SAE or AESI 
considered by the Investigator to be related to FMT or SER-401 occurs, or 2) any infection with 
an organism acquired from FMT or SER-401 occurs in any participant during the study. All 
study participants will immediately discontinue administration of the oral microbiome study 
intervention but may continue to receive nivolumab should one of these events occur. In 
addition, further enrollment of new participants into the study will be suspended until the event is 
adjudicated by the Data Monitoring Committee (see Section 9.5.1).  


 
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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM 
STUDY 
When study intervention is discontinued, participants should have an end of treatment 
discontinuation assessment followed up by assessment 100 days post last dose as outlined in the 
SOA (see Section 1.3). Information on survival follow-up will be collected for every 3 months 
for approximately 2 years from the initiation of study intervention until any of the following 
occurs: 
• Death 
• Lost to follow-up 
• Study termination by the Sponsor 
• Participant requests to be withdrawn from follow-up 
• Investigator requests that the participant is withdrawn from follow-up 
 
A participant may withdraw a consent at any time and discontinue study intervention and further 
participation on the study. This request must be documented in the source documents and signed 
by the Investigator. The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent. Participants who withdraw consent will not be followed for any reason 
after consent has been withdrawn. However, the study staff may use a public information source 
(eg, county records) to obtain information about survival status only. 
Other reasons for discontinuation of study intervention and/or participation in a follow-up phase 
of the study may include death, adverse events, physician decision, protocol deviation, eligibility 
not met, progressive disease. A participant is considered to have completed the study if he/she 
has completed all phases of the study, including the antibiotic/microbiome lead-in phase, the 
microbiome/anti-PD-1 phase, the anti-PD-1 phase, and the safety and survival follow-up. 
The primary reason for treatment and study discontinuation are documented on the appropriate 
eCRF page. 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 


 
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schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Please see Section 1.3 for the schedule of activities to be performed during the study. All 
activities must be performed and documented for each participant in the order of schedule of 
activities. Participants will be closely monitored for safety and tolerability throughout the study. 
Participants should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable as deemed by the Principal 
Investigator (PI). 
If the timing of a protocol-mandated study visit coincides with the holiday, weekend, or other 
administrative disruption that precludes the visit, the visit should be scheduled on the nearest 
following feasible date. The time between nivolumab doses must not be less than 25 days. Refer 
to the Schedule of Activities (Section 1.3) for visit windows. 
Collection of any non-safety-related data or participant samples may be terminated by the 
Sponsor at any time if further collection of such data or samples is also not related to the study’s 
primary or secondary objectives. The decision to discontinue any data collection will be 
communicated to the sites and Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) by means of a memorandum and will not require a protocol amendment. 
8.1 
EFFICACY ASSESSMENTS 
Participants will undergo tumor assessments as designated in the schedule of activities (see 
Section 1.3) regardless of dose delays, until loss of clinical benefit as determined by the 
Investigator (unless the participant withdraws consent or the Sponsor terminates the study). All 
participants who discontinue study intervention for reasons other than disease progression (eg, 
AEs) will continue tumor assessments for up to 1 year from initiation of nivolumab treatment or 
until study completion, death, disease progression, initiation of another systemic anticancer 
therapy, loss to follow-up, withdrawal of consent, or study termination, whichever occurs first. 
At the Investigator’s discretion, tumor assessments may be repeated at any time if progressive 
disease is suspected.  


 
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Measurable and evaluable lesions should be assessed and documented at screening. Tumor 
assessments performed as standard of care prior to obtaining informed consent and within 
28 days prior to randomization do not have to be repeated at screening 
Screening assessments must include CT scans (with IV contrast unless contraindicated and oral 
contrast as appropriate per institutional standards) of the chest, abdomen, and pelvis. A spiral CT 
scan of the chest may be obtained but is not a requirement. If a CT scan with contrast is 
contraindicated (ie, in participants with contrast allergy or impaired renal clearance), a non-
contrast CT scan of the chest may be performed, and MRI scans may be performed. If the 
participant has a known history of brain metastases or is symptomatic in the opinion of the 
Investigator, scans of the head should be obtained. 
If a CT scan for a tumor assessment is performed in a positron emission tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standards for a full contrast diagnostic 
CT scans. 
Bone scans (technetium-99m [TC-99m]) should be performed at screening if clinically indicated. 
If bone metastases are present at screen and cannot be seen on CT or MRI scans, or if clinically 
indicated, TC-99m bone scan should be repeated when complete response (CR) is identified in 
target disease or when progression in bone is suspected. 
CT scans of the neck or extremities should also be performed if clinically indicated and repeated 
throughout the study if there is evidence of disease at screening.  
All measurable and evaluable lesions should be reassessed at each subsequent tumor evaluation. 
The same radiographic procedures used to assess disease sites at screening should be used for 
subsequent tumor assessments (eg, same contrast protocol for CT scans). 
Response will be assessed by the Investigator using RECIST v1.1 (see Appendix 3). 
Assessments should be performed by the same evaluator, if possible, to ensure internal 
consistency across visits. Results must be reviewed by the Investigator before dosing at the next 
cycle. 
8.2 
SAFETY ASSESSMENTS 
Safety assessments will consist of monitoring and recording AEs, including serious adverse 
events (SAEs) and adverse events of special interest (AESIs), performing protocol-specified 
safety laboratory assessments, measuring protocol-specified vital signs, and conducting other 
protocol-specified tests that are deemed critical to the safety evaluation of the study. Planned 
timing for all safety assessments is provided in the schedule of activities (Section 1.3).  
Certain types of events require immediate reporting to the Sponsor, as described in 
Section 8.3.1.1. 


 
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8.2.1 
Medical History and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history (including, 
stage, date of diagnoses, and prior cancer therapies and procedures), reproductive status, 
smoking history, use of alcohol, and drugs of abuse, will be recorded at baseline. In addition, all 
medications (eg, prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, probiotics, nutritional supplements, FMT) used by the participant within 28 days prior 
to initiation of study intervention will be recorded. Demographic data may include age, sex, and 
race/ethnicity. 
8.2.2 
Physical Examinations 
A complete physical examination should be performed at screening and should include an 
evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems. Any 
abnormality identified at baseline should be recorded on the Medical History eCRF page. 
ECOG Performance Status (see Appendix 2) should be assessed per the schedule of activities in 
Section 1.3. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be recorded in 
participant notes. New or worsened clinically significant abnormalities should be recorded as 
AEs on the Adverse Event eCRF page. 
8.2.3 
Vital Signs 
Vital signs should include measurements of respiratory rate, pulse rate, systolic and diastolic 
blood pressure, pulse oximetry (required only at screening), and temperature and should be 
collected as outlined in the Schedule of Activities (Section 1.3). Vital signs collected at the 
screening visit should be recorded on the appropriate eCRF. For each visit thereafter, only vital 
signs obtained prior to the study intervention administration as outlined in the Schedule of 
Activities or during an AE (eg, temperature or event of fever) should be recorded on the eCRF. 
All vital signs collected per protocol should be documented in the participant’s medical record. 
Vital signs should be measured within 15 minutes prior to and after the administration of 
nivolumab (see Section 6). Vital signs may be measured, if medically indicated, at other time 
points. 
8.2.4 
Electrocardiograms 
Single electrocardiogram (ECG) recordings will be obtained at specified time points, as outlined 
in the Schedule of Activities (Section 1.3), and may be obtained at unscheduled timepoints as 
indicated.  


 
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All ECG recordings must be performed using an institutionally-approved ECG. Lead placement 
should be as consistent as possible. ECG recordings should be performed after the participant has 
been resting in a supine position for at least 10 minutes. 
For safety monitoring purposes, the Investigator must review, sign, and date all ECG tracings. 
Paper copies of ECG tracings will be kept as part of the participant's permanent study file at the 
site. The investigator’s assessment (ie, normal, abnormal [not clinically significant], or abnormal 
[clinically significant]) should be recorded on the appropriate eCRF. 
8.2.5 
Participant Diary  
Participants will complete a paper diary to track compliance to the self-administered oral 
antibiotic and microbiome interventions throughout the study and to record the occurrence of 
solicited symptoms commonly associated with microbiome study intervention. Symptoms 
collected include: gas or flatulence; abdominal discomfort (distention, bloating, pain or 
cramping); diarrhea; vomiting; constipation, and oral temperature. Symptoms will be tracked on 
a daily basis from the start of the study intervention administration through the end of Cycle 2 
using a paper diary card (Appendix 8). Participants will be asked to bring this diary to each 
clinical visit so that the staff can discuss the compliance and safety information with the 
participant. After discussion with the participant, should the Investigator determine a symptom is 
on an AE, the event should be documented in the medical records and on his/her eCRF, as 
appropriate. 
8.2.6 
Clinical Safety Laboratory Assessments 
Clinical laboratory tests will be performed as described in the Schedule of Activities 
(Section 1.3). 
The Investigator must review the laboratory report, document this review, and designate results 
as being not clinically significant or clinically significant. Clinically significant abnormal 
laboratory findings include those are those for which an action was taken (ie, providing fluid, 
transfusion, medication, and/or holding, delaying, or discontinuing study intervention) or those 
that are not associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the participant's condition. Clinically significant changes occurring 
during the study should be documented on the appropriate eCRF. The laboratory reports must be 
filed with the source documents. 
In the event of a Grade 3 or Grade 4 laboratory toxicity, the test for the abnormal laboratory 
value should be repeated until the event is resolved to ≥ Grade 1 or baseline. 


