A Phase 1a/1b Study of FPT155 in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Solid Tumors
Sponsor: Five Prime Therapeutics, Inc.

FPT155-001 Clinical Protocol 
Amendment 4 
14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 1 of 143 
A PHASE 1A/1B STUDY OF FPT155 IN PATIENTS 
WITH ADVANCED SOLID TUMORS 
Protocol Number: 
FPT155-001 
Investigational Product: 
FPT155 
Study Phase: 
1a/1b 
Indication Studied: 
Advanced Solid Tumors 
Protocol Version: 
Amendment 4 
Date of Protocol: 
14 September 2020 
Regulatory Agency Identifier Number(s): 
NCT: NCT04074759  
Sponsor: Name and Legal Registered 
Address: 
Five Prime Therapeutics, Inc.  
111 Oyster Point Boulevard 
South San Francisco, CA 94080 
Responsible Medical Officer: 
 MD PhD 
Senior Director, Clinical Sciences 
Five Prime Therapeutics, Inc.  
 
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FPT155-001 Clinical Protocol 
Amendment 4 
14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 2 of 143 
PROTOCOL APPROVAL SIGNATURE PAGE 
Declaration of Sponsor 
A Phase 1a/1b Study of FPT155 in Patients with Advanced Solid Tumors 
The study will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), the Declaration of Helsinki, and other applicable regulatory requirements.  
Essential study documents will be archived in accordance with applicable regulations. 
This study protocol was subjected to critical review.  The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational product (IP), as well as 
with the moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, 1989, and the International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines on GCP.  
Chief Medical Officer 
Five Prime Therapeutics, Inc. 
Date 
DocuSign Envelope ID: 834B8F29-8730-4005-9098-F5F4E041D4BF
September 14, 2020
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FPT155-001 Clinical Protocol 
Amendment 4 
14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 3 of 143 
DECLARATION OF THE INVESTIGATOR 
A Phase 1a/1b Study of FPT155 in Patients with Advanced Solid Tumors 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence.  This documentation includes this study 
protocol, Investigator’s Brochure (IB), electronic case report forms (eCRFs), and other scientific 
data. 
The study will not be commenced without the prior written approval of a properly constituted 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC).  No changes will be 
made to the study protocol without the prior written approval of the Sponsor and the IRB or IEC, 
except as necessary to eliminate an immediate hazard to the patients. 
I confirm that I have read the above-mentioned protocol/protocol amendments and its 
attachments.  I agree to conduct the described trial in compliance with all stipulations of the 
protocol, applicable laws, regulations and ICH E6 Guideline for GCP. 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
Name (printed) 
 
 
 
 
 
Institution or Company Name 
 
 
 
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FPT155-001 Clinical Protocol 
Amendment 4 
14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 4 of 143 
Document History 
Document 
Date 
Original Protocol 
30 July 2018  
Version 1 
17 June 2019 
Version 1.1 (South Korea) 
23 July 2019 
Version 2 
08 October 2019 
Version 2.1 (United States) 
29 January 2020 
Version 3 
17 March 2020 
Version 4  
14 September 2020 
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FPT155-001 Clinical Protocol 
Amendment 4 
14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 5 of 143 
SUMMARY OF CHANGES PROTOCOL FPT155-001 
A Phase 1a/1b Study of FPT155 in Patients with Advanced Solid Tumors 
Protocol Version: 
Amendment 4 – 14 September 2020 
Supersedes: 
Amendment 3 – 17 March 2020 
 
 
Protocol Section 
Change 
Rationale 
Section 1.1 Synopsis, Section 4.0 
Study Design, and Section 6.2 
Pembrolizumab Identity 
Added: Evaluation of FPT155 + pembrolizumab will be 
conducted in South Korea  
Allows for South Korean enrollment in evaluation of 
FPT155 + pembrolizumab combination in South Korea as 
well as Australia 
Section 1.1 Synopsis, Section  4.0  
Study Design, and Section 6.2  
Pembrolizumab Identity 
Clarified that treatment with single-agent therapy for 
12 months applies only to combination cohorts where 
one agent is discontinued due to toxicity. Patients 
enrolled into FPT155 monotherapy cohorts should 
continue treatment until protocol-specified end-of-
treatment criteria are met. 
Correction of erroneous language introduced in prior 
protocol amendment at time of addition of 
FPT155+pembrolizumab cohorts  
Section 1.1 Synopsis, Section 2.3 
Clinical Experience with FPT155, 
Section 4.0 Study Design, 
Section 4.6 Justification for Dose, 
Table 8: FPT155 Phase 1 Dose 
Escalation Cohorts 
Updated dose escalation above 560mg:  FPT155 700mg 
dose level replaced by FPT155 840mg; FPT155 1260mg 
dose level added. Addition of up to 20 patients in dose 
exploration for new dose levels. Addition of two Phase 
1b cohorts (up to 60 patients total) to allow for potential 
expansion at higher doses. Potential total increase in 
number of patients: 86. 
There have been no DLTs through the 560mg dose level and 
preliminary PK is consistent with dose proportional 
increases in exposure through 560mg. In the absence of 
identification of the MTD and immune related adverse 
events that have been manageable with standard of care 
supportive care, escalation will continue with 1.5-fold 
increments in dose. 
Section 6.1 FPT155 Identity  
FPT 155 drug product consisting of 140 mg/vial added 
Facilitates preparation of higher doses  
Appendix 11 Additional Cohorts 
for Phase 1b Expansion, 
Section 1.1 Synopsis, Section 5.2 
Additional Inclusion Criteria – 
Monotherapy (Phase 1b Only)  
Specification of dose and additional cohorts for 
Phase 1b  
Specification of additional cohorts for phase 1b enrollment 
as outlined in protocol Section 4.1.3  
Global 
Minor administrative changes and clarifications involving grammar, diction, punctuation, and other editorial changes 
that do not affect study design have been made throughout the document. 
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FPT155-001 Clinical Protocol 
Amendment 3 
17 March 2020 
Five Prime Therapeutics 
Confidential 
Page 5 of 184 
SUMMARY OF CHANGES PROTOCOL FPT155-001 
A Phase 1a/1b Study of FPT155 in Patients with Advanced Solid Tumors 
Protocol Version: 
Amendment 3 – 17 March 2020 
Supersedes: 
Amendment 2 – 08 October 2019 
 
 
Protocol Section 
Change 
Rationale 
 
Included language to incorporate for FPT155 in combination with 
pembrolizumab and to clarify existing objectives or endpoints for 
FPT155 monotherapy 
Objectives and Endpoints for Safety, 
Pharmacokinetic, Immunogenicity, 
Efficacy,
 
 
 
 
 
 
Table 1 Schedule of Assessments 
Clarified that Schedule of Assessments is applicable to both 
monotherapy and combination therapy  
Added language to clarify the requirements for Study drug dosing 
Clarified study procedures 
Table 3 Dose Escalation (monotherapy 
and FPT155+pembrolizumab): Schedule 
of Pharmacokinetic, Immunogenicity, 
and Pharmacodynamic Biomarker 
Specimens to be Submitted to Central 
Laboratory 
Added language to include pembrolizumab to all impacted samples 
Clarified study procedures 
Table 4 Dose Exploration/Expansion 
(Monotherapy and FPT155 + 
pembrolizumab): Schedule of 
Pharmacokinetic, Immunogenicity, and 
Pharmacodynamic Biomarker Specimens 
to be Submitted to Central Laboratory 
Added language to include pembrolizumab to all impacted samples 
Clarified study procedures 
Section 2.2.2.2 In Vivo Pharmacology 
Added background language to include pembrolizumab 
Added to include pembrolizumab  
Section 1.1 Synopsis, and Section 2.4 
Benefit/Risk 
Added supporting language regarding  
 
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FPT155-001 Clinical Protocol 
Amendment 3 
17 March 2020 
Five Prime Therapeutics 
Confidential 
Page 6 of 184 
Protocol Section 
Change 
Rationale 
Synopsis, Section 3.0 Objectives and 
Endpoints, Section 9.4.3 Pharmacokinetic 
Analyses, and Section 9.4.4 
Immunogenicity Analyses  
Included language to incorporate for FPT155 in combination with 
pembrolizumab and to clarify existing objectives or endpoints for 
FPT155 monotherapy 
 
Objectives and Endpoints for Safety, 
Pharmacokinetic, Immunogenicity, 
Efficacy,
 
 
 
 
 
 
 
Section 4.1 Overall Design, Section 1.1 
Synopsis 
Included language to clarify monotherapy treatment and to incorporate 
combination with pembrolizumab 
Clarified monotherapy guidance and 
added pembrolizumab 
Section 4.1.1.3 Dose Limiting Toxicity 
Definitions 
Added language to define dose limiting toxicities for combination 
cohorts 
Added to include pembrolizumab 
Section 4.2 Study Treatment and 
Duration, Section 1.1 Synopsis 
Added language to include pembrolizumab combination treatment 
Added to include pembrolizumab 
Section 4.5 Scientific Rationale for Study 
Design, Section 4.6 Justification for 
Dose, and Section 1.1 Synopsis 
Added language for starting dose of combination treatment for 
FPT155 
Added rationale to how the starting 
dose was defined 
Section 5.1, and Section 1.1 Synopsis 
Added language to Inclusion criteria 2.01 for combination treatment 
disease type 
Added to include pembrolizumab 
Section 6 Study Intervention 
Added language to include pembrolizumab as a study intervention 
Added to include pembrolizumab 
Section 6.1 Study Intervention(s) 
Administered 
Section was removed 
All information is captured in other 
sections  
Section 6.2 Pembrolizumab  
Added language for pembrolizumab formulation and packaging  
Added to include pembrolizumab 
Section 6.3 Handling, Storage, and 
Accountability, 6.4 Administration  
Added language to reference the local pembrolizumab package insert 
Clarifying to ensure sites remember to 
refer to the pembrolizumab package 
insert.  
Section 6.9.6 Dose Interruptions During 
Study Treatment Administration  
Clarified sections for FPT155 and added language for pembrolizumab  
Added to include pembrolizumab 
Section 9.2 Sample Size Determination, 
and Section 1.1 Synopsis 
Updated overall number of patients to include pembrolizumab  
Added to include patients participating 
in combination treatment 
Global 
Minor administrative changes and clarifications involving grammar, diction, punctuation, and other editorial 
changes that do not affect study design have been made throughout the document. 
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FPT155-001 Clinical Protocol 
Amendment 2.1 United States 
29 January 2020 
Five Prime Therapeutics 
Confidential 
Page 5 of 175 
SUMMARY OF CHANGES PROTOCOL FPT155-001 
A Phase 1a/1b Study of FPT155 in Patients with Advanced Solid Tumors 
Protocol Version: 
Amendment 2.1 – 29 January 2020 
Supersedes: 
Amendment 2 – 08 January 2020 
Protocol Section 
Change 
Rationale 
Section 1.1,Synopsis, 
Section 4.1 Overall Design 
There will be approximately 45 study centers in Australia, 
United States and South Korea. 
Added language and updated number of sites to include 
site participation in the United States.  
Global 
Minor administrative changes and clarifications involving grammar, diction, punctuation, and other editorial changes that do 
not affect study design have been made throughout the document. 
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FPT155-001 Clinical Protocol 
Amendment 2 
08 October 2019 
Five Prime Therapeutics 
Confidential 
Page 5 of 178 
SUMMARY OF CHANGES PROTOCOL FPT155-001 
A Phase 1a/1b Study of FPT155 in Patients with Advanced Solid Tumors 
Protocol Version: 
Amendment 2 – 08 October 2019 
Supersedes: 
Amendment 1 – 17 June 2019 
 