 
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8.2.6.1 
Local Laboratory Assessments 
Samples for the laboratory tests in Table 7 will be sent to the study site local laboratory for 
analysis: 
Table 7: 
Laboratory Tests Sent to the Study Site Local Laboratory for Analysis 
Profile 
Laboratory Test 
Hematology 
CBC, including WBC count 
RBC count 
hemoglobin 
hematocrit 
platelet count 
differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells), if clinically indicated 
Chemistry Panel 
(Serum or Plasma) 
sodium 
potassium 
magnesium 
chloride 
bicarbonate 
glucose 
BUN or urea 
creatinine 
total protein 
albumin 
phosphorus 
calcium 
total bilirubin 
alkaline phosphatase 
ALT 
AST 
LDH 
TSH (T3 and FT4 should be checked if TSH is outside the normal range) 
Urinalysis 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete 
blood count; LDH = lactate dehydrogenase; RBC = red blood cell; TSH = thyroid-stimulating hormone; 
WBC = white blood cell 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The definitions of an AE or SAE can be found in Appendix 5. 
Investigators will seek information on AEs at each participant contact. Symptoms reported by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative), including those captured on the participant diary, or those noted by study 
personnel should be assessed by the Investigator according to Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0, which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. If the event meets 


 
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the definition of an AE, it should be recorded in the participant’s medical record and on the 
Adverse Event eCRF page, as appropriate. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE, AESI, or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention (see Appendix 5). 
8.3.1 
Time Period and Frequency for Collecting AE, AESI, SAE, and 
Other Reportable Safety Event Information 
All SAEs will be collected from the time the participant signs informed consent until at least 100 
days after the last dose of nivolumab. However, in the case of early discontinuation, participants 
should be followed for SAEs for up to 26 weeks after the last dose of microbiome study 
intervention.  
All AEs, including AESIs, will be collected from the start of study intervention until at least 100 
days after the last dose of study intervention. However, in the case of early discontinuation, 
participants should be followed for AESIs for up to 26 weeks after the last dose of microbiome 
study intervention. 
Prior to initiation of study intervention, only SAEs that are related to a protocol-mandated 
intervention, including those that occur prior to the assignment of study procedures (eg, 
screening invasive procedures, such as biopsies) should be reported. After obtaining informed 
consent, but prior to initiation of study intervention, other medical occurrences will be recorded 
as medical history. 
If the Investigator learns of any SAE, including a death, at any time after the end of the AE 
reporting period, and he/she considers the event to be reasonably related to the study intervention 
or study participation, the Investigator must promptly notify the Sponsor or its designee. The 
Investigator should report these events directly to the Sponsor or its designee, either by faxing or 
emailing the SAE report form. 
The method of recording and reporting AE, AESI, and SAE are provided in Appendix 5. The 
procedure for submitting SAE reports is provided in Section 8.3.8.2. 
During the 9-week microbiome study intervention administration, participants will use a 
participant-reported diary to record, on a daily basis during administration, the occurrence of 
solicited symptoms commonly associated with microbiome study intervention. For this study, 
solicited symptoms include: gas or flatulence; abdominal discomfort (distention, bloating, pain 
or cramping); diarrhea; vomiting; and constipation. 
The method of reporting all deaths are provided in Appendix 5. 


 
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8.3.1.1 
Events Requiring Expedited Reporting to the Sponsor 
Certain events require immediate reporting to allow the Sponsor to take appropriate measures to 
address potential new risks in a clinical trial. The Investigator must report such events to the 
Sponsor immediately; under no circumstances should reporting take place more than 24 hours 
after the Investigator becomes aware of the event. The following is a list of events that the 
Investigator must report to the Sponsor within 24 hours of becoming aware of the event, 
regardless of relationship to study intervention: 
• All SAEs (defined in Appendix 5) 
• Protocol-specified AEs of special interest (defined in Section 8.3.7) 
• Pregnancy (see Section 8.3.5 for details on reporting requirements) 
• Occurrence of overdose (see Section 8.4 for details on reporting requirements) 
 
8.3.2 
Follow-up Event Reporting 
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (ie, no more than 24 hours after becoming aware of the information). New 
significant information includes the following: 
• New signs or symptoms or a change in the diagnosis 
• Significant new diagnostic test results 
• Change in causality based on new information 
• Change in the event’s outcome, including recovery 
• Additional narrative information on the clinical course of the event 
 
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and AEs of special interest (as defined 
in Section 8.3.7) will be followed through at least 100 days post-last dose of study intervention, 
until event resolution or death, the participant is lost to follow-up (as defined in Section 7.3), or 
the participant withdraws consent. Further information on follow-up procedures is provided in 
Appendix 5. 
For SAEs and AEs of special interest, the Sponsor or a designee may follow up by telephone, 
fax, electronic mail, and/or a monitoring visit to obtain additional case details and outcome 
information (eg, from hospital discharge summaries, consultant reports, autopsy reports) in order 
to perform an independent medical assessment of the reported case. 


 
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8.3.3 
Method of Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for discussion of 
symptoms and eliciting AE information at all participant evaluation time points. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences including symptoms reported on the diary cards. Examples of non-directive 
questions include: “How have you felt since your last clinic visit?”, “Have you had any new or 
changed health problems since you were last here?” 
8.3.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met (see Section 8.3.1.1). Investigators must also 
comply with local requirements for reporting SAEs to the IRB/IEC or other local health 
authorities. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, Investigators, and drug manufacturer(s). 
Expectedness will be assessed using the Investigator Brochure(s) as reference documents. 
Reporting requirements will also be based on the Investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary.  
An Investigator who receives specific safety-related information (eg, SUSAR notification; 
summary or listing of SAEs) from the Sponsor will review and then file it along with the 
Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy 
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until at least 7 (female partners of male 
participants) and 5 (female participants) months after the last dose of nivolumab. Female 
participants, as well as female partners of male participants, of childbearing potential will be 
instructed to immediately inform the Investigator if they become pregnant during the study or 
within 5 or 7 months, respectively, after the last dose of nivolumab. If a pregnancy is reported, 


 
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the Investigator should inform the Sponsor within 24 hours of becoming aware of the pregnancy 
and should follow the procedures outlined in Appendix 6. Abnormal pregnancy outcomes that 
meet serious criteria (eg, spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs. 
A clinical trial specific Pregnancy Reporting form should be completed and submitted 
immediately to the Sponsor or its designee, either by faxing or by scanning and emailing the 
form using the fax number or email address provided to Investigators (see Section 8.3.8.2). 
Pregnancy should not be recorded on the Adverse Event eCRF page. The Investigator should 
discontinue study intervention and counsel the participant, discussing the risks of the pregnancy 
and the possible effects on the fetus. Monitoring of the participant should continue until 
conclusion of the pregnancy. Any SAEs associated with the pregnancy (eg, an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the SAE report form. In addition, the Investigator will submit an 
updated clinical trial specific Pregnancy Reporting form when updated information on the course 
and outcome of the pregnancy becomes available. 
8.3.6 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs 
Progression of the cancer under study, as judged by the Investigator, is not considered a 
reportable event. If upon further review by the Investigator, the event is determined as not being 
associated with underlying progression of disease, it must be reported as an SAE within 24 hours 
to the Parker Institute for Cancer Immunotherapy Pharmacovigilance Group as described in 
Section 8.3.8.2. 
8.3.7 
Adverse Events of Special Interest 
Selected non-serious and serious AEs, known as adverse events of special interest (AESIs), are 
those of scientific and medical concern specific to the product or program for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor is appropriate. 
Adverse events of special interest for this trial include: 
• An invasive infection (eg, bacteremia, abscess, meningitis) at least possibly related to 
FMT or SER-401 interventions. Microbiologic testing should be performed, if possible, 
to assess whether the infection is due to an organism acquired from FMT or SER-401. 
 
All AEs and AEs of special interest will be collected and reported according to Section 8.3.1. 
Serious AESIs will be adjudicated by the DMC. 


 
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8.3.8 
Sponsor Contact Information 
8.3.8.1 
Emergency Medical Contacts 
Parker Institute for Cancer Immunotherapy Medical Monitor Contact Information: 
Medical Monitor: 
Marko Spasic, MD 
 
Parker Institute for Cancer Immunotherapy  
 
1 Letterman Drive, Ste. D3500 
 
San Francisco, CA 94080 
 
mspasic@parkerici.org 
Telephone No.: 
(415) 539-3165 (Office; United States) 
8.3.8.2 
Safety Reporting Contacts 
The following contact information should be used when submitting safety-related paper forms 
(SAE report form and Pregnancy Report Form) as described in Appendix 5 for SAEs and other 
reportable safety events. These forms should be completed and submitted to the Sponsor 
immediately (ie, no more than 24 hours after becoming aware of the event), by faxing to the 
Parker Institute for Cancer Immunotherapy Pharmacovigilance Group at:  415-610-5471 within 
24 hours of event awareness. If technical issues arise, please contact Parker Institute for Cancer 
Immunotherapy Pharmacovigilance Group immediately at 415-930-4414, and the form may be 
scanned and emailed to safety@parkerici.org. 
Parker Institute for Cancer Immunotherapy Pharmacovigilance Group: 
• Pharmacovigilance Fax Number:  415-610-5471 
• Pharmacovigilance email:  safety@parkerici.org 
• Pharmacovigilance Telephone Number:  415-930-4414 
 
8.4 
TREATMENT OF OVERDOSE 
Overdose is defined as any dose higher than the dose specified to be administered in accordance 
with the protocol. 
The Investigator must immediately notify the Parker Institute for Cancer Immunotherapy 
Pharmacovigilance Group of any occurrence of overdose with study intervention. 
All overdoses should be reported as an SAE with the safety criteria of “other important 
medical event.” Details of signs and symptoms, clinical management, and outcome should be 
reported, if applicable. Overdoses should also be captured as protocol deviations. 
The PI has the obligation to report the deviations to the IRB/IEC. 