 
Protocol Section 
Change 
Rationale 
Section 1.2, Schedule of 
Assessments, Tables 1 & 2, 
Sample Collection 
All samples are assessed locally. Labs may be drawn up to 24 hours in advance 
of treatment. 
Added language to allow for labs to be 
drawn 24 hours in advance of treatment 
to provide flexibility for sites to collect 
labs in advance of treatment  
Section 1.2, Schedule of 
Assessments, Tables 1 & 2, 
Sample Collection 
During dose escalation, laboratory testing as outlined in the schedule of assessments 
will be performed weekly through Cycle 4 Day 1. 
Additional monitoring to ensure patient 
safety. 
Section 1.2, Schedule of 
Assessments, Tables 1 & 2, 
CT or MRI 
Tumor evaluation by CT or MRI should be conducted according to RECIST v1.1 at 
screening, every 6 (± 1) weeks from the first dose for 24 weeks, and then 
approximately every 12 (±2) weeks thereafter. Imaging performed as standard of 
care may be used if it has been performed within 28 days of treatment 
Addition of language to allow sites to 
submit previously-obtained CT or MRI 
evaluation as protocol required scans as 
long as the evaluation was performed 
within 28 days of starting treatment and 
satisfies protocol requirements 
otherwise. 
Appendix 1, Table 13 
blood urea level may be collected as an alternative to BUN: 
BUN or Urea 
To allow for lab collection of blood 
urea level as an alternative to blood 
urea nitrogen in the evaluation of renal 
function per standard of care. 
Appendix 1, Table 13 
Added TSH, Free T4 and ACTH to routine lab testing 
Systematic monitoring for potential 
endocrinopathies specified to be 
consistent with standard of care 
monitoring for anti-CTLA4 directed 
therapy. There have been no adverse 
events related to autoimmune disease in 
dose escalation with FPT155 to date.   
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FPT155-001 Clinical Protocol 
Amendment 2 
08 October 2019 
Five Prime Therapeutics 
Confidential 
Page 6 of 178 
Protocol Section 
Change 
Rationale 
Section 1.1 Synopsis, 
Section 4.6 (Table 8), 
Section 6.1 
Cohort 
Dose Level (mg) 
1aM1 
0.07  
1aM2 
0.21 
1aM3 
0.70  
1aM4 
2.1  
1aM5 
7  
1aM6 
21  
1aM7 
42  
1aM8 
70  
1aM9 
140 
1aM10 
280 
1aM11 
560 
1aM12 
700 
Addition of 4 additional dose escalation 
levels (1aM9 through 1aM12) given the 
ongoing absence of DLTs or significant 
clinical toxicity through 1aM7. 
Section 1.1 Synopsis, 
Section 5.3 Exclusion 
Criteria (Phase 1a and 
Phase 1b) 
Added clarification that both male and woman of childbearing potential agree to 
follow contraceptive guidance as detailed in the protocol (Appendix 3) during the 
study treatment period and at least 2 months, or 5 half-lives, whichever is longer, 
after study treatment 
Provided clarification on the 
contraception requirements following 
completion of study treatment.  
Section 1.1 Synopsis, 
Section 5.3 Exclusion 
Criteria (Phase 1a and 
Phase 1b)  
Exclusion Criteria (Phase 1a and Phase 1b) 
 
Active autoimmune disease, history of clinically significant autoimmune disease, 
or suspected autoimmune disease.  Patients with type I diabetes mellitus, 
hypothyroidism requiring only hormone replacement, 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 
Clarified that patients with a history of 
clinically significant autoimmune 
disease are excluded from this study.    
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FPT155-001 Clinical Protocol 
Amendment 2 
08 October 2019 
Five Prime Therapeutics 
Confidential 
Page 7 of 178 
Protocol Section 
Change 
Rationale 
Section 1.1 Synopsis, 
Section 4.1.1.5 Dose 
Escalation Within a Cohort, 
Section 6.6.1 Dose 
Escalation 
Intra-patient dose escalation will be permitted in patients enrolled at dose levels 
below 70.0 mg 
Absence of DLTs or significant toxicity 
through 1aM7 (42mg) 
Global 
Minor administrative changes and clarifications involving grammar, diction, punctuation, and other editorial changes that do 
not affect study design have been made throughout the document. 
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Five Prime Therapeutics 
1 of 1 
Confidential 
SUMMARY OF CHANGES PROTOCOL FPT155-001 
 
A Phase 1a/1b Study of FPT155 in Patients with Advanced Solid Tumors 
 
Protocol Version: 
Amendment 1.1  
Date of Protocol Amendment 
23 July 2019 
Supersedes: 
Amendment 1 – 17 June 2019 
Protocol Section 
Change 
Rationale 
Cover Page 
Updated protocol version to amendment 1.1 and date of finalization 
Updated version 
Document History 
Updated protocol version 1 and 1.1 
Updated document version history 
Section 1.2, Schedule of 
Assessments, Table 1  
*In dose escalation subsequent Cycles 2 & 3 require a chemistry panel to 
be drawn on Day 2, 8 and 15 at the 21mg dose level and higher. 
Additional chemistry testing 
added per MFDS recommendation 
 

 
Five Prime Therapeutics 
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Confidential 
SUMMARY OF CHANGES PROTOCOL FPT155-001 
A Phase 1a/1b Study of FPT155 in Patients with Advanced Solid Tumors 
Protocol Version: 
Amendment 1 – 17 June 2019 
Supersedes: 
Original – 30 July 2018 
 
 
Protocol Section 
Change 
Rationale 
Cover Page 
Updated Protocol version to amendment 1 and date of finalization 
 
Updated version 
List of Key Study Personnel 
 MBBS,  
Executive Medical Director 
 MD PhD 
Senior Director, Clinical Development 
Five Prime Therapeutics, Inc. 
111 Oyster Point Boulevard 
South San Francisco, CA 94080 
(main) 
(fax) 
Updated medical director contact 
information 
 
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FPT155-001 Clinical Protocol 
Amendment 1 
17 June 2019 
Five Prime Therapeutics 
2 of 2 
Confidential 
Protocol Section 
Change 
Rationale 
Section 1.2, Schedule of 
Assessments, Tables 1 & 2; 
Appendix 1, Table 13 
Specified additional pregnancy testing at the time of each cycle of treatment and prior to 
dosing. 
 
Section 1.2 (Tables 1 and 2): 
For WOCBP, a serum pregnancy test will be performed at screening (within 7 days of 
Cycle 1 Day 1) and pregnancy testing will be performed at each subsequent cycle of 
treatment prior to dosing.  All samples are assessed locally. 
 
Appendix 1: 
At Screening Only:   
Serology for Hepatitis B (HBsAg), and Hepatitis C (HCV RNA) 
Serum pregnancy test in women of childbearing potential only 
 
NOTES: 
• 
For WOCBP, a serum pregnancy test will be performed at screening and pregnancy 
testing will be performed at each subsequent cycle of treatment prior to dosing. 
Additional serum pregnancy testing may be performed if there is a concern with 
pregnancy, the patient missed a menstrual period, or did not follow the contraceptive 
guidance in Appendix 3. 
 
Regular pregnancy testing at each cycle 
of treatment will ensure prompt 
identification of pregnancies on study   
Section 6.6.3 
Added language to indicate the maximum length of treatment postponement which 
requires medical monitor attention: 
There is a ± 3-day window for subsequent cycles after Cycle 1.  The first dose of each 
cycle is considered Day 1 of each cycle.  Cycles will repeat every 21 days unless there is a 
treatment delay.  A treatment delay of longer than 4 weeks should be discussed with 
the medical monitor prior to continuation of that subject on study. Treatment is 
administered Q3W until disease progression, unacceptable toxicity, or until the patient 
meets any of the other protocol-specified withdrawal criteria.  
 
 Discussion in the event of an extended 
treatment interruption will help to ensure 
that the investigator’s assessment of 
benefit relative to risk is favorable for the 
patient remaining on study. 
 