 
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8.5 
PHARMACOKINETICS 
Pharmacokinetic parameters are not evaluated in this study. 
8.6 
ANTI-DRUG ANTIBODIES 
Antibodies to nivolumab are not evaluated in this study. 
8.7 
BIOMARKERS 
The secondary biomarker objective of this study is to determine the engraftment of FMT and 
SER-401 bacteria into the intestinal microbiome community in stool samples and if the 
percentage of tumoral CD8 cells changes from baseline (prior to antibiotic treatment) in response 
to microbiome administration and nivolumab treatment. Engraftment will be determined by 
evaluation of baseline and on treatment stool samples using deoxyribonucleic acid (DNA) 
sequencing and a comparison to the stool samples from the placebo group. An engrafting species 
is defined as any species which is detectable in the microbiome intervention, absent in the 
participant at baseline, and present in the participant at any time point after treatment initiation. 
The number of engrafting species will be summarized by participant, study intervention group, 
and time point.  
The composition of the GI microbiome of participants will be characterized using genomic data 
sets generated from stool. Genomic data sets will define the bacterial composition of the 
microbiome of a participant at a given time point and relative to baseline. Genomic sequence 
read data sets will be analyzed to assign a taxonomic identity at the resolution of an operational 
taxonomic unit (OTU) and, further, to define the relative proportion of each OTU to all other 
OTUs in a given sample. Changes in the composition of the fecal microbiome will be measured 
in terms of both the total number of unique types of bacteria (ie, α-diversity) and the microbial 
composition (ie, β-diversity). The composition of other constituents of the microbiome such as 
fungi and viruses in the stool may be characterized. 
Non-parametric and machine learning computational methods will be applied to the genomic 
datasets to characterize a participant’s GI tract post-treatment compared to baseline.  
Differences between changes in the microbiome across the various study intervention groups will 
be evaluated in terms of changes in α-diversity, β-diversity, and the prevalence and relative 
abundance of specific OTUs.  
The percentage of tumoral CD8 cells will be determined from tumor tissue using 
immunohistochemistry (IHC). Tumor biopsies at baseline and on-treatment will be assessed for 
the percentage of tumoral CD8 cells and any change in percentage of tumoral CD8 cells in 
response to treatment. Immunohistochemistry will be performed using an anti-CD8 antibody 
with 3,3' diaminobenzidine chromogen, counterstained with hematoxylin.  


 
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The exploratory biomarker objectives of this study are to identify biomarkers associated with 
nivolumab and microbiome study intervention by assessing tumor tissue and circulating soluble 
factors, including, but not limited to, DNA, ribonucleic acid (RNA), enzymes, growth factors, 
cytokines, antibodies, and immune cells in tissue and blood and their association with treatment 
outcome. Additionally, microbiome profile, DNA, and metabolomics, may be evaluated from 
stool samples. Changes from baseline in the functional profile of the GI tract will be delineated 
using metabolomics data sets. Non-parametric and machine learning computational methods will 
be applied to metabolomic datasets to characterize changes in the functional profile of 
participants across different study intervention groups. Evaluation of baseline levels and/or 
changes with study intervention may be performed to determine association with clinical 
outcomes, including clinical response and resistance, as well as study intervention tolerability. 
• Collection of samples for biomarker research is part of this study. The following samples 
for biomarker research are required and will be collected from all participants in this 
study as specified in the Schedule of Activities (Table 1) and processed in accordance 
with the laboratory manual: 
o Blood 
o Peripheral blood mononuclear cells (PBMCs) 
o DNA 
o RNA 
o Tumor tissue biopsy, ideally from the same tumor lesion (before and while on 
study intervention) 
o Stool 
• Samples may be tested for genetic analysis on tumor and blood samples, including, but 
not limited to, assays on circulating free DNA, DNA from tumor, blood, and/or immune 
cells and T cell receptor sequencing may be performed. This research may evaluate 
whether genetic variations correspond with outcomes of treatment. If genetic variation is 
found to predict efficacy or AEs, the data might inform optimal use of therapies in cancer 
patients. Circulating soluble analytes may be assessed that may include but are not 
limited to immune cytokines, growth factors, antibodies, and/or markers associated with 
immune characteristics and activation or cancer. Additionally, tumor and blood samples 
will be collected before and on study intervention for immune and/or tumor cell profiling, 
which may include immune cell phenotyping, enumerations, and/or activation state. Both 
genome-wide and targeted messenger RNA expression profiling and sequencing in tumor 
and/or blood may be performed to define gene signatures that correlate with treatment 
outcomes. Epigenetic analyses may also be performed as these are important biomarkers 
for some cancers. Stool samples at baseline and on treatment will be evaluated for 
microbiome and/or metabolite profiling and may be used to determine if there is any 
association with treatment outcome. 
• Other samples may be used for research, including future research to develop methods, 
assays, prognostics, and/or companion diagnostics related to immuno-oncology 


 
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treatment, disease process, pathways associated with disease state, and/or mechanisms of 
action of checkpoint inhibitor treatment. 
 
8.7.1 
Genetics 
Sample collection, storage, and shipment instructions for planned genetic analysis samples will 
be provided in the Laboratory Manual. Samples should be collected for planned analysis of 
associations between genetic variants in germline/tumor DNA and clinical outcomes to study 
interventions(s). Blood for planned genetic analysis will be collected for DNA as described in 
the Schedule of Activities in Section 1.3. If a documented law or regulation prohibits (or local 
IRB/IEC does not approve) sample collection for these purposes, then such samples should not 
be collected at the corresponding sites. Additional DNA extracted from planned genetic analysis 
samples will be stored for future biomedical research only if participant signs the Future 
Biomedical Research consent. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
See Appendix 7 for Information regarding genetic research. 
8.7.2 
Enrollment Biomarker 
Stool samples are required at screening to assess fecal microbiome composition of the 
Ruminococcaceae abundance-based metric at screening (high, low) for the randomization. This 
test is required to determine stratification. The test for Ruminococcaeae is a laboratory-
developed test. It is not an FDA-approved device, and its use is investigational. Sample 
collection, storage, and shipment instructions are provided in the Laboratory Manual. 
Quantitative polymerase chain reaction (qPCR) on DNA extracted from stool will be performed 
and the Ruminococcaeae abundance-based metric will be reported. 
8.7.3 
Exploratory Biomarkers 
A fresh tumor biopsy is required at screening (prior to antibiotic or antibiotic placebo 
administration). An additional on-treatment biopsy is required after 2 infusions with anti-PD-1 
study intervention, when medically feasible. An optional biopsy may be obtained during the 
course of the study or at the time of disease progression, including from participants who 
respond and subsequently progress. Core needle or incisional tumor biopsy samples are required. 
Further, every attempt should be made for the on-treatment biopsy(ies) to be taken from the same 
lesion site. Fine needle aspiration is not allowed. 


 
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Blood will be collected for exploratory biomarkers. Blood may be used for whole blood, 
PBMCs, plasma and/or serum preparation, and nucleic acid extraction. These blood samples will 
be collected as described in the Schedule of Activities in Section 1.3.  
Stool samples will be collected for microbiome analysis, which may include microbiome 
sequencing and/or metabolites as outlined in the Schedule of Activities in Section 1.3.  
Tissue, blood and stool sample collection, storage, and shipment instructions are provided in the 
Laboratory Manual. 
8.7.4 
Sample Collection for Long-term Future Biomedical Research 
8.7.4.1 
Overview of Long-term Future Biomedical Research  
Participants in this clinical trial will be asked to consent to provide biological samples for long-
term future biomedical research. The objective of collecting/retaining specimens for future 
biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of disease and/or their therapeutic treatments. The overarching goal is to use such 
information to understand disease, safety, and potential treatments for future participants. Such 
research is for biomarker testing and hypothesis testing to address emergent questions not 
described elsewhere in the protocol (as part of the main trial). 
This research may include genetic and genomic analyses (DNA), gene expression profiling 
(RNA), proteomics, microbiome, metabolomics (serum, plasma, stool) and/or the measurement 
of other analytes, depending on which specimens are consented for future biomedical research. 
The collection and submission of biological samples to be stored for long-term future biomedical 
research must be detailed in the IRB/IEC-approved ICF. Participants who do not wish to 
participate in the future biomedical research may still participate in the study. 
8.7.4.2 
Sample Collection 
The following samples will be collected and stored in accordance with applicable law for long-
term research purposes, including but not limited to, research on biomarkers related to 
immunotherapies, such as anti-PD-1, and diseases such as cancer or inflammatory disorders: 
• Blood, including but not limited to PBMCs, plasma, and/or serum 
• DNA 
• RNA 
• Tumor tissue 
• Stool samples 
 
These samples may be sent to one or more laboratories. 