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FPT155-001 Clinical Protocol 
Amendment 4 
14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 6 of 143 
TABLE OF CONTENTS 
PROTOCOL APPROVAL SIGNATURE PAGE ...........................................................................2 
DECLARATION OF THE INVESTIGATOR ................................................................................3 
DOCUMENT HISTORY .................................................................................................................4 
SUMMARY OF CHANGES PROTOCOL FPT155-001................................................................5 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................10 
LIST OF APPENDICES ................................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS ....................................................................12 
1.0 
PROTOCOL SUMMARY .................................................................................................17 
1.1 
Synopsis .................................................................................................................17 
1.2 
Schedule of Assessments .......................................................................................38 
2.0 
INTRODUCTION .............................................................................................................53 
2.1 
Study Rationale ......................................................................................................54 
2.2 
Background ............................................................................................................54 
2.2.1 
FPT155, A CD80-Fc Fusion Protein .....................................................54 
2.2.2 
Nonclinical Pharmacology Studies with FPT155 .................................55 
2.2.2.1 
In Vitro Biology .............................................................................55 
2.2.2.2 
In Vivo Pharmacology ...................................................................56 
2.2.3 
Nonclinical Pharmacokinetics ...............................................................56 
2.2.4 
Toxicology ............................................................................................57 
2.3 
Clinical Experience with FPT155 ..........................................................................60 
2.4 
Benefit/Risk Assessment .......................................................................................60 
3.0 
OBJECTIVES AND ENDPOINTS ...................................................................................63 
4.0 
STUDY DESIGN...............................................................................................................67 
4.1 
Overall Design .......................................................................................................67 
4.1.1 
Phase 1a Dose Escalation ......................................................................67 
4.1.1.1 
Cohort Review Committee ............................................................68 
4.1.1.2 
Proposed FPT155 Dose Levels ......................................................69 
4.1.1.3 
Dose Limiting Toxicity Definitions ...............................................70 
4.1.1.4 
Dose Escalation Decisions in Phase 1a FPT155 Monotherapy .....71 
4.1.1.5 
Dose Escalation Within a Cohort ...................................................72 
4.1.1.6 
Determination of Recommended Dose and Maximum 
Tolerated Dose ...............................................................................72 
4.1.2 
Phase 1a FPT155 Monotherapy Dose Exploration ...............................72 
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4.1.3 
Phase 1b FPT155 Monotherapy Dose Expansion .................................73 
4.1.4 
Phase 1a FPT155+Pembrolizumab Dose Escalation ............................73 
4.1.5 
FPT155 + Pembrolizumab Dose Exploration .......................................73 
4.1.6 
Requirements for Archival Tumor Tissue and Fresh Biopsies .............74 
4.2 
Study Treatment and Duration ...............................................................................74 
4.3 
Treatment Beyond Disease Progression ................................................................74 
4.4 
End of Study Definition .........................................................................................75 
4.5 
Scientific Rationale for Study Design ....................................................................75 
4.6 
Justification for Dose .............................................................................................76 
5.0 
STUDY POPULATION ....................................................................................................79 
5.1 
Inclusion Criteria ...................................................................................................79 
5.2 
Additional Inclusion Criteria - Monotherapy (Phase 1b Only) .............................81 
5.3 
Exclusion Criteria ..................................................................................................82 
5.4 
Lifestyle Considerations ........................................................................................84 
5.5 
Screen Failures .......................................................................................................84 
6.0 
STUDY INTERVENTION ................................................................................................85 
6.1 
FPT155 Identity .....................................................................................................85 
6.2 
Pembrolizumab Identity .........................................................................................85 
6.3 
Handling, Storage, and Accountability ..................................................................86 
6.3.1 
FPT155 ..................................................................................................86 
6.3.2 
Pembrolizumab .....................................................................................86 
6.4 
Administration .......................................................................................................87 
6.4.1 
FPT155 ..................................................................................................87 
6.4.2 
Pembrolizumab .....................................................................................87 
6.5 
Method of Treatment Assignment .........................................................................87 
6.6 
Measures to Minimize Bias: Randomization and Blinding ...................................87 
6.7 
Study Intervention Compliance .............................................................................87 
6.8 
Concomitant Therapy.............................................................................................88 
6.8.1 
Permitted Concomitant Medications .....................................................88 
6.8.2 
Prohibited Concomitant Medications ....................................................88 
6.8.3 
Imaging Restrictions and Precautions ...................................................88 
6.9 
Dose Modifications ................................................................................................89 
6.9.1 
Dose Escalation .....................................................................................89 
6.9.2 
Toxicity at Lowest Dose Level .............................................................89 
6.9.3 
Dose Modification and Delay Criteria ..................................................89 
6.9.4 
Management of irAEs ...........................................................................90 
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Amendment 4 
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Page 8 of 143 
6.9.5 
Management of CRS .............................................................................91 
6.9.6 
Dose Interruptions During Study Treatment Administration................91 
6.9.6.1 
FPT155 ...........................................................................................91 
6.9.6.2 
Pembrolizumab ..............................................................................92 
6.10 
Treatment After the End of the Study ....................................................................92 
7.0 
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..........................................................................93 
7.1 
Discontinuation of Study Intervention ...................................................................93 
7.2 
Patient Discontinuation/Withdrawal from the Study .............................................93 
7.3 
Lost to Follow Up ..................................................................................................94 
7.4 
Replacement of Patients .........................................................................................94 
8.0 
STUDY ASSESSMENTS AND PROCEDURES .............................................................95 
8.1 
Efficacy Assessments .............................................................................................95 
8.1.1 
Tumor Assessment for the Study ..........................................................95 
8.1.2 
Methods of Measurement ......................................................................96 
8.2 
Informed Consent, Screening, and Enrollment ......................................................96 
8.3 
Safety Assessments ................................................................................................97 
8.3.1 
Medical History and Demographics......................................................97 
8.3.2 
Physical Examinations ..........................................................................97 
8.3.3 
Vital Signs .............................................................................................97 
8.3.4 
Electrocardiograms ...............................................................................97 
8.3.5 
Eastern Cooperative Oncology Group Performance Status ..................98 
8.3.6 
Clinical Safety Laboratory Assessments ...............................................98 
8.4 
Adverse Events and Serious Adverse Events ........................................................98 
8.4.1 
Time Period and Frequency for Collecting AE and SAE 
Information ............................................................................................99 
8.4.2 
Method of Detecting AEs and SAEs .....................................................99 
8.4.3 
Follow-up of AEs and SAEs ...............................................................100 
8.4.4 
Regulatory Reporting Requirements for SAEs ...................................100 
8.4.5 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .................................................................100 
8.5 
Treatment of Overdose ........................................................................................101 
8.6 
Tumor Tissue .......................................................................................................101 
8.6.1 
Archival Tumor Tissue .......................................................................101 
8.6.2 
Tumor Tissue Biopsy ..........................................................................101 
8.7 
Pharmacokinetics .................................................................................................102 
8.8 
Pharmacodynamics ..............................................................................................102 
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8.9 
Biomarkers ...........................................................................................................102 
8.9.1 
Immunogenicity Assessments .............................................................103 
8.9.2 
RNA Expression Research ..................................................................103 
8.9.3 
Immunohistochemistry/Immunofluorescence .....................................103 
8.9.4 
PBMC Collection ................................................................................104 
8.9.5 
Cytokine Analysis ...............................................................................104 
8.9.6 
Circulating Tumor DNA Blood Assay ................................................104 
8.10 
Medical Resource Utilization and Health Economics .........................................104 
9.0 
STATISTICAL CONSIDERATIONS.............................................................................105 
9.1 
Statistical Hypotheses ..........................................................................................105 
9.2 
Sample Size Determination ..................................................................................105 
9.3 
Populations for Analyses .....................................................................................106 
9.4 
Statistical Analyses ..............................................................................................106 
9.4.1 
Efficacy Analyses ...............................................................................107 
9.4.2 
Safety Analyses ...................................................................................107 
9.4.3 
Pharmacokinetic Analyses ..................................................................108 
9.4.4 
Immunogenicity Analyses ...................................................................109 
9.4.5 
Other Analyses ....................................................................................109 
9.5 
Interim Analyses ..................................................................................................109 
10.0 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .......110 
10.1 
Regulatory and Ethical Considerations ................................................................110 
10.1.1 
Good Clinical Practice ........................................................................110 
10.1.2 
Institutional Review Board/Independent Ethics Committee ...............111 
10.1.3 
Compliance with the Protocol and Protocol Revisions .......................111 
10.2 
Financial Disclosure .............................................................................................112 
10.3 
Informed Consent Process ...................................................................................112 
10.4 
Data Protection.....................................................................................................113 
10.5 
Clinical Study Data and Publication Policy .........................................................113 
10.6 
Data Quality Assurance .......................................................................................114 
10.7 
Source Documents ...............................................................................................115 
10.8 
Study and Site Closure .........................................................................................116 
11.0 
REFERENCES ................................................................................................................117 
12.0 
APPENDICES .................................................................................................................119 
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LIST OF TABLES 
Table 1: 
Schedule of Assessments – Dose Escalation (monotherapy and FPT155 + 
pembrolizumab) .....................................................................................................39 
Table 2: 
Schedule of Assessments – Dose Exploration/Expansion (monotherapy and 
FPT155 + pembrolizumab) ....................................................................................44 
Table 3: 
Dose Escalation (monotherapy and FPT155 + pembrolizumab): Schedule of 
Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarker 
Specimens to be Submitted to Central Laboratory ................................................49 
Table 4: 
Dose Exploration/Expansion (Monotherapy and FPT155 + pembrolizumab): 
Schedule of Pharmacokinetic, Immunogenicity, and Pharmacodynamic 
Biomarker Specimens to be Submitted to Central Laboratory ..............................51 
Table 5: 
Anticipated Dose Levels ........................................................................................69 
Table 6: 
Algorithm for 3+3 Dose Escalation Decisions ......................................................71 
Table 7: 
Phase 1b Monotherapy Dose Expansion Cohorts and Tumor Types ....................73 
Table 8: 
FPT155 Phase 1 Dose Escalation Cohorts .............................................................77 
Table 9: 
Dose Modification and Delay Criteria for FPT155 (Non-Infusion Toxicity) ........90 
Table 10: 
Two-Sided 90% Confidence Intervals of the Observed Response Rates ............106 
Table 11:  
Efficacy – Statistical Analyses .............................................................................107 
Table 12:  
Safety – Statistical Analyses ................................................................................108 
Table 13: 
Protocol-Required Clinical Laboratory Assessments ..........................................120 
Table 14:  
Highly Effective Contraceptive Methods ............................................................128 
Table 15: 
New York Heart Association Classification ........................................................133 
Table 16: 
Cytokine Release Syndrome Grading and Treatment Guidelines .......................141 
Table 17:  
High Dose Vasopressors (all doses are required for ≥ 3 hours) ..........................142 
LIST OF FIGURES 
Figure 1: 
Schema Monotherapy Dose Escalation .................................................................36 
Figure 2: 
Schema Combination .............................................................................................37 
 
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LIST OF APPENDICES 
Appendix 1: 
Phase 1a and Phase 1b Clinical Laboratory Tests ...............................................119 
Appendix 2: 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ....................................................................................122 
Appendix 3:  Contraceptive Guidance and Collection of Pregnancy Information ....................126 
Appendix 4:  Genetics................................................................................................................130 
Appendix 5:  Eastern Cooperative Oncology Group (ECOG) Performance Status ..................131 
Appendix 6:  Response Evaluation Criteria in Solid Tumors Version 1.1 ................................132 
Appendix 7:  New York Heart Association Classification ........................................................133 
Appendix 8:  Algorithms for Early Detection and Treatment of Immune Related Adverse 
Events (irAEs) ......................................................................................................134 
Appendix 9:  Management of Toxicities from Immunotherapy: ESMO Clinical Practice 
Guidelines for Diagnosis, Treatment and Follow-Up ..........................................140 
Appendix 10:  Cytokine Release Syndrome Grading and Treatment Guidelines .......................141 
Appendix 11:  Additional Cohorts for Phase 1b Expansion ........................................................143 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
ACTH 
Adrenocorticotropic hormone 
ADA 
Anti-drug antibody 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome  
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase  
ANA 
Anti-nuclear antibody 
ANC 
Absolute neutrophil count  
APCs 
Antigen presenting cells 
APTT 
Activated partial thromboplastin time 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase  
AUC 
Area under serum concentration-time curve  
β-hCG 
Β-human chorionic gonadotropin  
BOR 
Best overall response 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CD28 
Cluster of differentiation 28 
CD80 
Cluster of differentiation 80 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
Clearance  
CO2 
Carbon dioxide 
Cmax 
Maximum observed serum concentration/ maximum concentration  
Ctrough 
Trough observed serum concentration at the end of each dose interval 
CNS 
Central nervous system  
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
Complete response 
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Abbreviation 
Definition 
CrCl 
Creatinine clearance  
CRF 
Case report form  
CRC 
Cohort review committee  
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
CT 
Computed tomography  
ctDNA 
Circulating tumor deoxyribonucleic acid 
CTLA-4 
Cytotoxic T-lymphocyte-associated protein 4 
CTCAE 
Common Terminology Criteria for Adverse Events  
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response  
ECD 
Extracellular domain 
ECG 
Electrocardiogram  
ECOG 
Eastern cooperative oncology group  
eCRF 
Electronic case report forms  
ELISA 
Enzyme linked immunosorbent assay  
EOT 
End of Treatment 
eSAE Form 
Electronic serious adverse event form 
GALT 
Gut-associated lymphoid tissue 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
G-CSF 
Granulocyte-colony stimulating factor 
GCP 
Good clinical practices 
GGT 
Gamma-glutamyltransferase 
GI 
Gastrointestinal 
GLP 
Good laboratory practices 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B virus surface antigen  
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus  
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Abbreviation 
Definition 
HPV 
Human papilloma virus 
HRT 
Hormone replacement therapy 
IB 
Investigator’s brochure  
ICF 
Informed consent form  
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent ethics committee  
IHC 
Immunohistochemistry 
IGF-1 
Insulin-like growth factor-1 
IgG 
Immunoglobulin G 
IND 
Investigational new drug (application) 
IF 
Immunofluorescence 
IFNγ 
Interferon gamma 
IHS 
Intrauterine hormone-releasing system 
INR 
International normalized ratio  
IP 
Investigational product 
irAEs 
Immune-related adverse events 
IRB 
Institutional review board  
IUD 
Intrauterine device 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin G 
IVRS/IWRS 
Interactive voice/web response system 
LCI 
Liver cytosol 1 autoantibody 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
LH 
Lactate dehydrogenase 
LKM 
Liver kidney microsome 
LP 
Lipoprotein 
LTFU 
Long-term follow-up 
mAB 
Monoclonal antibody 
MABEL 
Minimum anticipated biological effect level 
MHC 
Major histocompatibility complex 
MMF 
Mycophenolate mofetil 
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Abbreviation 
Definition 
MRI 
Magnetic resonance imaging  
MTD 
Maximum tolerated dose  
NCI 
National cancer institute 
NOAEL 
No-observed-adverse-effect level 
NYHA 
New York heart association 
ORR 
Objective response rate  
OS 
Overall survival  
PA 
Pharmacological activity 
PBMC 
Peripheral blood mononuclear cell(s) 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic(s) 
PD-1 
Programmed death 1 
PDL-1 
Programmed death ligand 1 
PFS 
Progression free survival  
PK 
Pharmacokinetic(s)  
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
Q3W 
Once every 3 weeks  
QTc 
QT interval corrected for heart rate 
RBC 
Red blood cell 
RCC 
Renal cell carcinoma 
RD 
Recommended dose  
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan  
SD 
Standard deviation  
SOC 
System organ class 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SLA 
Soluble liver antigen 
SMA 
Smooth muscle antibody 
SPR 
Surface plasmon resonance 
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Abbreviation 
Definition 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Terminal half-life  
TCR 
T cell receptor 
TK 
Toxicokinetics 
TNF 
Tumor necrosis factor 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal  
UPCR 
Urine protein to creatinine ratio 
USPI 
United States product insert 
Vss 
Volume of distribution at steady state 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
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1.0 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Phase 1a/1b Study of FPT155 in Patients with Advanced Solid Tumors 
Study Phase: 1a/1b 
Study Centers: There will be approximately 30 study centers in Australia and South Korea. 
FPT155 monotherapy and FPT155 + pembrolizumab will be conducted in Australia and South 
Korea.   
Rationale: FPT155 is an immune modulating CD80-Fc (cluster of differentiation 80 fused with 
the fragment crystallizable [Fc] domain of human immunoglobulin G1 [IgG1]) fusion protein 
that is thought to act both as an agonist for cluster of differentiation 28 (CD28) and an inhibitor 
of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4).  This is a first in human clinical 
study of FPT155 to evaluate safety and tolerability in patients with advanced solid tumors, and to 
determine a recommended dose (RD) for further clinical evaluation. 
The dual anti-CD28 and anti-CTLA-4 mechanisms of FPT155 lead to synergy with anti-PD1 
antibodies in pre-clinical tumor models and may lead to similar clinical benefit in patients with 
advanced tumors. Evaluation of the combination of pembrolizumab and FPT155 for safety and 
tolerability in patients with advanced non-small cell lung cancer will determine a recommended 
dose of FPT155 in combination with pembrolizumab for further clinical evaluation. 
Objectives and Endpoints – Phase 1a Dose Escalation/Exploration – FPT155 Monotherapy:  
Objectives 
Endpoints 
Primary 
Safety 
• 
To assess the safety and tolerability of FPT155 as 
monotherapy in patients with advanced solid 
tumors 
• 
To determine the RD of FPT155 as monotherapy 
Safety 
• 
The incidence of adverse events (AEs), serious 
adverse events (SAEs), clinical laboratory 
abnormalities, and electrocardiogram (ECG) 
abnormalities 
• 
The incidence of AEs defined as dose limiting 
toxicities (DLTs), clinical laboratory 
abnormalities defined as DLTs, and overall 
assessment of pharmacokinetics (PK) and 
pharmacodynamics (PD) 
Secondary 
Pharmacokinetics 
• 
To characterize the PK profile of FPT155 as 
monotherapy in patients with advanced solid 
tumors 
Pharmacokinetics 
The following PK parameters will be derived from 
concentration-time data for FPT155 when appropriate 
and applicable.   
• 
Area under serum concentration-time curve (AUC) 
• 
Maximum observed serum concentration (Cmax) 
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• 
Trough observed serum concentration at the end 
of each dose interval (Ctrough) 
• 
Clearance (CL) 
• 
Terminal half-life (t1/2) 
• 
Volume of distribution at steady state (Vss) 
Other parameters, such as dose proportionality, 
accumulation ratio, and attainment of steady state, will 
also be calculated if the data are available. 
Immunogenicity 
• 
To characterize the immunogenicity of FPT155 as 
monotherapy in patients with advanced solid 
tumors 
Immunogenicity 
• 
Incidence of treatment emergent anti-FPT155 
antibody response 
Exploratory 
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Objectives and Endpoints – Phase 1b Dose Expansion – FPT155 Monotherapy:  
Objectives 
Endpoints 
Primary 
Safety 
• 
To evaluate the safety and tolerability of FPT155 
as monotherapy in patients with selected advanced 
solid tumors treated at the RD 
Safety 
• 
The incidence of AEs, SAEs, clinical laboratory 
abnormalities, and ECG abnormalities 
• 
The incidence of treatment discontinuations, 
modifications, and interruptions due to AEs 
Secondary 
Efficacy  
• 
To evaluate the clinical benefit of FPT155 as 
monotherapy in patients with selected advanced 
solid tumors treated at the RD through the analysis 
of ORR, DOR., PFS, and DCR  
Efficacy  
• 
ORR, DOR, and PFS   
• 
Disease Control Rate (DCR) defined as total 
number of patients with confirmed responses of 
either CR, PR, or stable disease as determined by 
the investigator per RECIST v1.1, divided by the 
total number of patients who are evaluable for a 
response 
Pharmacokinetics 
• 
To characterize the PK profile of FPT155 as 
monotherapy in patients with selected advanced 
solid tumors treated at the RD 
Pharmacokinetics 
The following PK parameters will be derived from 
concentration-time data for FPT155 when appropriate 
and applicable.   
• 
AUC 
• 
Cmax 
• 
Ctrough 
• 
CL 
• 
t1/2 
• 
Vss 
Other parameters, such as dose proportionality, 
accumulation ratio, attainment of steady state, will also 
be calculated if the data are available.  Assessment of 
time-dependence of PK, the effect of body weight as 
well as other covariates on PK, and the exposure-
response relationship, when the data allow, will be 
conducted to determine the appropriate dosing 
approach (eg, body weight-based or fixed dosing) for 
future trials. 
Immunogenicity 
• 
To characterize the immunogenicity of FPT155 as 
monotherapy in patients with selected advanced 
solid tumors treated at the RD 
Immunogenicity 
• 
Incidence of treatment emergent anti-FPT155 
antibody response 
Exploratory 
 