 
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For sampling procedures, storage conditions, and shipment instructions, see the Laboratory 
Manual. 
8.7.4.3 
Withdrawal from Long-term Sample Storage 
Participants have the right to withdraw their consent for the future biomedical research of his/her 
specimens at any time for any reason and request that their specimens be destroyed. If the 
participant wishes to withdraw consent for this testing, the Investigator must inform the Sponsor 
in writing. Any analyses in progress at the time of request for withdrawal or already performed 
prior to the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is received. 
In the event that the medical records for the main trial are no longer available (eg, if the 
Investigator is no longer required by regulatory authorities to retain the main trial records) or the 
specimens have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for specimen 
withdrawal cannot be processed. 
8.7.4.4 
Protection of Data Privacy and Data Generation 
Participant specimens and associated data will be labeled with a unique participant identification 
number. Participant medical information associated with the long-term storage of specimens is 
confidential and may be disclosed to third parties only as permitted by the ICF signed by the 
participant or as permitted or required by law. 
Given the complexity and research nature of the exploratory analyses, data derived from long-
term stored specimens will generally not be provided to study Investigators or participants unless 
required by law. 
Data generated from specimens that are stored long term must be available for inspection upon 
request by representatives of national or local health authorities and Sponsor monitors, 
representatives, and collaborators as appropriate and as described in Section 10.1.11. 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS 
Not applicable. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESIS 
This study is designed to evaluate the safety and tolerability of treatment with 1 of 2 oral 
microbiome study interventions (FMT or SER-401) in combination with anti-PD-1 therapy in 
participants with unresectable or metastatic melanoma. The study also intends to assess the 


 
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impact on the microbiome profile and assess the association of microbiome study intervention 
administration with clinical outcomes. 
9.2 
SAMPLE SIZE DETERMINATION 
The study is not intended or powered for hypothesis testing, including comparisons between 
study intervention groups. The study is intended to provide preliminary estimates of AE rates, 
response rates, effect sizes and confidence intervals to aid the design of future studies. A sample 
size of approximately 20 participants per group (FMT, SER-201, and pooled placebo in 
combination with nivolumab) will provide these preliminary estimates while limiting exposure.  
Table 8 provides 95% confidence intervals for the true proportion of responders for a sample size 
of 20 participants per group. These confidence intervals provide information needed for the 
design of further studies. 
Table 8: 
Confidence Intervals for the True Proportion of Responders 
Observed Proportion of 
Responders 
Lower 95% Confidence 
Bound 
Upper 95% Confidence 
Bound 
0.3 
0.119 
0.543 
0.4 
0.191 
0.639 
0.5 
0.272 
0.728 
0.6 
0.361 
0.809 
 
9.3 
POPULATIONS FOR ANALYSIS 
For purposes of analysis, the following populations are defined: 
Table 9: 
Populations for Analysis 
Population 
Description 
Safety Population 
All participants who receive at least 1 dose of any study intervention 
(vancomycin, FMT, SER-401, nivolumab or placebo). Participants 
will be analyzed according to the study intervention they actually 
received. Group 2 and Group 3 will be pooled as a single placebo 
group. Participants enrolled into Group 5 after progression will be 
included in the Safety Population twice: (1) the pooled placebo group 
prior to enrollment in Group 5 and (2) Group 5. The Safety 
Population will be the primary analysis population for all safety 
analyses. 
Antibiotic Safety Population 
All participants who receive at least 1 dose of any antibiotic study 
intervention (vancomycin or placebo). 
Microbiome Safety Population 
All participants who receive at least 1 dose of any microbiome study 
intervention (FMT, SER-401 or placebo). 
Anti-PD-1 Safety Population 
All participants who receive at least 1 dose of nivolumab. 


 
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Population 
Description 
Intent-to-Treat (ITT) 
Population 
All participants randomly assigned to study intervention, regardless 
of whether any study intervention was administered. Participants will 
be analyzed according to the study intervention to which they were 
allocated. 
Efficacy Population 
All participants randomly assigned to study intervention who receive 
at least 1 dose of nivolumab and at least 1 dose of any microbiome 
study intervention (FMT, SER-401 or placebo). Participants will be 
analyzed according to the study intervention to which they were 
allocated. Group 2 and Group 3 will be pooled as a single placebo 
group. Participants enrolled into Group 5 after progression will not be 
included in the Efficacy Population as Group 5 but will be included 
as part of the pooled placebo group. The Efficacy Population will be 
the primary analysis population for all efficacy analyses. 
Cross-over Efficacy 
Population 
All participants enrolled in Group 5 who receive at least 1 dose of 
nivolumab and at least 1 dose of SER-401. 
FMT = fecal microbiota transplant; ITT = intent-to-treat; PD-1 = programmed cell death-1 
 
9.4 
STATISTICAL ANALYSES 
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the study populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. The SAP will serve as a compliment to the protocol and 
supersedes it in case of differences. 
9.4.1 
Efficacy Analyses 
The analyses for clinical activity will be performed on the Efficacy Population, consisting of all 
participants randomly assigned to study intervention who receive at least 1 dose of nivolumab 
and at least 1 dose of any microbiome study intervention (FMT, SER-401, or placebo). 
Participants will be analyzed according to the study intervention to which they were allocated. 
Participants randomly allocated to either of the placebo groups (Group 2 or Group 3) will be 
pooled as a single placebo group for all efficacy analyses. A subset of efficacy analyses will also 
be conducted on the intent-to-treat (ITT) Population, as described in the SAP. 
Analyses of efficacy endpoints (secondary and exploratory) will be adjusted for the fecal 
microbiome composition of the Ruminococcaceae abundance-based metric at screening (high, 
low). 
This study is not intended or powered for hypothesis testing, including comparisons between 
study intervention groups. Due to the exploratory nature of this study, no control of type I error 
will be applied for any of the endpoints. 


 
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9.4.1.1 
Primary Efficacy Endpoints 
There are no primary efficacy objectives or endpoints for this study. 
9.4.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
• ORR: Defined as CR or PR as best response by RECIST v1.1 assessment. Participants 
who do not have RECIST assessment for any reason will be counted as not responding. 
• DCR: Defined as CR, PR, or stable disease (SD) for ≥ 24 weeks as best response by 
RECIST v1.1. Participants who do not have RECIST assessment for any reason will be 
counted as not responding. 
• PFS: Defined as the time from randomization to date of first documented radiographic 
progression of disease or date of death due to any cause, whichever occurs first. 
Participants who have not progressed or died will be censored at the last tumor 
assessment date. 
• PFS rate at 1 year: Defined as the proportion of participants without documented 
progression of disease or death due to any cause at 1 year. 
• OS: Defined as the time from randomization until death due to any cause. Participants 
who have not died will be censored at the most recent contact date they were known to be 
alive. 
• OS rate at 1 year: Defined as the proportion of participants alive at 1 year. 
• Duration of response: Defined as time from date of documented CR or PR to date of first 
documented radiographic progression of disease or date of death due to any cause, 
whichever occurs first. Participants who have not progressed or died will be censored at 
the last tumor assessment date. 
 
Response rates for ORR, DCR, PFS, and OS will be estimated within each study intervention 
group and 95% confidence intervals (CIs) will be estimated using the Clopper-Pearson method. 
PFS and OS will be estimated using Kaplan-Meier techniques, and the median survival time and 
95% CIs will be estimated within each study intervention group.  
9.4.1.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints include: 
• ORR in participants who receive SER-401 after progressing while on placebo (Group 5). 
• DCR in participants who receive SER-401 after progressing while on placebo (Group 5). 
• PFS rate at 1 year in participants who receive SER-401 after progressing while on 
placebo (Group 5). 
• OS rate at 1 year in participants who receive SER-401 after progressing while on placebo 
(Group 5). 


 
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The above exploratory endpoints will be analyzed on the Cross-over Efficacy Population. 
Further analysis details will be described in the SAP. 
9.4.2 
Safety Analyses 
All safety analyses will be performed on the Safety Population, consisting of all participants who 
receive at least 1 dose of any study intervention (vancomycin, FMT, SER-401, nivolumab, or 
placebo). Participants will be analyzed according to the study intervention they actually received. 
A subset of safety analyses will also be conducted on the Anti-PD-1 Safety Population, as 
described in the SAP. 
Safety will be assessed through summaries of AEs, laboratory test results (hematology and serum 
chemistry), vital signs, ECGs, and ECOG performance score. Verbatim descriptions of 
treatment-emergent AEs (defined in Section 10.5.1.4) will be coded using the current version of 
the Medical Dictionary for Regulatory Activities (MedDRA), and their incidence will be 
summarized by study intervention group. In addition, separate summaries will be generated for 
AESIs, SAEs, deaths, AEs leading to study discontinuation, and AEs leading to treatment 
discontinuation. 
Safety analyses will also be performed for events and assessments that occur during the 
antibiotic/microbiome lead-in phase. Events and assessments occurring during the antibiotic or 
antibiotic placebo administration and washout (Day -14 to Day -7) will be summarized for the 
Antibiotic Safety Population, defined as all participants who receive at least 1 dose of any 
antibiotic study intervention (vancomycin or placebo). Events and assessments occurring during 
the microbiome lead-in (Day -7 to Cycle 1 Day 1) will be summarized for the Microbiome 
Safety Population, defined as all participants who receive at least 1 dose of any microbiome 
study intervention (FMT, SER-401 or placebo). 
9.4.3 
Other Analyses 
The number of participants who were screened, enrolled and treated, enrolled and not treated, 
and completed the study will be presented in summary tables. The reason for discontinuation 
from the study will be listed by participant and summarized in a table. The number of 
participants in each study intervention group and analysis population will be summarized. 
Demographic and baseline characteristics of the study population will be summarized overall and 
for each study intervention group. Categorical measures will be summarized using frequencies 
and percentages. Continuous variables will be summarized using means, standard deviations, 
medians, minimums, and maximums. 


 
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9.4.3.1 
Biomarker Analyses 
The secondary biomarker endpoints include: 
• Determination of the engraftment of FMT or SER-401 bacteria into each of the 
microbiome study intervention groups relative to placebo. 
• Change in the percentage of CD8 cells in tumor tissue from baseline at Cycle 2. 
The exploratory biomarker endpoints include: 
• Changes in the composition of the fecal microbiome from baseline to on treatment 
following administration of FMT, SER-401, or placebo. 
• Functional changes in transcriptomic, metabolomic, and/or proteomic profiles from 
baseline to on treatment. 
• Association of T-cell phenotypic characteristics and immune characteristics in the tumor 
with clinical outcomes (eg, ORR, DCR, PFS, OS) and/or AEs. 
• Molecular (genomic, metabolic, and/or proteomic) or microbial biomarkers that may be 
indicative of clinical response/resistance, safety, pharmacodynamic activity, and/or 
mechanism of action of anti-PD-1 therapy and their relationship to microbiome study 
intervention administration. 
 