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Objectives 
Endpoints 
Objectives and Endpoints – Phase 1a Dose Escalation/Exploration – FPT155 + 
Pembrolizumab:  
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the safety and tolerability of 
FPT155 in combination with pembrolizumab in 
patients with advanced non-small cell lung 
cancer 
• 
To determine the RD of FPT155 in combination 
with pembrolizumab in patients with advanced 
non-small cell lung cancer 
• 
The incidence of adverse events (AEs), serious 
adverse events (SAEs), clinical laboratory 
abnormalities, and electrocardiogram (ECG) 
abnormalities 
• 
The incidence of dose limiting toxicities (DLTs) 
Secondary 
 
• 
To evaluate the preliminary clinical response 
rate of FPT155 in combination with 
pembrolizumab in patients with non-small cell 
lung cancer 
• 
Objective Response Rate (ORR), defined as the total 
number of patients with responses of either CR or 
PR, as determined by the investigator per RECIST 
v1.1, divided by the total number of patients who are 
evaluable for a response 
Exploratory 
 
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Objectives 
Endpoints 
Overall Design: 
This study is a Phase 1a/1b open-label, multicenter, dose escalation, dose exploration, and dose 
expansion study to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of FPT155 
in patients with advanced solid tumors.  FPT155 (CD80-Fc) is a recombinant fusion protein 
composed of the extracellular domain (ECD) of human CD80 (cluster of differentiation 80, also 
known as B7, B7.1, B7-1) fused with the Fc domain of IgG1.  It is designed to act as a potent 
stimulator of anti-tumor immunity. FPT155 as monotherapy and in combination with 
pembrolizumab will be evaluated. 
FPT155 Monotherapy 
FPT155 will be administered once every 3 weeks (Q3W) over approximately 60 minutes by 
intravenous (IV) infusion.   
The monotherapy part of the study will initiate with Phase 1a dose escalation consisting of 
approximately 13 planned dose escalation cohorts, with the starting dose of 0.07 mg.  
Phase 1a dose exploration consists of approximately 50 patients in total who may be enrolled at 
one or more dose levels to further evaluate safety, PK, PD, and clinical activity (conditional upon 
the dose levels clearing dose escalation criteria).  
Phase 1b dose expansion consists of up to 8 tumor-specific expansion cohorts, enrolling 
approximately 30 patients each.  Patients in Phase 1b will be treated with FPT155 at an RD 
selected after assessment of data obtained in Phase 1a. (See Appendix 11). 
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Treatment will continue until disease progression, unacceptable toxicity, consent withdrawal, or 
if any of the specified withdrawal criteria listed in Section 7.0 of the protocol are met. 
Dose Escalation:  
The Phase 1a dose escalation will include an initial accelerated titration design enrolling at least 
1 patient at lower doses followed by a standard 3+3 design until the RD for Phase 1b is 
determined.  Eligible patients with advanced solid tumors (except primary central nervous 
system [CNS] tumors) who are refractory to all standard therapy for their malignancy or for 
whom standard therapies would not be appropriate will be enrolled.  All dose escalation 
decisions will be based on the assessment of DLTs, overall safety and tolerability, and will be 
made after the last patient enrolled in each cohort has completed the 21-day DLT evaluation 
interval.  Dose escalation decisions will be agreed upon by the Cohort Review Committee (CRC) 
after all available laboratory and clinical information is reviewed. 
Patients enrolled into the first monotherapy dose cohort will have 48 hours of inpatient 
monitoring from the start of infusion of FPT155 at Cycle 1 Day 1 to evaluate for any signs or 
symptoms of cytokine release syndrome (CRS).  There will be an interval of at least 48 hours 
between administration of the first dose in each patient in the first dose cohort, if more than one 
patient is enrolled.  For the second infusion of FPT155, patients in the first monotherapy dose 
cohort will undergo intensive monitoring in the outpatient setting, including a minimum 6-hour 
observation window. 
For subsequent dose cohorts, intensive monitoring will occur in the outpatient setting and include 
a minimum 6-hour observation window following completion of the first and second infusions.  
There will be an interval of at least 24 hours between administration of the first dose in each 
patient in subsequent dose cohorts.  Inpatient hospitalization will not be required for the first 
dose in subsequent dose cohorts unless there is evidence of CRS ≥ Grade 2 at the previous dose 
level. 
If any patient reports a Grade 2 or higher drug-related toxicity in the first 24 hours after 
completion of their first dose, enrollment of subsequent patients will be delayed until the toxicity 
for that patient returns to baseline or ≤ Grade 1, or the CRC determines that it is safe to continue 
enrollment.  In this setting, the CRC will review all available data to determine if enrollment 
should continue at the same or a lower dose level, or with a less frequent dosing schedule, or if 
enrollment should be discontinued. 
The CRC is comprised of, but not limited to, Phase 1a study investigators, the Sponsor’s medical 
monitor, and the Sponsor’s safety representative. 
FPT155 + Pembrolizumab 
FPT155 will be administered once every 3 weeks (Q3W) over approximately 60 minutes by 
intravenous IV infusion followed by 200 mg of pembrolizumab administered over 30 minutes by 
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intravenous (IV) infusion a minimum of 30 minutes after the completion of FPT155. Eligible 
patients with advanced lung cancer will be enrolled for treatment with the combination of 
FPT155 and pembrolizumab. 
Combination dose escalation will start with a FPT155 dose that is a minimum of two dose levels 
lower than the highest dose cleared in FPT155 monotherapy. 
Combination dose exploration will include up to 30 patients who may be enrolled at one or more 
dose levels to further evaluate safety, PK, PD, and clinical activity (conditional upon the dose 
level clearing dose escalation criteria). 
For patients enrolled for treatment with FPT155 and pembrolizumab, treatment will continue 
until disease progression, unacceptable toxicity or consent withdrawal.  If one drug is 
discontinued, treatment may continue with the other alone for up to an additional 12 months.  
Proposed FPT155 Dose Levels: 
FPT155 will be initially administered Q3W, on Day 1 of each 21-day cycle.  The anticipated 
dose levels are as follows: 
Design 
Dose 
Regimen 
Accelerated titration design 
0.07 mg FPT155 
Q3W 
0.21 mg FPT155 
Q3W 
0.70 mg FPT155 
Q3W 
2.1 mg FPT155 
Q3W 
3+3 design 
7 mg FPT155 
Q3W 
21 mg FPT155 
Q3W 
42 mg FPT155 
Q3W 
70 mg FPT155 
Q3W 
140 mg FPT155 
Q3W 
280 mg FPT155 
Q3W 
560 mg FPT155 
Q3W 
840 mg FPT155 
Q3W 
 
1260 mg FPT155 
Q3W  
Planned dosing increments take into account conservative estimates of receptor occupancy (RO) 
and pharmacological activity (PA) through both CD28 and CTLA-4.  Fixed 3-fold escalation 
increments are proposed while projected engagement of CD28 is low; more conservative 
increments (2-fold or less) are proposed at higher CD28 occupancy levels. 
The Sponsor may add cohorts with alternative dose levels or dose regimens (eg, different dosing 
frequency, intermediate dose levels) upon review of safety, PK, and PD profiles to achieve 
optimal target exposure with acceptable tolerability. 
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Dose Limiting Toxicity Definitions: 
The DLT evaluation interval begins on the first day of treatment upon start of infusion and 
continues for 21 days.  Patients who receive at least 1 dose of study treatment and remain on 
study for the 21-day DLT evaluation interval or patients who discontinue study treatment for 
drug-related AEs before clearing the 21-day DLT evaluation interval will be considered 
evaluable for DLT determination. 
DLTs during Phase 1a dose escalation are defined as any of the following deemed by the 
investigator as related to FPT155: 
• Absolute neutrophil count (ANC) < 1.0 x 109/L for > 5 days duration or Grade 3 febrile 
neutropenia (eg, ANC < 1.0 x 109/L with a single temperature of > 38.3°C or fever > 38°C 
for more than 1 hour) 
• Platelets < 25 x 109/L or platelets < 50 x 109/L with clinically significant hemorrhage 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of 
normal (ULN) with concomitant total bilirubin > 2 x ULN not related to liver involvement 
with cancer 
• Grade 3-4 non-hematological toxicity except: 
• Grade 3 fatigue < 7 days 
• Grade 3 nausea and Grade 3-4 vomiting and diarrhea lasting < 72 hours in patients who 
have not received optimal anti-emetic and/or anti-diarrheal therapy 
• Grade 3 endocrinopathy that is adequately treated by hormone replacement 
• Laboratory value that may be corrected through replacement within 48 hours 
• Grade 2 neurological toxicity except headache and peripheral neuropathy in patients with 
Grade 1-2 peripheral neuropathy at entry 
Dose Escalation Decisions in Phase 1a FPT155 Monotherapy: 
An initial accelerated titration design enrolling at least 1 patient at each dose level is planned for 
dose levels 0.07, 0.21, 0.70, and 2.1 mg.  Dose escalation to the next dose level may proceed 
after at least 1 patient completes the 21-day DLT evaluation interval. 
If a single patient experiences a DLT during the 21-day DLT evaluation interval, standard 
3+3 dose escalation criteria will apply for that cohort with enrollment of additional patients.  
All subsequent dosing cohorts will then follow standard 3+3 dose escalation criteria. 
Alternatively, if 2 patients experience moderate AEs (at any planned accelerated titration dose 
level), standard 3+3 dose escalation criteria will apply for the highest dose level at which a 
moderate AE was experienced, with enrollment of additional patients.  All subsequent dosing 
cohorts will then follow standard 3+3 dose escalation criteria.  Moderate AEs are defined as 
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≥ Grade 2 AEs deemed by the investigator as related to FPT155.  Grade 2 laboratory values will 
not be considered as moderate AEs for this purpose unless accompanied by clinical sequalae.  
The algorithm outlined in the table below will be used for all dose escalation decisions in 
Phase 1a.  If not already applied at a lower dose level according to the criteria stated above, 
enrollment at all dose levels ≥ 7.0 mg will follow a standard 3+3 dose escalation design. 
Algorithm for 3+3 Dose Escalation Decisions: 
Number of Patients with DLT at a 
Given Dose Level 
Dose Escalation Decision Rule 
0/3 or 1/6 
Enroll 3 patients at next dose level (next/higher cohort) 
1/3 
Enroll 3 additional patients at current dose level (current cohort) 
≥2 
Stop enrollment.  If at the starting dose level, the study will be stopped.  
If at any other dose level, enroll 3 more patients at the previous dose 
level (previous/lower cohort) if only 3 were previously enrolled, or at 
an intermediate dose level 
Abbreviations: DLT = dose limiting toxicity. 
The maximum tolerated dose (MTD) will be defined as the dose level below that in which 
≥2 DLTs are identified. If dose escalation completes without the identification of 2 DLTs at a 
given dose level, no MTD will have been identified. The Sponsor may discontinue dose 
escalation prior to determining a MTD based on the available observed safety, tolerability, PK, 
and PD.  Intra-patient dose escalation will be permitted in patients enrolled at dose levels below 
70 mg provided the criteria in Section 4.1.1.5 are met.  Intra-patient dose escalation will only be 
permitted after a discussion between the Sponsor and investigator, taking into account the overall 
safety experience, PK, and PD data available at the time of the request.  Safety data from such 
patients will be reviewed as part of the overall safety and tolerability of FPT155. 
The RD of FPT155 will be identified based on an evaluation of all available safety, tolerability, 
PK, and PD data.  The determination of RD will consider toxicities observed both during and 
beyond the DLT evaluation period as well as dose reductions and discontinuations due to toxicity 
that do not meet the DLT criteria.  The RD, therefore, may or may not be the same as the MTD 
but cannot be higher than the MTD.  
FPT155 Monotherapy Dose Exploration: 
Phase 1a dose exploration consists of up to approximately 50 patients in total who may be 
enrolled at one or more dose levels to further evaluate safety, PK, PD, and clinical activity 
(conditional upon the dose level clearing dose escalation criteria).  Toxicities observed in these 
patients will contribute to the overall assessments of safety and tolerability, and may inform 
selection of the RD. 
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FPT155 Monotherapy Dose Expansion: 
Enrollment in Phase 1b dose expansion will begin when the MTD and/or RD has been identified 
by the CRC.  Up to 8 tumor-specific cohorts consisting of approximately 30 patients each will 
evaluate the safety, efficacy, PK, and PD of FPT155 at the RD (see Appendix 11).  Patients with 
advanced renal cell carcinoma (RCC) and melanoma that have failed prior anti-programmed 
death-ligand 1 (PD[L]1) therapy will be enrolled in a minimum of 1 of the 8 cohorts.  Additional 
tumor types are specified in Appendix 11 for the remaining Phase 1b cohorts and will be 
determined based on emerging safety, translational, and clinical data for FPT155, as well as any 
potential new safety signals from other immunotherapies, such as significant changes to 
prescribing information for approved immunotherapies. 
FPT155+Pembrolizumab Dose Escalation: 
FPT155 will start at a dose level a minimum of 2 levels below that cleared in dose escalation 
with FPT155 monotherapy.  
Pembrolizumab will be administered Q3 weeks at 200mg over 30 minutes on Day 1 of each 
21-day cycle. 
Dose escalation decisions will follow the standard 3+3 algorithm described above and continue 
up to the dose level established as the MTD for FPT155 monotherapy. Additional intermediate 
dose levels or dose regimens may be considered upon review of emerging safety, PK and PD 
results. 
Additional DLT Considerations for FPT155 in combination with pembrolizumab 
Because pembrolizumab is a known immune checkpoint inhibitor and one of the proposed 
mechanisms of action of FPT155 is immune checkpoint blockade, immune-related adverse 
events (irAEs) are anticipated with this combination. An irAE is defined as a clinically 
significant AE that is associated with study drug exposure, without a clear alternate cause, and 
consistent with an immune-mediated mechanism. Based on that background, the first occurrence 
of the following irAEs will not be considered a DLT because they may occur with immune 
therapy and are likely to be fully reversable per Appendix 8:  
• Grade 3 tumor flare (defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor) 
• Grade 3 non-skin immune-related adverse event (irAE) that resolve to a Grade 1 or less 
within 14 days with management per Appendix 8 
• Transient (resolving within 6 hours of onset) Grade 3 infusion-related AEs 
• Grade 3 drug-related bronchospasm or anaphylactic or anaphylactoid reactions 
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Dose escalation may be discontinued prior to determining an MTD based on observed safety, 
tolerability, or emerging PK or PD results. 
FPT155 + Pembrolizumab Dose Exploration:  
Enrollment in combination dose exploration may occur at one more dose levels that have been 
cleared during combination dose escalation. 
Requirements for Archival Tumor Tissue and Fresh Biopsies:  
 Dose Escalation (Monotherapy and FPT155 + pembrolizumab): 
• Archival tumor tissue is required.  If archival tumor tissue is not available, a fresh biopsy is 
required prior to treatment for retrospective biomarker analysis. 
• Optional pre- and on-treatment biopsies will be requested during screening (prior to 
treatment) and during treatment (prior to the Cycle 3 Day 1 dose) to explore the relationship 
between baseline tumor immune phenotype and PD response. 
• An additional optional biopsy will be requested at disease progression. 
 Dose Exploration/Expansion (Monotherapy and FPT155 + pembrolizumab): 
• Archival tumor tissue is required for retrospective biomarker analysis.  The fresh biopsy 
required at screening will be accepted in lieu of archival tumor tissue if archival tissue is not 
available. 
• Pre- and on-treatment biopsies will be mandatory during screening (prior to treatment) and 
during treatment (prior to the Cycle 3 Day 1 dose) to explore the relationship between 
baseline tumor immune phenotype and PD response. 
An additional optional biopsy will be requested at disease progression. 
Number of Patients: 
The total number of patients planned for this study is estimated to be up to approximately 408. 
• FPT155 Monotherapy: Up to approximately 58 patients will participate in Phase 1a dose 
escalation, depending on the number of dose levels evaluated and the incidence of DLTs; up 
to approximately 50 patients in the Phase 1a dose exploration; up to approximately 240 
patients in Phase 1b dose expansion in 8 cohorts of approximately 30 patients each. 
• FPT155+pembrolizumab: Up to approximately 30 patients in Phase 1a dose escalation; up to 
approximately 30 patients in dose exploration. 
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Eligibility Criteria: 
Inclusion Criteria  
Patients are eligible to be included in the study only if all of the following criteria apply: 
Age 
1.01) Patient must be 18 years of age or older at the time of signing the informed consent. 
Type of Patient and Disease Characteristics 
2.01) Histologically confirmed solid tumors (except primary CNS tumors). For patients 
enrolled for treatment with FPT155+pembrolizumab: histologically confirmed non-small 
cell lung cancer not eligible for curative therapy. 
2.02) For patients in Phase 1a dose escalation (all) and Phase 1a dose exploration (FPT155 
monotherapy) only:  Disease that is unresectable, locally advanced, or metastatic and has 
progressed following all standard treatments or is not appropriate for standard treatments.  
Appendix 11 
2.03) All patients must have at least one measurable lesion at baseline according to RECIST 
v1.1.  Tumor sites situated in a previously irradiated area, or in an area subjected to other 
loco-reginal therapy, are not considered measurable unless there has been demonstrated 
progression in the lesion. 
2.04) Availability of archival tumor tissue and consent to provide archival tumor for 
retrospective biomarker analysis, or consent to undergo a fresh tumor biopsy during 
screening 
2.05) For patients participating in Phase 1a dose exploration cohorts and Phase 1b dose 
expansion: consent to undergo a mandatory fresh tumor biopsy during screening and on 
treatment 
2.06) ECOG performance status of 0 or 1 
2.07) Life expectancy of at least 3 months in the opinion of the investigator 
2.08) Willing and able to comply with all study procedures 
2.09) Prior radiotherapy must be completed at least 2 weeks before first dose of study treatment 
administration.  No radiopharmaceuticals (eg, strontium, samarium) within 8 weeks 
before first dose of study treatment administration 
2.10) Prior surgery that requires general anesthesia must be completed at least 14 days before 
first dose of study treatment administration unless patients have recovered, and it is 
considered safe after discussion with medical monitor.  Surgery requiring local/epidural 
anesthesia must be completed at least 72 hours before first dose of study treatment 
administration and patients must have recovered. 
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2.11) Screening laboratory values must meet the following criteria: 
Hematologic 
a. Neutrophils ≥ 1.2 x 109/L 
b. Platelets ≥ 75 x 109/L 
c. Hemoglobin ≥ 9.0 g/dL 
d. Serum creatinine < 1.5 x upper limit of normal (ULN) or creatinine clearance of 
≥ 40 mL/minute (using Cockcroft/Gault Formula) 
Female creatinine clearance 
(CrCl) = 
(140 – age in years) × (weight in kg) × 0.85 
 
72 × (serum creatinine in mg/dL) 
Male CrCl =  
(140 – age in years) × (weight in kg) 
 