Absolute change in percentage of CD8 tumoral cells will be summarized by study intervention 
group using means and 95% CIs. Other biomarker analyses will be performed as described in 
Section 8.7. 
9.5 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
9.5.1 
Data Monitoring Committee 
Ongoing safety data review will be conducted by the Data Monitoring Committee (DMC). This 
is a committee that is formed of select Sponsor personnel, including the Medical Monitor and 
representatives from other functions including, but not limited to, Biostatistics, Clinical Science, 
and Drug Safety. Members of the DMC will be unblinded to participant treatment assignment. 
To ensure participants’ safety during the study, the DMC will review the emerging safety data on 
a regular basis. Roles and responsibilities of the DMC will be detailed in a separate charter. 
Safety monitoring will include unblinded evaluation of all AEs, AESIs, SAEs, relevant protocol 
deviations, and laboratory data. If the DMC deems a benefit-risk assessment necessary, the DMC 
may also review unblinded efficacy data. The DMC may decide to stop the study early or 
suspend enrollment of a study intervention group for safety reasons. 


 
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Study-holding criteria as described in Section 7.1.1 will be adjudicated by the DMC per the 
study-specific DMC charter.  
For safety monitoring purposes, a trial-limiting toxicity is defined as: 
1. Any event listed in Table 4. 
2. Any SAE assessed as at least possibly related to the study intervention. 
3. Any AESI (defined in Section 8.3.7) assessed as at least possibly related to the 
microbiome study interventions. 
 
A Bayesian rule will be employed to monitor toxicity throughout the study (Table 10). A 
minimally informative beta (0.5, 2.5) prior has been assumed. For each study intervention group, 
if the number of participants with a trial-limiting toxicity (defined above) is greater than or equal 
to the number in Table 10, then enrollment and dosing of that study intervention group will be 
immediately halted, as it is likely that the toxicity rate is >30%, as noted by the Bayesian 
posterior probabilities. The rule is intentionally conservative early in the enrollment phase. If 
administration of a study intervention group is halted, all available safety data will be reviewed 
by an independent medical monitor who will determine, in consultation with the DMC, whether 
to resume administration of study intervention and/or enrollment. 
Table 10: 
Stopping Rules for Trial-limiting Toxicity Rate Greater Than 30% 
Participants administered study intervention within a group 
10 
15 
20 
Participants with Trial-limiting Toxicity 
4 
6 
9 
Posterior Probability [toxicity rate >30%] 
0.61 
0.69 
0.87 
 


 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
APPENDIX 1: REGULATORY, ETHICAL AND STUDY 
OVERSIGHT CONSIDERATIONS 
10.1.1 
Compliance with Laws and Regulations 
This study will be conducted in full conformance with the International Council for 
Harmonisation (ICH) E6 guideline for Good Clinical Practice and the consensus ethical 
principles derived from international guidelines, including the Declaration of Helsinki and 
Council for International Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines, and applicable laws and regulations. The study will comply with the requirements of 
the ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. Investigational 
New Drug (IND) application will comply with U.S. FDA regulations and applicable local, state, 
and federal laws. Studies conducted in the European Union or European Economic Area will 
comply with the E.U. Clinical Trial Directive (2001/20/EC). 
10.1.2 
Institutional Review Board or Independent Ethics Committee 
The protocol, protocol amendments, ICF(s), Investigator’s Brochure, any information to be given 
to the participant, and relevant supporting information must be submitted to the IRB/IEC and 
reviewed and approved by the IRB/IEC before the study is initiated. In addition, any participant 
recruitment materials (eg, advertisements) must be approved by the IRB/IEC. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants or changes that involve logistical or administrative aspects only (eg, 
change in Medical Monitor or contact information).  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Promptly documenting and reporting any deviations that might have an impact on 
participant safety and data integrity to the Sponsor and to the IRB/IEC in accordance with 
established requirements, policies and procedures 


 
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• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations. 
 
10.1.3 
Financial Disclosure 
Investigators and Sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate health authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study (see definition of end of study in Section 4.5). 
10.1.4 
Informed Consent 
The Investigator or his/her representative will explain the nature of the study to the participant or 
his/her legally authorized representative and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
The ICF will contain separate signature sections for the following procedures which include: 1) 
blood, tumor, and stool samples for biomarker analysis intended to be used for future or 
exploratory research purposes and 2) a tumor biopsy at the time of disease progression or 
additional on-treatment timepoint.  
The Investigator or authorized designee will explain to each participant the objectives, methods, 
and potential risks associated with each optional procedure. Participants will be told that they are 
free to refuse to participate and may withdraw their consent at any time for any reason. A 
separate, specific signature will be required to document a participant's agreement to participate 
in optional procedures. Participants who decline to participate will not provide a separate 
signature. 
Participants must be re-consented to the most current version of the ICF(s) (or to a significant 
new information/findings addendum in accordance with applicable laws and IRB/IEC policy) 
during their participation in the study. The medical record should document the re-consent 
process and that written informed consent was obtained using the updated/revised ICF for 
continued participation in the study. 


 
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A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. All signed and dated ICFs must remain in the participant’s study file or in the site 
study file and must be available for verification by study monitors at any time. 
The final revised IRB/IEC-approved ICFs must be provided to the Sponsor for the purpose of 
health authority submission. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date. 
A participant who receives placebo in Groups 2 or 3 and has radiographic evidence of 
progression of disease while on study and agrees to receive active SER-401 and nivolumab 
treatment as part of a cross-over to Group 5 will be required to sign another ICF prior to entering 
Group 5. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a participant's agreement to 
allow any remaining specimens to be used for exploratory research. Participants who decline to 
participate in this optional research will not provide this separate signature. 
10.1.5 
Data Protection 
The Sponsor maintains confidentiality standards by assigning a unique participant identification 
number to each participant enrolled in the study. This means that participant names are not 
included in data sets that are transmitted to any Sponsor location. 
Participant medical information obtained by this study is confidential and may be disclosed to 
third parties only as permitted by the ICF (or separate authorization for use and disclosure of 
personal health information) signed by the participant or as permitted or required by law. 
Medical information may be given to a participant’s personal physician or other appropriate 
medical personnel responsible for the participant’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by representatives of 
national and local health authorities, Sponsor monitors, representatives and collaborators, and the 
IRB/IEC for each study site, as appropriate. 
10.1.6 
Dissemination of Clinical Study Data 
The results of this study may be reported to the public, in the form of a publication or 
presentation at scientific congresses, before completion of the study. 


 
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10.1.7 
Administrative Structure 
This trial will be sponsored and managed by the Parker Institute for Cancer Immunotherapy. The 
Sponsor will provide clinical operations management, data management, medical monitoring, 
and safety oversight. 
Central facilities will be used for certain study assessments throughout the study (eg, specified 
laboratory tests and biomarker analyses), as specified in Section 8.2.5 and Section 8.7, 
respectively. Accredited local laboratories will be used for routine monitoring; local laboratory 
ranges will be collected. 
10.1.8 
Data Quality Assurance 
All participant data relating to the study will be collected via the electronic data collection (EDC) 
system on an eCRF unless transmitted to the Sponsor or designee electronically (eg, central 
laboratory data, biomarker and other biological sample data). Sites will be responsible for data 
entry into the EDC system and will receive training for appropriate eCRF completion. The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing and dating the eCRF. 
The Investigator must maintain accurate documentation (source data, see Section 10.1.9) that 
supports the information entered in the eCRF. The Investigator must permit study-related 
monitoring, audits, IRB/IEC review, and regulatory agency inspections and provide direct access 
to source data documents. 
The Sponsor is responsible for the data management of this study, including quality checking of 
the data. Study monitors will perform ongoing source data verification to confirm that data 
entered on the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH Good Clinical Practice (GCP), and all applicable regulatory requirements. 
At the end of the study, the Investigator will receive participant data for his/her site in a readable 
format on a compact disc (or other readable digital format) that must be kept with the study 
records. Acknowledgement of receipt of the compact disc is required. 
10.1.9 
Source Documentation 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. Data entered 
on the eCRF that are transcribed from source documents must be consistent with the source 
documents or the discrepancies must be explained. The Investigator may need to request 


 
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previous medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
Source documents (paper or electronic) are those in which participant data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, clinical outcome assessment (COA)/patient reported 
outcomes (PRO), evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies of transcriptions that are certified after verification as being 
accurate and complete, microfiche, photographic negatives, microfilm or magnetic media, 
X-rays, participant files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
When clinical observations are entered directly into a study site’s computerized medical record 
system (ie, in lieu of original hardcopy records), the electronic record can serve as the source 
document if the system has been validated in accordance with health authority requirements 
pertaining to computerized systems used in clinical research. An acceptable computerized data 
collection system allows preservation of the original entry of data. If original data are modified, 
the system should maintain a viewable audit trail that shows the original data as well as the 
reason for the change, name of the person making the change, and date of the change. 
Source documents that are required to verify the validity and completeness of data entered on the 
eCRFs must not be obliterated or destroyed and must be retained as described in Section 10.1.12. 
10.1.10 
Study and Site Closure 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Reasons for terminating the study may 
include, but are not limited to, the following: 
• Discontinuation of further study intervention development 
• The incidence or severity of AEs in this or other studies indicates the potential hazard to 
participants 
• Participant enrollment is unsatisfactory 
 
The Sponsor will notify the Investigator if the Sponsor decides to discontinue the study. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 


 
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• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
• No study activity (ie, all participants have completed the study and all obligations have 
been fulfilled) 
 
10.1.11 
Site Inspections 
Site visits will be conducted by the Sponsor or an authorized representative for inspection of 
study data, participants' medical records, and eCRFs. The Investigator will permit national and 
local health authorities; Sponsor monitors, representatives and collaborators; and the IRBs/IECs 
to inspect facilities and records relevant to this study. 
10.1.12 
Retention of Records 
Records and documents pertaining to the conduct of this study and distribution of the 
investigational medicinal product, including signed eCRFs, electronic or paper COA/PROs data 
(if applicable), signed informed consent forms, laboratory test results, and medication inventory 
records, must be retained by the Investigator for the maximum period required by applicable 
regulations of relevant national or local health authorities. No records may be disposed of 
without the written approval of the Sponsor. The Sponsor will notify the Investigator when the 
records are no longer needed. Following notification from the Sponsor, the documents may be 
destroyed, subject to local regulations.  
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
10.1.13 
Publication Policy and Protection of Trade Secrets 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing information on 
the trial to healthcare professionals and to the public, both at scientific congresses and in peer-
reviewed journals. The Sponsor will comply with all requirements for publication of study 
results. 
The Investigator must agree to submit all manuscripts or abstracts to the Sponsor prior to 
submission for publication or presentation. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may not yet 
be available to the Investigator. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter trials only in their entirety and not as individual center data. In this case, a 
Coordinating Investigator will be designated in accordance with the Parker Institute for Cancer 


 
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Immunotherapy publication policy. Authorship will be based on overall scientific contribution 
and participant enrollment. 
 