72 × (serum creatinine in mg/dL) 
e. Prothrombin time (PT)/International normalized ratio (INR) < 1.5x ULN and partial 
thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5x 
ULN except for patients receiving anticoagulation, who must be on a stable dose of 
warfarin for 6 weeks prior to enrollment 
Hepatic 
f. AST or ALT < 3x ULN  
g. Bilirubin < 1.5x ULN (except patients with Gilbert's syndrome, who must have total 
bilirubin < 3 mg/dL) 
h. Albumin ≥ 3.0 g/dL (patients with pancreatic cancer only) 
Sex 
3.01) Male or female 
General Inclusion Criteria 
Reproductive Status 
Male patients: 
4.01) A male patient must agree to use contraception as detailed in Appendix 3 of this protocol 
during the treatment period and for at least 2 months or 5 half-lives, whichever is longer,  
after the last dose of study treatment and refrain from donating sperm during this period. 
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Female patients: 
5.01) A female patient is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, and at least one of the following conditions applies: 
• Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 
OR 
• A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and  for at least 2 months or 5 half-lives, whichever is longer, after the 
last dose of study treatment. 
Informed Consent 
6.01) Capable of giving signed informed consent as described in Section 10.3 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
Additional Inclusion Criteria – Monotherapy (Phase 1b Only) 
Cohort 1b1: Renal Cell Carcinoma 
7.01) Patients with histologically or cytologically confirmed advanced or metastatic renal cell 
carcinoma with a clear-cell component. 
7.02) Must have received at least one prior anti-angiogenic therapy regimen (eg, sunitinib, 
sorafenib, pazopanib, axitinib, tivozanib, or bevacizumab) in the advanced or metastatic 
setting 
7.03) Must have received at least one anti-PD(L)1 therapy (eg, nivolumab, pembrolizumab, 
atezolizumab, durvalumab, or avelumab) in the advanced or metastatic setting.  Prior 
cytokine therapy (eg, IL-2, IFN-α) and anti-CTLA4 therapy (eg, ipilimumab) is allowed 
but not required. 
Cohort 1b2: Melanoma 
8.01) Patients with histologically- or cytologically-confirmed unresectable stage III or stage IV 
cutaneous melanoma not amenable to local therapy 
8.02) Must have received at least one anti-PD(L)1 therapy (including but not limited to 
nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab) in the advanced 
or metastatic setting.  Prior cytokine therapy (eg, IL-2, IFN-α) and anti-CTLA4 therapy 
(eg, ipilimumab) is also allowed. 
8.03) Patients with BRAF mutations must have received prior BRAF inhibitor therapy 
(eg, vemurafenib and dabrafenib) in the advanced or metastatic setting. 
9.01) Inclusion Criteria for Additional Phase 1b Cohorts are included in Appendix 11. 
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Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1.01) Decreased cardiac function with New York Heart Association (NYHA) > Class 2 
1.02) Uncontrolled or significant heart disorder such as unstable angina 
1.03) Current unresolved infection or history of chronic, active, clinically significant infection 
(viral, bacterial, fungal, or other) which, in the opinion of the investigator, would 
preclude the patient from exposure to a biologic agent or pose a risk to patient safety 
1.04) Any uncontrolled medical condition or psychiatric disorder which, in the opinion of the 
investigator, would pose a risk to patient safety or interfere with study participation or 
interpretation of individual patient results 
1.05) Active autoimmune disease, history of clinically significant autoimmune disease, or 
suspected autoimmune disease.  Patients with type I diabetes mellitus, hypothyroidism 
requiring only hormone replacement, 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 
1.06) Symptomatic interstitial lung disease or inflammatory pneumonitis 
1.07) Untreated or active CNS or leptomeningeal metastases.  Patients are eligible if metastases 
have been treated and patients are neurologically returned to baseline or neurologically 
stable (except for residual signs or symptoms related to the CNS treatment) for at least 
2 weeks prior to the first dose of study treatment  
1.08) Evidence of coagulopathy or bleeding diathesis 
Prior/Concomitant Therapy 
2.01) Treatment with any anti-cancer therapy or participation in another investigational drug or 
biologics trial within 28 days or ≤ 5 half-lives (whichever is shorter) prior to first dose of 
study treatment administration or while on this study 
2.02) For patients participating in Phase 1a dose escalation and exploration cohorts: Prior 
treatment with a CTLA-4 antagonist, including ipilimumab and tremelimumab 
2.03) Patients who have received prior immune-modulating therapies (including regimens 
containing an immune agonist or a programmed death-ligand 1 ([PD-L1]/programmed 
cell death protein 1 [PD-1] antagonist) are NOT permitted to enroll unless all the 
following apply: 
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a. Must not have experienced a drug-related toxicity that led to permanent 
discontinuation of prior immunotherapy 
b. Last treatment was administered a minimum of 5 half-lives or 90 days (whichever is 
shorter) prior to first dose of study treatment 
2.04) Ongoing adverse effects from prior treatment > National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE version 4.3) Grade 1 (with the 
exception of Grade 2 alopecia or peripheral neuropathy) 
Other Exclusions 
3.01) Immunosuppressive doses of systemic medications, such as steroids or absorbed topical 
steroids (doses > 10 mg/day prednisone or equivalent daily) must be discontinued at least 
2 weeks before study treatment administration 
3.02) QTcF > 450 msec for males or > 470 msec for females at screening 
3.03) Severe allergic, anaphylactic, or other infusion-related reaction to a previous biologic 
agent 
3.04) Known history of sensitivity to infusions containing Tween 20 (polysorbate 20), 
L-histidine, and sucrose 
3.05) Vaccines (eg, human papillomavirus [HPV] vaccine) within 4 weeks of study treatment 
administration.  The inactivated seasonal influenza vaccine can be given to patients 
before treatment and while on therapy without restriction.  Influenza vaccines containing 
live virus or other clinically indicated vaccinations for infectious diseases (eg, 
pneumovax, varicella) may be permitted, but must be discussed with the Sponsor’s 
medical monitor and may require a study treatment washout period prior to and after 
administration of vaccine 
3.06) Patients with abnormal serum chemistry values that in the opinion of the investigator are 
considered to be clinically significant.  This will include patients who show clinical signs 
and symptoms related to their abnormal serum chemistry values as well as patients whose 
serum chemistry values are asymptomatic but clinically significant per investigator 
(eg, hypokalemia or hyponatremia). 
3.07) Pregnant or breastfeeding 
3.08) Known history of testing positive for human immunodeficiency virus (HIV) 1 or 2 or 
known acquired immunodeficiency syndrome (AIDS) 
3.09) Positive test for hepatitis B virus surface antigen (HBsAg) or detectable hepatitis C virus 
ribonucleic acid (HCV RNA) indicating acute or chronic infection 
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3.10) Transfusion of blood or platelets or granulocyte-colony stimulating factor (G-CSF) 
administration completed within 72 hours prior to first dose of study treatment 
No waivers of these inclusion or exclusion criteria will be granted 
Treatment and Duration: 
As monotherapy, FPT155 will be administered over approximately 60 minutes by IV infusion 
Q3W.   
In combination, FPT155 will be administered over approximately 60 minutes by IV infusion 
Q3W. Pembrolizumab will be administered at a dose of 200 mg IV over 30 minutes, a minimum 
of 30 minutes after the completion of FPT155 infusion.  
Dose reductions or delays for FPT155 or pembrolizumab may be permitted for patients on 
treatment beyond the DLT evaluation interval in Phase 1a dose escalation, or any patients 
enrolled in the exploration, or expansion parts of the study per the guidelines in Section 6.9.3.  
If dose reductions or interruptions that do not fall within these guidelines are being considered by 
the investigator, these will require discussion with and approval by the Sponsor or designee. 
Treatment is administered Q3W until disease progression, unacceptable toxicity, or until the 
patient meets any of the other protocol-specified withdrawal criteria.  If one drug in the 
combination is discontinued, the other may be administered for up to an additional 12 months on 
study.  If treatment is permanently discontinued for any reason other than consent withdrawal, 
the patient will undergo end of treatment (EOT) follow-up visits approximately 28 days and 
100 days after the last dose of any study drug. 
In the Phase 1b dose expansion portion of the study, patients will also undergo long-term follow-
up (LTFU) for survival by clinic visit or by telephone approximately every 3 months after the 
Day 100 EOT visit, or until death, loss to follow-up, withdrawal of consent, or study termination 
by the Sponsor (whichever occurs first). 
Tests and Observations: 
In Phase 1a, safety monitoring at each study visit will include an evaluation of the signs and 
symptoms of autoimmune toxicities such as enterocolitis, dermatitis, neuropathy, and 
endocrinopathies.  Management of immune-related adverse events (irAEs) and CRS are 
described in Section 6.9.4 and Appendix 10 respectively.  Changes in key CRS-promoting 
cytokine levels from baseline (including IL-6, IFNγ, TNFα, and others) will be evaluated to 
assess the cytokine response to FPT155 in treated patients.  
Safety assessments for all patients include vital signs, body weight, physical exam, ECOG score, 
laboratory tests (hematology, serum chemistries, coagulation, and urinalysis), ECG, and 
monitoring of AEs and concomitant medications.  Specimens for PK, anti-drug antibodies 
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(ADA), and PD will be collected at the timepoints described in Table 1, Table 2, Table 3, and 
Table 4. 
Tumor assessments will be performed at screening, then every 6 weeks from the first dose for 
24 weeks, and then every 12 weeks thereafter.  Once an initial CR or PR is reported by the 
investigator, confirmatory scans must be performed 4–6 weeks later.  Responses will be assessed 
according to RECIST v1.1.  In the Phase 1b portion of the study, patients in LTFU for survival 
must have tumor scans every 12 weeks if tumor progression was not previously determined 
and/or use of alternative anti-cancer therapy has not been initiated. 
Data Monitoring Committee: No 
Statistical Methods: 
Hypothesis 
This is an estimation trial.  There is no clinical hypothesis. 
General Approach 
All analyses will be descriptive and will be presented by phase, dose group, cohort, and overall 
as appropriate.  In addition, all patients dosed at the MTD and/or RD will also be summarized as 
appropriate.  Data collected in this study will be presented using summary tables and patient data 
listings.  Continuous variables will be summarized using descriptive statistics, specifically the 
number of subjects, mean, median, standard deviation (SD), minimum, and maximum.  
Categorical variables will be summarized by frequencies and percentages. 
Sample Size Determination 
This study is designed as a dose escalation, dose exploration, and dose expansion study with 
objectives that include determination of an MTD and/or RD and assessments of the safety and 
tolerability of FPT155 as monotherapy and in combination with pembrolizumab.  The sample 
size of Phase 1a is defined by the requirements of the 3+3 dose escalation design.  The total 
number of patients planned for this study is estimated to be approximately 408. 
 Approximately 108 patients will participate in Phase 1a monotherapy, depending on the number 
of dose levels evaluated and the incidence of DLTs; this includes up to 58 patients in the Phase 
1a monotherapy dose escalation portion and allows for up to approximately 50 patients in the 
Phase 1a monotherapy dose exploration to further explore safety, PK, PD, and clinical activity at 
one or more dose levels (conditional upon the dose level clearing dose escalation criteria).  Up to 
approximately 240 patients will participate in the Phase 1b monotherapy dose expansion in up to 
8 cohorts of approximately 30 patients each.  
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Up to approximately 30 patients will participate in Phase 1a combination dose escalation, 
depending on the number of dose levels evaluated and the incidence of DLTs.  Up to 
approximately 30 patients will participate in the combination dose exploration. 
Safety Analysis 
Safety analyses will be performed separately within phases of the study and by dose, cohort, and 
all patients combined.  Data from all patients that receive any portion of at least 1 dose of 
FPT155 will be included in the safety analyses.  AEs, SAEs, clinical laboratory information, vital 
signs, ECOG performance status, weight, ECGs, and concomitant medications/procedures will 
be tabulated and summarized.  In addition, the incidence of DLTs in Phase 1a dose escalation 
will be summarized. 
Efficacy Analysis 
Objective Response Rate (ORR) will be summarized with frequencies and percentages with 90% 
exact confidence interval (CI) using the binomial distribution.  Progression-free survival (PFS) 
and overall survival (OS) will be summarized using Kaplan-Meier (KM) estimates and 
corresponding 90% CIs.  Duration of response (DOR) will be summarized similarly as for PFS 
and OS for all treated subjects who achieved a confirmed CR of PR. ORR, DOR and PFS will be 
determined based on investigator’s assessments as per RECIST v1.1. 
Pharmacokinetic Analysis 
Individual and mean (± SD) serum FPT155 and pembrolizumab (if applicable) concentration-
time data will be tabulated and plotted by dose level.  PK parameters will be tabulated and 
summarized by dose level when appropriate and applicable.  The impact of immunogenicity on 
FPT155 exposure will be assessed, tabulated, and summarized by dose level as data allow. 
The effect of body size on PK and correlation of exposure with clinical outcomes and toxicity 
will be assessed when the data allow.  These analyses will be used to determine the appropriate 
dosing approach (eg, body size-based or fixed dosing) to support the proposed dose and dose 
regimen(s) for further trials. 
Immunogenicity Analysis 
A baseline ADA-positive patient is defined as a patient who has an ADA positive sample at 
baseline.  A treatment induced ADA-positive patient is a patient with at least 1 ADA-positive 
sample relative to baseline after initiation of the treatment.  The frequency distribution of 
baseline ADA-positive patients and induced ADA-positive patients after initiation of study 
treatment will be summarized. 
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Figure 1: 
Schema Monotherapy Dose Escalation 
 
Abbreviations: DLT = dose limiting toxicity; RCC = renal cell carcinoma; RD = recommended dose.  
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Figure 2: 
Schema Combination 
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1.2 
Schedule of Assessments 
Study assessments and procedures are presented in Table 1, Table 2, Table 3, and Table 4.  
Protocol waivers or exemptions are not allowed.
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Table 1: 
Schedule of Assessments – Dose Escalation (monotherapy and FPT155 + pembrolizumab) 
Study Phase 
Screening 
Cycle 1  
(21 Days) 
Subsequent 
Cycles*  
(21 Days) 
EOT 
Follow-Up 
Notes 
Cycle Day 
Screening 
D1 
D2 
D4 
D8 
D15 
D1 
28- and 100-
Days Post 
Last Dose 
Window (Days) 
-28 
 
 
± 1 
± 1 
± 1 
± 3 
± 7 
Study Assessments: Unless specified, procedure is to be performed prior to administration of study treatment.  Any clinical assessment, laboratory test, or additional 
non-specified test may be obtained at any time if clinically indicated.  If all study treatment is permanently discontinued for any reason other than withdrawal of consent, EOT 
follow-up visits should take place at the specified time points.  The EOT follow-up visit at approximately 100 days after the last dose of study drug will be considered the end of 
study in Phase 1a. 
Review / 
Confirm 
Eligibility 
Criteria 
X 
X 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
Medical History 
/ Demographics 
X 
X 
 
 
 
 
 
 
Medical history includes significant past medical events including 
surgeries or hospitalizations, a review of the disease under study, 
prior anti-cancer therapies, and any concurrent medical illnesses. 
Physical 
Examination 
X 
X 
 
 
X 
X 
X 
X 
A complete physical examination including height and weight will be 
performed at screening.  A limited physical examination (e.g., 
symptom-directed examination of specific organ systems/body area) 
should be conducted at the specified time points after screening.  
Additional physical examinations may be performed as clinically 
indicated for patients in the first dose cohort that are hospitalized for 
the initial infusion or for any patients showing evidence of ≥ Grade 2 
CRS. 
Height and 
Weight 
X 
X 
 
 
X 
X 
X 
X 
Height (without shoes) should be measured at screening only and 
recorded in centimeters.  Weight (without shoes) should be measured 
at each physical examination and reported in kilograms. 
 
 
 
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14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 40 of 143 
Table 1: 
Schedule of Assessments – Dose Escalation (monotherapy and FPT155 + pembrolizumab) (monotherapy and 
FPT155 + pembrolizumab) (Contd) 
Study Phase 
Screening 
Cycle 1  
(21 Days) 
Subsequent 
Cycles*  
(21 Days) 
EOT 
Follow-Up 
Notes 
Cycle Day 
Screening 
D1 
D2 
D4 
D8 
D15 
D1 
28- and 100-
Days Post 
Last Dose 
Window (Days) 
-28 
 
 
± 1 
± 1 
± 1 
± 3 
± 7 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs include blood pressure, respiratory rate, pulse and 
temperature. 
For the first and second infusions of FPT155, measure vital signs 
prior to dosing, every 15 minutes during the infusion, and after 
completion of each FPT155 IV infusion at the following timepoints: 
5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 
5 hours, and 6 hours post-dose.  Additional vital signs may be 
performed as clinically indicated for patients in the first dose cohort 
that are hospitalized for the initial infusion or for any patients 
showing evidence of ≥ Grade 2 CRS. 
For all subsequent infusions, measure vital signs prior to dosing, 
every 15 minutes during the infusion, and after completion of each 
FPT155 IV infusion.   
12-Lead ECG 
X 
X 
 
 
 
 
X 
X 
ECG is required at screening, pre-dose on Day 1 of every cycle, and 
at the EOT visits. 
ECOG 
Performance 
Status 
X 
X 
 
 
 
 
X 
X 
 
Prior / 
Concomitant 
Medications 
 
===========================================  
Adverse Events 
Review 
 
=========================================== AEs will be assessed before and after study drug dosing on 
applicable visits. AEs ascribed to study drug and SAEs should be 
assessed through the Day 100 EOT visit. 
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FPT155-001 Clinical Protocol 
Amendment 4 
14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 41 of 143 
Table 1: 
Schedule of Assessments – Dose Escalation (monotherapy and FPT155 + pembrolizumab) (Contd) 
Study Phase 
Screening 
Cycle 1  
(21 Days) 
Subsequent 
Cycles*  
(21 Days) 
EOT 
Follow-Up 
Notes 
Cycle Day 
Screening 
D1 
D2 
D4 
D8 
D15 
D1 
28- and 100-
Days Post 
Last Dose 
Window (Days) 
-28 
 
 
± 1 
± 1 
± 1 
± 3 
± 7 
CT or MRI 
X 
 
 
 
 
 
X 
X 
Tumor evaluation by CT or MRI should be conducted according to RECIST 
v1.1 at screening, every 6 (± 1) weeks from the first dose for 24 weeks, and 
then every 12 (± 2) weeks thereafter. Imaging performed as standard of care 
may be used if it has been performed within 28 days of treatment.  Once an 
initial CR or PR is noted, confirmatory scans must be performed 4-6 weeks 
later. Patients who terminate treatment prior to the next scheduled CT or 
MRI assessment should have a scan performed at the EOT visits (if not 
conducted in the previous 8 weeks or if tumor progression was previously 
determined). 
After discontinuation of study treatment for reasons other than progressive 
disease, withdrawal of consent, or initiation of additional anti-cancer 
therapy, tumor assessments will continue approximately every 12 (± 1) 
weeks until disease progression, withdrawal of consent or start of new anti-
cancer therapy.  
Archival Tumor 
Tissue (or Fresh 
Biopsy if 
Archival Not 
Available) 
X 
 
 
 
 
 
 
 
In dose escalation cohorts, archival tumor tissue is required.  If archival 
tumor tissue is not available, a fresh biopsy is required prior to treatment.  
Blocks are preferred, if not available, a minimum of 15 slides are acceptable. 
 
Sample Collection 
Chemistry 
X 
X 
X 
 
X 
X 
X** 
X 
All samples are assessed locally. Labs may be drawn up to 24 hours 
in advance of treatment.  Refer to Appendix 1 for additional details.   
Additional labs may be performed as clinically indicated for patients 
in the first dose cohort that are hospitalized for the initial infusion or 
for any patients showing evidence of ≥ Grade 2 CRS. 
** During dose escalation, chemistry and hematology panel will be 
drawn on Day 2, 8 and 15 of Cycles 2 and 3. 
Hematology 
X 
X 
X 
 
X 
X 
X** 
X 
Coagulation 
X 
X 
 
 
 
 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
X 
X 
HBsAg and HCV 
RNA 
X 
 
 
 
 
 
 
 
 
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FPT155-001 Clinical Protocol 
Amendment 4 
14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 42 of 143 
Table 1: 
Schedule of Assessments – Dose Escalation (monotherapy and FPT155 + pembrolizumab) (Contd) 
Study Phase 
Screening 
Cycle 1  
(21 Days) 
Subsequent 
Cycles*  
(21 Days) 
EOT 
Follow-Up 
Notes 
Cycle Day 
Screening 
D1 
D1 
D4 
D8 
D15 
D1 
28- and 100-
Days Post 
Last Dose 
Window (Days) 
-28 
 
 
± 1 
± 1 
± 1 
± 3 
± 7 
Pregnancy Test 
X 
X 
 
 
 
 
X 
 
For WOCBP, a serum pregnancy test will be performed at screening (within 
7 days of Cycle 1 Day 1) and pregnancy testing will be performed at each 
subsequent cycle of treatment prior to dosing.  All samples are assessed 
locally. 
PK Sampling 
Refer to Table 3 
Blood samples will be collected for PK analyses at the timepoints specified 
in Table 3 and submitted to the central laboratory. 
PD Sampling 
Refer to Table 3 
Blood samples will be collected for PD analyses at the timepoints specified 
in Table 3 and submitted to the central laboratory.   
ADA Sampling 
Refer to Table 3 
Blood samples will be collected for ADA analyses at the timepoints 
specified in Table 3 and submitted to the central laboratory.   
Tumor Tissue 
Biopsy 
X  
 
 
 
 
 
X 
X  
In dose escalation cohorts, optional pre- and on-treatment fresh biopsies will 
be requested from the primary tumor or metastatic tumor site at screening 
(prior to treatment) and Cycle 3 Day 1, from the same lesion where feasible.  
An additional optional biopsy will be requested at the Day 28 EOT visit 
from patients who have documented disease progression. 
 
Study Drug Dosing 
Study Drug 
Dosing 
 
X 
 
 
 
 
X 
 
FPT155 will be administered over approximately 60 minutes by IV infusion 
Q3W.  Patients may continue receiving study treatment Q3W at the 
investigator’s discretion until any of the protocol-specified treatment 
discontinuation criteria are met.  For FPT155 + pembrolizumab cohorts, 
pembrolizumab will be administered 30 minutes after completion of the 
FPT155 IV infusion at a dose of 200 mg by 30 min IV infusion.  If one study 
drug is discontinued, the other may be administered for up to 12 months or 
until protocol-specified discontinuation criteria are met.  The DLT 
evaluation period consists of 21 days.  Upon completion of the DLT 
evaluation period, patients may continue receiving study treatment per the 
parameters above.  
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Amendment 4 
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Five Prime Therapeutics 
Confidential 
Page 43 of 143 
Abbreviations: ADA = anti-drug antibody; AE = adverse event; CR = complete response; CRS = cytokine release syndrome; CT = computed tomography; DLT = dose limiting 
toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; IV = intravenous; HBsAG = hepatitis B surface antigen; HCV RNA 
= hepatitis C virus ribonucleic acid; MRI = magnetic resonance imaging; PD = pharmacodynamic; PK = pharmacokinetic; PR = partial response; Q3W = every 3 weeks; RECIST 
= Response Evaluation Criteria in Solid Tumors; WOCBP = women of childbearing potential. 
*There is a ± 3-day window for subsequent cycles after Cycle 1 
 
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Amendment 4 
14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 44 of 143 
Table 2: 
Schedule of Assessments – Dose Exploration/Expansion (monotherapy and FPT155 + pembrolizumab) 
Study Phase 
Screening 
Cycle 1  
(21 Days) 
Subsequent 
Cycles*  
(21 Days) 
EOT 
Follow-Up 
LTFU 
Notes 
Cycle Day 
Screening 
D1 
D2 
D4 
D8 
D15 
D1 
28- and 100-
Days Post 
Last Dose 
 
Window 
(Days) 
-28 
 
 
± 1 
± 1 
± 1 
± 3 
± 7 
± 14 
Study Assessments: Unless specified, procedure is to be performed prior to administration of study treatment.  Any clinical assessment, laboratory test, or additional non-
specified test may be obtained at any time if clinically indicated.  If all study treatment is permanently discontinued for any reason other than withdrawal of consent, EOT follow-
up visits should take place at the specified time points.  In the Phase 1b portion of the study, patients will also undergo LTFU for survival by clinic visit or by telephone 
approximately every 3 months after the Day 28 EOT visit, or until death, loss to follow-up, withdrawal of consent, or study termination by the Sponsor (whichever occurs first), 
which will be considered the end of the study in Phase 1b. 
Review / 
Confirm 
Eligibility 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
Medical 
History / 
Demographics 
X 
X 
 
 
 
 
 
 
 
Medical history includes significant past medical events 
including surgeries or hospitalizations, a review of the disease 
under study, prior anti-cancer therapies, and any concurrent 
medical illnesses. 
Physical 
Examination 
X 
X 
 
 
X 
X 
X 
X 
 
A complete physical examination including height and weight 
will be performed at screening.  A limited physical examination 
(e.g., symptom-directed examination of specific organ 
systems/body area) should be conducted at the specified time 
points after screening.  Additional physical examinations may be 
performed as clinically indicated. 
Height and 
Weight 
X 
X 
 
 
X 
X 
X 
X 
 
Height (without shoes) should be measured at screening only 
and recorded in centimeters.  Weight (without shoes) should be 
measured at each physical examination and reported in 
kilograms. 
 