 
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10.2 
APPENDIX 2: EASTERN COOPERATIVE ONCOLOGY 
GROUP (ECOG) 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, eg, 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 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 


 
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10.3 
APPENDIX 3: RECIST CRITERIA (VERSION 1.1) 
Tumor response will be assessed according to RECIST v1.1 (Eisenhauer et al., 2009) as 
described below. 
10.3.1 
Measurability of Tumor at Baseline 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or nonmeasurable as 
follows: 
• Measurable 
Tumor lesions: Must be accurately measured in ≥ 1 dimension (longest diameter in the 
plane of measurement to be recorded) with a minimum size of: 
o 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
o 10 mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable) 
o 20 mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). 
• Nonmeasurable 
o All other lesions (or disease sites), including small lesions (longest diameter < 10 mm 
or pathological lymph nodes with ≥ 10 to < 15 mm short axis) 
o Lesions considered truly nonmeasurable include the following: leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, and abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques 
 


 
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10.3.2 
Tumor Response Evaluation 
10.3.2.1 
Baseline Documentation of Target and Nontarget Lesions 
• Target lesions 
o When > 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 
lesions total (and a maximum of 2 lesions per organ) representative of all involved 
organs should be identified as target lesions 
o It may be the case that, on occasion, the largest lesion which can be measured 
reproducibly should be selected 
• Nontarget lesions 
o All other lesions (or disease sites), including pathological lymph nodes, should be 
identified as nontarget lesions 
o It is possible to record multiple nontarget lesions involving the same organ as a single 
item (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’) 
10.3.2.2 
Evaluation of Target Lesions 
Target lesions will be evaluated and response recorded as defined in Appendix Table 1. 
Appendix Table 1: 
Response Based on Evaluation of Target Lesions at Each Assessment 
Complete response 
Disappearance of all target lesions; if a pathologic lymph node, 
reduction in the shortest axis to < 10 mma 
Partial responseb 
≥ 30% decrease in the sum of the diameters of target lesions relative 
to the baseline sum diametersc 
Stable diseaseb,d 
Neither a sufficient reduction to qualify as a partial response nor a 
sufficient increase to qualify as progressionc 
Progressive diseaseb 
≥ 20% increase in the sum diameters relative to the smallest sum 
diameters recorded (including the baseline sum diameters) in 
conjunction with an increase of at least 5 mm in that smallest sum 
diameters, or the appearance of 1 or more new lesionsc,e 
a For each pathologic lymph node considered a target lesion, the node must have a short axis measuring < 10 mm to 
be considered as a complete response. In such cases, the sum diameters may not be zero (as a normal lymph node 
can have a short axis of < 10 mm). 
b For each pathologic lymph node considered a target lesion, the measurement of the short axis of the node is to be 
included in the sum diameters when determining partial response, stable disease, and progression. 
c In this study, the “baseline sum diameters” is calculated based on the lesion measurements obtained at screening. 
d Duration of stable disease is measured from the date of the first dose of study intervention until criteria for 
progressive disease are met based on the smallest sum diameters recorded (including the baseline sum diameters). 
e The finding of a new lesion should be unequivocal and not possibly attributable to a difference in imaging 
modality or scanning technique. Post-baseline, fluorodeoxyglucose positron emission tomography (FDG-PET) 
may be useful in assessing new lesions apparent on CT scan. 


 
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10.3.2.3 
Evaluation of Nontarget Lesions 
Nontarget lesions will be evaluated and response recorded as defined in Appendix Table 2. 
Appendix Table 2: 
Response Based on Evaluation of Nontarget Lesions at Each 
Assessment 
Complete response 
Disappearance of all non-target lesions; all lymph nodes must be 
nonpathologic in size (ie, < 10 mm on the short axis) 
Not complete response nor 
progressive disease 
Persistence of 1 or more non-target lesions 
Progressive disease 
Unequivocal progressiona of any existing non-target lesion or the 
appearance of 1 or more new lesionsb 
a The participant should stop study intervention, even in the presence of a partial response or stable disease, based 
on assessment of target lesions. 
b The finding of a new lesion should be unequivocal and not possibly attributable to a difference in imaging 
modality or scanning technique. Post-baseline, fluorodeoxyglucose positron emission tomography (FDG-PET) 
may be useful in assessing new lesions apparent on computerized tomography (CT) scan. 
 
10.3.2.4 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (eg, some ‘new’ bone 
lesions may be simply healing or flare of pre-existing lesions). This is particularly important 
when the participant’s baseline lesions show PR or CR. For example, necrosis of a liver lesion 
may be reported on a CT scan as report as a ‘new’ cystic lesion, which it is not. 
10.3.2.5 
Evaluation of Overall Response 
Overall response based on the evaluation of target and nontarget lesions will be determined as 
shown in Appendix Table 3. 
Appendix Table 3: 
Evaluation of Overall Response at Each Assessment 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response 
No 
Complete response 
No target lesiona 
Complete response 
No 
Complete response 
Complete response 
Not evaluableb 
No 
Partial response 
Complete response 
Not complete response/ 
non-progressive disease 
No 
Partial response 


 
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Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
Partial response 
Non-progressive disease and 
not evaluableb 
No 
Partial response 
Stable disease 
Non-progressive disease and 
not evaluableb 
No 
Stable disease 
Not all evaluated 
Non-progressive disease 
No 
Not evaluable 
No target lesiona 
Not all evaluated 
No 
Not evaluable 
No target lesiona 
Non-complete response/ 
non-progressive disease 
No 
Non-complete response/ 
non-progressive disease 
Progressive disease 
Any 
Yes or no 
Progressive disease 
Any 
Progressive disease 
Yes or no 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
No target lesiona 
Unequivocal progressive disease 
Yes or No 
Progressive disease 
No target lesiona 
Any 
Yes 
Progressive disease 
a Defined as no target lesions at baseline. 
b Not evaluable is defined as either when no or only a subset of lesion measurements are made at an assessment. 
 
 


 
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10.4 
APPENDIX 4: CLINICAL LABORATORY TESTS 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol and the protocol appendix for each respective combination. 
• Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 
 


 
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10.5 
APPENDIX 5: ADVERSE EVENTS: DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING 
10.5.1 
Definitions 
10.5.1.1 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a participant, temporally associated with the 
use of study intervention, whether or not considered related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention. 
 
Events Meeting the AE Definition  
• Any abnormality or deterioration in a laboratory test results (hematology, clinical 
chemistry, or urinalysis) or other safety assessments (eg, ECG, radiological scans, vital 
signs measurements), including those that worsen from baseline, or are considered 
clinically significant in the medical and scientific judgment of the Investigator. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• A new condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.  
• Serious events that are related to a protocol-mandated intervention, including those that 
occur prior to assignment of study procedures (eg, screening invasive procedures, such as 
biopsies, discontinuation of study intervention). 
• Any new cancer (that is not a condition of the study) including basal and squamous cell 
carcinoma.  
• Note: Progression of the cancer under study is not a reportable event. Refer to 
Section 8.3.6 for additional details. 
 


 
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Events NOT Meeting the AE Definition  
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
• Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened. 
 
10.5.1.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met. 
An SAE is defined as any AE that suggests a significant hazard, contraindication, side 
effect, or untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained at the hospital or 
emergency ward for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Hospitalization is defined as an inpatient admission, 
regardless of length of stay, even if the hospitalization is a precautionary measure for 
continued observation. 
Note: Hospitalizations for the following reasons are not considered SAEs in this study: 
• a visit to the emergency room or other hospital department for < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
• elective surgery, planned prior to signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy) 


 
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• medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases 
• admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
d. 
Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
In offspring of a participant exposed to the study intervention regardless of timing as 
determined for study intervention based on product half-life. Any spontaneous abortion should 
be reported in the same fashion (as the Sponsor considers spontaneous abortions to be 
medically significant). 
f. 
Other important medical events: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
 
10.5.1.3 
Definition of Unexpected AE 
Unexpected AE Definition 
• Any AE, the specificity or severity of which is not consistent with the current 
Investigator’s Brochure. Expected means that the event has previously been observed with 
the study intervention and is identified and/or described in the current IB. It does not mean 
that the event is expected with the underlying disease(s), co-morbidities or concomitant 
medications. 
 


 
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10.5.1.4 
Definition of Treatment-emergent AE 
Treatment-emergent AE Definition 
• Any unfavorable and unintended diagnosis, symptom, sign (including an abnormal 
laboratory finding that is considered to be clinically significant), syndrome or disease that 
either occurs during the study, having been absent at baseline, or, if present at baseline, 
appears to have worsened in severity or frequency, whether or not the event is considered 
related to the study intervention. 
10.5.2 
Additional Events Reported in the Same Manner as an SAE 
Additional Events Reported in the Same Manner as a SAE 
• In addition to the SAE criteria in Section 10.5.1.2, AEs meeting any of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by the Sponsor for collection purposes. 
o A new invasive or malignant cancer (not the indicated condition of the study) 
o An overdose or is an associated event that meets safety criterion with an 
overdose (as specified in Section 8.4) 
o Protocol-specified AESIs (as defined in Section 8.3.7) 
o Pregnancy (as specified in Section 8.3.5) 
 
10.5.3 
Recording AEs and SAEs 
AE and SAE Recording 
• When an AE/AESI/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event. Only a single AE term should be recorded for the event. 
• The Investigator will record all relevant AE/AESI/SAE information in the eCRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the Adverse Event eCRF/SAE report form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor. 


 
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• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/AESI/SAE.  
Assessment of Severity 
• The terms ‘severe’ and ‘serious’ are not synonymous. An event is defined as ‘serious’ 
when it meets at least 1 of the predefined outcomes as described in the definition of an 
SAE, NOT when it is rated as severe. Severity (intensity) and seriousness need to be 
independently assessed for each AE recorded on the eCRF. 
• The Investigator will assess the intensity for each AE, including AESI, and SAE (and other 
reportable safety events) according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 5.0, which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
The following grading will be used for assessing intensity for AEs not specifically listed in 
the NCI CTCAE: 
o Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
o Grade 2: Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living. 
o 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. 
o Grade 4: Life threatening consequences; urgent intervention indicated. 
o Grade 5: Death related to AE. 
• Any changes to CTCAE grade over the course of a given episode (ie, persistent AE) will 
have each change of grade recorded on the Adverse Event CRFs. 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/AESI/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use their clinical judgment, knowledge of the participant, the 
circumstances surrounding the event, and an evaluation of any potential alternative causes 
to determine the relationship. 
• The following guidance will be considered and investigated: 
o Temporal relationship of the event onset to study intervention administration 


 
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o Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study intervention, or reintroduction of study intervention (as 
applicable) 
o Known association of the event with the study intervention or with similar 
treatments 
o Known association of the event with the disease under study 
o Presence of risk factors in the participant or use of concomitant medications 
known to increase the occurrence of the event 
o Presence of non-treatment-related factors that are known to be associated with 
the occurrence of the event 
• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/AESI/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/AESI/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
• For studies in which multiple agents are administered as part of a combination regimen, 
the Investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the Investigator’s opinion, there are sufficient data to 
support full attribution of the AE to the single agent. 
Causality of AEs, AESIs, and SAEs in this protocol will be assessed as follows: 
• Unrelated: This category applies to those AEs that are clearly and incontrovertibly due to 
extraneous causes (disease, environment, etc.). 
Note: If an AE is assessed as unrelated to the study intervention(s), there must be an 
alternative etiology in the Investigator’s assessment for that event documented in the 
participant’s medical records. 
• Unlikely Related: This category applies to those AEs that are judged to be unrelated to the 
study intervention(s), but for which no extraneous cause may be found. An AE may be 
considered unlikely to be related to study intervention(s) if or when it meets 2 of the 
following criteria: 


 
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o it does not follow a reasonable temporal sequence from administration of the 
study intervention(s); 
o it could readily have been produced by the participant’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
participant; 
o it does not follow a known pattern of response to the study intervention(s); or 
o it does not reappear or worsen when the study intervention(s) is 
re-administered. 
• Possibly Related: This category applies to those AEs for which a connection with the 
study intervention administration appears unlikely but cannot be ruled out with certainty. 
An AE may be considered possibly related if or when it meets 2 of the following criteria: 
o it follows a reasonable temporal sequence from administration of the study 
intervention(s); 
o it could not readily have been produced by the participant’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
participant; or 
o it follows a known pattern of response to the study intervention(s). 
• Probably Related: This category applies to those AEs that the Investigator feels with a 
high degree of certainty are related to the study intervention(s). An AE may be considered 
probably related if or when it meets 3 of the following criteria: 
o it follows a reasonable temporal sequence from administration of the study 
intervention(s); 
o it could not be reasonably explained by the known characteristics of the 
participant’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the participant; 
o it disappears or decreases on cessation or reduction in dose (note that there are 
exceptions when an AE does not disappear upon discontinuation of the study 
intervention, yet study intervention relatedness clearly exists; for example, as in 
bone marrow depression, fixed study intervention eruptions, or tardive 
dyskinesia); or 
o it follows a known pattern of response to the study intervention(s). 
• Definitely Related: This category applies to those AEs that the Investigator believes are 
incontrovertibly related to study intervention(s). An AE may be assigned an attribution of 
definitely related if or when it meets all of the following criteria: 
o it follows a reasonable temporal sequence from administration of the study 
intervention(s); 
o it could not be reasonably explained by the known characteristics of the 
participant’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the participant; 


 
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o it disappears or decreases on cessation or reduction in dose and recurs with 
re-exposure to study intervention(s) (if rechallenge occurs); and 
o it follows a known pattern of response to the study intervention(s). 
 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• New or updated information will be recorded on the eCRF. 
• The Investigator will submit any updated data related to SAEs or AESIs to the Sponsor 
within 24 hours of receipt of the information. 
 
10.5.4 
Reporting of AEs, AESIs, SAEs, and Other Reportable Safety 
Events to the Sponsor 
Reporting of AEs, AESIs, SAEs, and Other Reportable Safety Events to the Sponsor via 
an Electronic Data Collection Tool  
• The primary mechanism for reporting AEs to the Sponsor will be via the electronic data 
collection (EDC) tool.  
• Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent). 
• If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper AE reporting tool (see next section). 
• Reference Section 8.3.1– Time Period and Frequency for Collecting AE, AESI, SAE, and 
Other Reportable Safety Event Information for reporting time requirements  
• After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data. 
• The site will report all AESIs on the study-specific SAE report form to the Parker Institute 
for Cancer Immunotherapy study team within 24 hours of site awareness. The AESI should 
also be reported on the Adverse Event eCRF. 
• The site will report all SAE data on the study-specific SAE report form to the Parker 
Institute for Cancer Immunotherapy study team within 24 hours of site awareness. 


 
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• Contacts for reporting SAEs, AESIs, and other reportable safety event can be found in 
Section 8.3.8.2. 
 
SAE and Other Reportable Safety Event Reporting to the Sponsor 
• In the instance where an SAE or AESI occurs, a facsimile transmission of the SAE report 
form and/or Pregnancy form is the preferred method to transmit this information to the 
Parker Institute for Cancer Immunotherapy Pharmacovigilance Group. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE report form sent via email. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE report form within the designated reporting time frames. 
• Contacts for SAE, AESI, and other reportable safety event reporting can be found in 
Section 8.3.8.2. 
 
10.5.5 
Additional Reporting Considerations 
AE and SAE Recording for Special Circumstances 
Diagnosis versus Signs and Symptoms 
• Symptoms reported on the diary cards should be assessed by the Investigator for clinical 
significance and should be added as an Adverse Event according to the Investigator’s 
judgement or CTCAE 5.0 criteria, if appropriate.  
• A diagnosis (if known) or cause of death should be recorded on the Adverse Event eCRF 
page rather than individual signs and symptoms (eg, record only liver failure or hepatitis 
rather than jaundice, asterixis, and elevated transaminases). 
• If a constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
separately on the Adverse Event eCRF page. 
• If a diagnosis is subsequently established, all previously reported AEs based on signs and 
symptoms should be nullified and replaced by one AE report based on the single diagnosis, 
with a starting date that corresponds to the starting date of the first symptom of the 
eventual diagnosis. 
Adverse Events That Are Secondary to Other Events 
• In general, AEs that are secondary to other events (eg, cascade events or clinical sequelae) 
should be identified by their primary cause, with the exception of severe or serious 
secondary events. A medically significant secondary AE that is separated in time from the 


 
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initiating event should be recorded as an independent event on the Adverse Event eCRF 
page. For example: 
o If vomiting results in mild dehydration with no additional treatment in a healthy 
adult, only vomiting should be reported on the eCRF. 
o If vomiting results in severe dehydration, both events should be reported 
separately on the eCRF. 
o If a severe gastrointestinal hemorrhage leads to renal failure, both events should 
be reported separately on the eCRF. 
o If dizziness leads to a fall and consequent fracture, all 3 events should be 
reported separately on the eCRF. 
o If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
• All AEs should be recorded separately on the Adverse Event eCRF page if it is unclear 
as to whether the events are associated. 
Persistent or Recurrent Adverse Events 
• A persistent AE is one that extends continuously, without resolution, between participant 
evaluation time points. Such events should only be recorded once on the Adverse Event 
eCRF page. The initial severity (intensity or grade) of the event will be recorded at the 
time the event is first reported. 
• If a persistent AE becomes more severe, the most extreme severity should also be recorded 
on the Adverse Event eCRF page, and details regarding any increases or decreases in 
severity will be captured on the Adverse Event eCRF. 
• If the event becomes serious, it should be reported to the Sponsor as an SAE, and the 
Adverse Event eCRF page should be updated by changing the event from "non-serious" to 
"serious," providing the date that the event became serious, and completing all data fields 
related to SAEs. 
• A recurrent AE is one that resolves between participant evaluation time points and 
subsequently recurs. Each recurrence of an AE should be recorded as a separate event on 
the Adverse Event eCRF page. 
Abnormal Laboratory Values 
• A clinical laboratory test value must be reported as an AE if it meets any of the following 
criteria: 
o is accompanied by clinical symptoms 
o results in a change in study intervention (eg, dose modification, treatment 
interruption, or treatment discontinuation) 
o results in a medical intervention or change in concomitant medication 
o is clinically significant in the Investigator’s judgment 


 
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Abnormal Vital Sign Values 
• Medical and scientific judgment should be exercised in deciding whether an isolated vital 
sign abnormality should be classified as an AE. 
• If a clinically significant vital sign abnormality is a sign of a disease or syndrome (eg, high 
blood pressure), only the diagnosis (ie, hypertension) should be recorded on the Adverse 
Event eCRF page. 
• Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF page (see above for details on 
recording persistent AE). 
Abnormal Liver Function Tests 
• The finding of an elevated ALT or AST (> 3 x baseline value) in combination with either 
an elevated total bilirubin (>2 x ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law). Therefore, Investigators must report as an AE the occurrence of 
either of the following: 
o Treatment-emergent ALT or AST > 3 x baseline value in combination with 
total bilirubin > 2 x ULN (of which ≥ 35% is direct bilirubin) 
o Treatment-emergent ALT or AST > 3 x baseline value in combination with 
clinical jaundice 
• The most appropriate diagnosis or if a diagnosis cannot be established, the abnormal 
laboratory values should be recorded on the Adverse Event eCRF page and reported to the 
Sponsor immediately as an SAE or an AESI (see Section 8.3.7). 
Lack of Efficacy or Worsening of Underlying Disease 
• Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs. These data will be captured as efficacy 
assessment data only. In most cases, the expected pattern of progression will be based on 
RECIST criteria. In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration. However, every effort should be made to document progression 
through use of objective criteria. If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an AE. 
Deaths 
• All deaths that occur during the protocol-specified AE reporting period, regardless of 
relationship to study intervention, must be recorded on the Death eCRF page and 
immediately reported to the Sponsor (see Section 8.3.1), unless the death is attributed to 
progression of disease. 
• Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 


 
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concept on the Adverse Event eCRF page. Generally, only one such event should be 
reported. 
• If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF page and reported as 
an SAE. 
• If the cause of death later becomes available (eg, after autopsy), "unexplained death" 
should be replaced by the established cause of death. 
• The term "sudden death" should not be used unless combined with the presumed cause of 
death (eg, "sudden cardiac death"). 
• If the death is attributed to progression of underlying disease, “underlying disease" should 
be recorded on the appropriate eCRF page; no SAE form is necessary. 
• Deaths that occur after the AE reporting period should be reported as described in 
Section 8.3.2. 
Pre-existing Medical Conditions 
• A pre-existing medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the Medical History eCRF page. 
• A pre-existing medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such 
events on the Adverse Event eCRF page, it is important to convey the concept that the pre-
existing condition has changed by including applicable descriptors (eg, "more frequent 
headaches"). 
Adverse Events Associated with Overdose or Error in Drug Administration 
• An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied. An overdose or incorrect administration of study intervention is not 
itself an AE, but it may result in an AE. All AEs associated with an overdose or incorrect 
administration of study intervention should be recorded on the Adverse Event eCRF page. 
• If the associated AE fulfills seriousness criteria, the event should be reported to the 
Sponsor as a separate SAE. 
 


 
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10.6 
APPENDIX 6: CONTRACEPTIVE GUIDANCE AND 
COLLECTION OF PREGNANCY INFORMATION 
10.6.1 
Definitions 
10.6.1.1 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
o 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 level > 40 mIU/mL to confirm menopause.  
o Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
 
10.6.2 
Contraception Guidance: 
10.6.2.1 
Male Participants 
Male participants 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 protocol-defined time frame and at least 7 months after the last dose of study intervention. 
• 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 participants are required to use a condom for study duration and until end of 
relevant systemic exposure, defined as at least 7 months after the end of study 
intervention. 


 
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• Female partners of males participating in the study to consider use of effective methods 
of contraception as described in Appendix Table 4 until the end of relevant systemic 
exposure, defined as at least 7 months after the end of study intervention in the male 
participant. 
• Male participants 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 protocol-defined time frame and at least 7 months after the last 
dose of study intervention. 
• Refrain from donating sperm for the duration of the study and at least 7 months after the 
last dose of study intervention. 
 
10.6.2.2 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Appendix 
Table 4 during study duration and until the end of relevant systemic exposure, defined as at least 
5 months after the end of study treatment. 
Appendix Table 4: 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
• Oral  
• Intravaginal  
• Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral  
• Injectable 
Highly Effective Methods That Are User Independenta 
• Implantable progestogen only hormonal contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 


 
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• 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 intervention. 
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 participant. 
• It is not necessary to use any other method of contraception when complete abstinence is 
elected.  
• WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in the SOA (Section 1.3).  
• Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants 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 
participants participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study intervention, 
which may reduce the efficacy of the contraceptive method. In this case, 2 highly effective 
methods of contraception should be utilized during the treatment period and for at least 5 
months after the last dose of study intervention 
 
10.6.3 
Pregnancy Testing 
• WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test within 24 hours of first dose of study 
intervention. 
• Additional pregnancy testing should be performed at every 4 weeks prior to nivolumab 
administration during the treatment period, at the End of Treatment visit (ie, 30 days after 
the last dose of study intervention), at the Follow-up visit 100 days after the last dose of 
study interventions, and as required locally. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
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10.6.4 
Collection of Pregnancy Information 
10.6.4.1 
Male Participants with Partners who Become Pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
10.6.4.2 
Female Participants who Become Pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. A 
spontaneous abortion is always considered to be an SAE and will be reported as such. 
Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 


 
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10.7 
APPENDIX 7: GENETICS 
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility to, 
and severity and progression of disease. Variable response to study intervention may be due 
to genetic determinants that impact immune response, drug absorption, distribution, 
metabolism, and excretion; mechanism of action of the drug; disease etiology; and/or 
molecular subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a blood and tumor sample will be collected for DNA analysis from 
consenting participants. 
• Stool samples will be collected, and microbiome DNA extracted and analyzed to evaluate a 
participant’s response to study intervention, susceptibility to, and severity and progression of 
disease. Variable response to study intervention may be due to bacterial genetic determinants 
that impact immune response, drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug. 
• Germline, tumor and bacterial DNA samples will be used for research related to anti-PD-1 
therapy or cancer and/or immune disorders and related diseases or evaluation of new assay 
technologies. They may also be used to develop tests/assays including diagnostic tests related 
to treatment, including anti-PD-1 therapy, and cancer. Genetic research may consist of the 
analysis of one or more candidate genes or the analysis of genetic markers throughout the 
genome or analysis of the entire genome (as appropriate). 
• DNA samples may be analyzed for whole genome sequencing and bacterial DNA may be 
analyzed by 16s and/or whole metagenomic sequencing and relationship to clinical outcomes 
in response to study intervention. Additional analyses may be conducted if it is hypothesized 
that this may help further understand the clinical data. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to anti-PD-1 therapy or study interventions of this class to understand study 
disease or related conditions. 
• The results of genetic analyses may be reported in the clinical study report or in a separate 
study summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
• The samples will be retained while research on anti-PD-1 therapy or study intervention 
continues in accordance with applicable law. 
 
 


 
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10.8 
APPENDIX 8: PARTICIPANT DIARY 
 
 


 
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10.9 
APPENDIX 9: LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ABX 
antibiotic 
AE(s) 
adverse event(s) 
AESI(s) 
AE(s) of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CDI 
Clostridium difficile infection 
cfDNA 
cell-free deoxyribonucleic acid 
CFU 
colony forming unit 
cHL 
classical Hodgkin lymphoma 
CI(s) 
confidence interval(s) 
CIOMS 
Council for International Organizations of Medical Sciences 
COA 
clinical outcome assessment 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
complete response 
CRC 
colorectal cancer 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DCR 
disease control rate 
dMMR 
mismatch repair deficient 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ED 
early discontinuation 
EDC 
electronic data collection 
EOT 
end of treatment 
FMT 
fecal microbiota transplant; fecal microbiota transplantation 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HCC 
hepatocellular carcinoma 
HIPAA 
Health Insurance Portability and Accountability Act 


 
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Abbreviation 
Definition 
HRT 
hormone replacement therapy 
Hx 
history 
IB 
Investigator's Brochure 
IBD 
inflammatory bowel disease 
IBS 
irritable bowel syndrome 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
I/E 
inclusion/exclusion 
IHC 
immunohistochemistry 
IND 
Investigational New Drug 
irAE(s) 
immune-related AE(s) 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
IWRS 
Interactive Web Response System 
LDH 
lactate dehydrogenase 
MDACC 
The University of Texas MD Anderson Cancer Center 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH 
Massachusetts General Hospital 
MSI-H 
microsatellite instability-high 
N 
number 
NCI 
National Cancer Institute 
NR 
non-responder 
NSAID(s) 
nonsteroidal anti-inflammatory drug(s) 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
OTU 
operational taxonimic unit 
PBMC 
peripheral blood mononuclear cell 
PBO 
placebo 
PD-1 
programmed cell death 1 
PD-L1 
programmed cell death ligand 1 
PE 
physical exam 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
Principal Investigator 
PO 
orally 


 
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Abbreviation 
Definition 
PR 
partial response 
PRO 
patient reported outcome 
Q3M 
every 3 months 
Q4W 
every 4 weeks 
QD 
daily 
QID 
four times daily 
QOD 
every other day 
QW 
every week 
R 
responders 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SCCHN 
squamous cell carcinoma of the head and neck 
SCFU 
spore colony forming unit 
SD 
stable disease 
SER-401 
Seres Therapeutics investigational product 
SJS 
Stevens-Johnson syndrome 
SporQs 
spore equivalents 
SUSAR 
suspected unexpected serious adverse reaction 
TC-99m 
technetium-99m 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
TOC 
Table of Contents 
TOX 
trial-limiting toxicities 
TSH 
thyroid-stimulating hormone 
UC 
ulcerative colitis 
ULN 
upper limit of normal 
vs 
versus 
WBC 
white blood cell 
WKS 
weeks 
WOCBP 
woman of childbearing potential 
 


 
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10.10 
APPENDIX 10: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
DOCUMENT HISTORY 
Documents 
Date of Issue 
Amendment 2 
08 Jan 2020 
Amendment 1 
14 Nov 2018 
Original Protocol 
25 Sep 2018 
 
 
 


 
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11 
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