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Amendment 4 
14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 45 of 143 
Table 2: 
Schedule of Assessments –Dose Exploration/Expansion (monotherapy and FPT155 + pembrolizumab) (Contd) 
Study Phase 
Screening 
Cycle 1  
(21 Days) 
Subsequent 
Cycles*  
(21 Days) 
EOT 
Follow-Up 
LTFU 
Notes 
Cycle Day 
Screening 
D1 
D2 
D4 
D8 
D15 
D1 
28- and 100-
Days Post 
Last Dose 
 
Window 
(Days) 
-28 
 
 
± 1 
± 1 
± 1 
± 3 
± 7 
± 14 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs include blood pressure, respiratory rate, pulse and 
temperature. For the first and second infusions of FPT155, 
measure vital signs prior to dosing, every 15 minutes during the 
infusion, and after completion of each FPT155 IV infusion at the 
following timepoints: 5 minutes, 15 minutes, 30 minutes, 1 hour, 
2 hours, 3 hours, 4 hours, 5 hours, and 6 hours post-dose.   
For all subsequent infusions, measure vital signs prior to dosing, 
every 15 minutes during the infusion, and after completion of 
each FPT155 IV infusion.  Additional vital signs may be 
performed as clinically indicated. 
12-Lead 
ECG 
X 
X 
 
 
 
 
 
X 
 
ECG is required at screening, pre-dose on Cycle 1 Day 1, and at 
the EOT visits.  Additional ECGs may be obtained at any time if 
clinically indicated. 
ECOG 
Performance 
Status 
X 
X 
 
 
 
 
X 
X 
 
 
Prior / 
Concomitant 
Medications 
 
===================================================== 
 
Adverse 
Events 
Review 
 
===================================================== AEs will be assessed before and after study drug dosing on 
applicable visits. AEs ascribed to study drug and SAEs should 
be assessed through the Day 100 EOT visit. 
 
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FPT155-001 Clinical Protocol 
Amendment 4 
14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 46 of 143 
Table 2: 
Schedule of Assessments –Dose Exploration/Expansion (monotherapy and FPT155 + pembrolizumab) (Contd) 
Study Phase 
Screening 
Cycle 1  
(21 Days) 
Subsequent 
Cycles*  
(21 Days) 
EOT 
Follow-Up 
LTFU 
Notes 
Cycle Day 
Screening 
D1 
D2 
D4 
D8 
D15 
D1 
28- and 100-
Days Post 
Last Dose 
 
Window 
(Days) 
-28 
 
 
± 1 
± 1 
± 1 
± 3 
± 7 
± 14 
CT or MRI 
X 
 
 
 
 
 
X 
X 
X 
Tumor evaluation by CT or MRI should be conducted according 
to RECIST v1.1 at screening, every 6 (± 1) weeks from the first 
dose for 24 weeks, and then every 12 (± 2) weeks thereafter. 
Imaging performed as standard of care may be used if it has 
been performed within 28 days of treatment.  Once an initial CR 
or PR is noted, confirmatory scans must be performed 4-6 weeks 
later.  Patients who terminate treatment prior to the next 
scheduled CT or MRI assessment should have a scan performed 
at the EOT visits (if not conducted in the previous 8 weeks or if 
tumor progression was previously determined). 
After discontinuation of study treatment for reasons other than 
progressive disease, withdrawal of consent, or initiation of 
additional anti-cancer therapy, tumor assessments will continue 
approximately every 12 (± 1) weeks until disease progression, 
withdrawal of consent or start of new anti-cancer therapy. 
Patients in LTFU for survival must have tumor scans every 
12 (±2) weeks if tumor progression was not previously 
determined and/or use of alternative anti-cancer therapy has not 
been initiated.  Any new anti-cancer therapy should be 
documented. 
Archival 
Tumor Tissue 
(or Fresh 
Biopsy if 
Archival Not 
Available) 
X 
 
 
 
 
 
 
 
 
Archival tumor tissue is required.  The fresh biopsy required at 
screening will be accepted in lieu of archival tumor tissue if 
archival tissue is not available.  Blocks are preferred, if not 
available, a minimum of 15 slides are acceptable.   
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FPT155-001 Clinical Protocol 
Amendment 4 
14 September 2020 
Five Prime Therapeutics 
Confidential 
Page 47 of 143 
Table 2: 
Schedule of Assessments –Dose Exploration/Expansion (monotherapy and FPT155 + pembrolizumab) (Contd) 
Study Phase 
Screening 
Cycle 1  
(21 Days) 
Subsequent 
Cycles*  
(21 Days) 
EOT 
Follow-Up 
LTFU 
Notes 
Cycle Day 
Screening 
D1 
D2 
D4 
D8 
D15 
D1 
28- and 100-
Days Post 
Last Dose 
 
Window 
(Days) 
-28 
 
 
± 1 
± 1 
± 1 
± 3 
± 7 
± 14 
Sample Collection 
Chemistry 
X 
X 
X 
 
X 
X 
X 
X 
 
All samples are assessed locally. Labs may be drawn up to 
24 hours in advance of treatment.  Refer to Appendix 1 for 
additional details. 
Additional labs may be performed as clinically indicated. 
Hematology 
X 
X 
X 
 
X 
X 
X 
X 
 
Coagulation 
X 
X 
 
 
 
 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
 
X 
X 
 
HBsAg and 
HCV RNA 
X 
 
 
 
 
 
 
 
 
Pregnancy 
Test 
X 
X 
 
 
 
 
X 
 
 
For WOCBP, a serum pregnancy test will be performed at 
screening (within 7 days of Cycle 1 Day 1) and pregnancy testing 
will be performed at each subsequent cycle of treatment prior to 
dosing.  All samples are assessed locally. 
PK Sampling 
 
Refer to Table 4 
Blood samples will be collected for PK analyses at the timepoints 
specified in Table 4 and submitted to the central laboratory. 
PD Sampling 
 
Refer to Table 4 
Blood samples will be collected for PD analyses at the timepoints 
specified in Table 4 and submitted to the central laboratory.   
ADA 
Sampling 
 
Refer to Table 4  
Blood samples will be collected for ADA analyses at the 
timepoints specified in Table 4 and submitted to the central 
laboratory.   
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Amendment 4 
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Five Prime Therapeutics 
Confidential 
Page 48 of 143 
Table 2: 
Schedule of Assessments –Dose Exploration/Expansion (monotherapy and FPT155 + pembrolizumab) (Contd) 
Study Phase 
Screening 
Cycle 1  
(21 Days) 
Subsequent 
Cycles*  
(21 Days) 
EOT 
Follow-Up 
LTFU 
Notes 
Cycle Day 
Screening 
D1 
D2 
D4 
D8 
D15 
D1 
28- and 100-
Days Post 
Last Dose 
 
Window 
(Days) 
-28 
 
 
± 1 
± 1 
± 1 
± 3 
± 7 
± 14 
Tumor Tissue 
Biopsy 
X 
 
 
 
 
 
X 
X 
 
In dose exploration and expansion, pre- and on-treatment fresh 
biopsies will be mandatory at screening (prior to treatment) and 
prior to the Cycle 3 Day 1 dose, from the same lesion where 
feasible.  An additional optional biopsy will be requested at the 
Day 28 EOT visit from patients who have documented disease 
progression. 
Study Drug Dosing 
Study Drug 
Dosing 
 
X 
 
 
 
 
X 
 
 
FPT155 will be administered over approximately 60 minutes by 
IV infusion Q3W.  Patients may continue receiving study 
treatment Q3W at the investigator’s discretion until any of the 
protocol-specified treatment discontinuation criteria are met.  For 
FPT155 + pembrolizumab cohorts, pembrolizumab will be 
administered 30 minutes after completion of the FPT155 IV 
infusion at a dose of 200 mg by IV infusion. If one study drug is 
discontinued, the other may be administered for up to 12 months 
or until protocol-specified discontinuation criteria are met. 
Survival Assessment 
Survival 
Assessment 
 
 
 
 
 
 
 
 
X 
Patients will undergo LTFU for survival by clinic visit or by 
telephone approximately every 3 months ± 14 days after the 
Day 100 EOT visit, or until death, loss to follow-up, withdrawal 
of consent, or study termination by the Sponsor (whichever 
occurs first).   
Abbreviations: ADA = anti-drug antibody; AE = adverse event; CR = complete response; CRS = cytokine release syndrome; CT = computed tomography; DLT = dose limiting 
toxicity; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; IV = intravenous; HBsAG = hepatitis B surface antigen; HCV RNA 
= hepatitis C virus ribonucleic acid; LTFU = long-term follow-up; MRI = magnetic resonance imaging; PD = pharmacodynamic; PK = pharmacokinetic; PR = partial response; 
Q3W = every 3 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; WOCBP = women of childbearing potential. 
* There is a ± 3-day window for subsequent cycles after Cycle 1
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Five Prime Therapeutics 
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Page 49 of 143 
Table 3: 
Dose Escalation (monotherapy and FPT155 + pembrolizumab): Schedule of 
Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarker 
Specimens to be Submitted to Central Laboratory 
Study Cycle 
Study Day 
Time Point & Window 
Type of Sample 
Screening 
Screening  
Screening (Day-28) 
Archival tumor, as specified in Table 1 
Tumor biopsy, as specified in Table 1 
Plasma for PD 
PBMC for PD 
Cycle 1 
Day 1 
≤ 4 hours prior to infusion 
FPT155 and/or pembrolizumab PK 
(serum) 
FPT155 and/or pembrolizumab ADA 
(serum) 
Plasma for PD 
PaxGene for PD 
ctDNA plasma for PD 
PBMC for PD 
15 (± 10) minutes after end 
of infusion 
FPT155 and/or pembrolizumab PK 
(serum) 
1 hour (± 15 minutes) after 
end of infusion 
FPT155 PK (serum) 
Plasma for PD 
2 hours (± 30 min) after the 
end of infusion 
FPT155 PK (serum) 
6 hours (± 60 minutes) after 
end of infusion 
FPT155 PK (serum) 
Plasma for PD 
Day 2 
24 hours (± 2 hours) after 
end of infusion 
FPT155 PK (serum) 
Plasma for PD 
Day 4 
72 hours (± 1 day) after end 
of infusion 
FPT155 PK (serum) 
Plasma for PD 
Day 8 
168 hours (± 1 day) after 
infusion 
FPT155 PK (serum) 
Plasma for PD 
PaxGene for PD 
PBMC for PD 
Day 15 
336 hours (± 1 day) after 
infusion 
FPT155 PK (serum) 
Plasma for PD 
PaxGene for PD 
PBMC for PD 
 
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Amendment 4 
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Five Prime Therapeutics 
Confidential 
Page 50 of 143 
Table 3: 
Dose Escalation (monotherapy and FPT155 + pembrolizumab): Schedule of 
Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarker 
Specimens to be Submitted to Central Laboratory (Contd) 
Study Cycle 
Study Day 
Time Point & Window 
Type of Sample 
Cycles 2 -6 
Day 1 
≤ 4 hours prior to infusion 
Tumor Biopsy (prior to Cycle 3 Day 1 ± 
1 week), as specified in Table 1 
FPT155 PK (serum) 
Pembrolizumab PK (serum) (Cycle 2) 
FPT155 ADA (serum) (Cycles 2, 3, and 5) 
Pembrolizumab ADA (serum) (Cycle 2) 
Plasma for PD (Cycles 2, 3, and 5) 
PaxGene for PD (Cycles 2, 3, and 5) 
ctDNA plasma for PD (Cycle 3) 
PBMC for PD (Cycles 2, 3, and 5) 
15 (± 10) minutes after end 
of infusion  
FPT155 PK (serum) 
1 hour (± 15 minutes) after 
end of infusion 
FPT155 PK (serum) (Cycle 3) 
Plasma for PD (Cycle 3) 
Cycles 9, 13, 
and 17 
Day 1 
≤ 4 hours prior to infusion 
FPT155 PK (serum) 
Pembrolizumab PK (Cycle 9) 
FPT155 ADA (serum)  
Pembrolizumab ADA (serum) (Cycle 9) 
15 (± 10) minutes after end 
of infusion 
FPT155 PK (serum) 
Every 8 Cycles 
starting from 
Cycle 17 
Day 1 
≤ 4 hours prior to infusion 
FPT155 PK (serum) 
FPT155 ADA (serum) 
15 (± 10) minutes after end 
of infusion 
FPT155 PK (serum) 
EOT  
Visit date  
(28 [±7] days 
and 100 [±7] 
days post-last 
dose) 
During visit 
Tumor Biopsy (Day 28 visit, as specified 
in Table 1 
FPT155 and/or pembrolizumab PK 
(serum) 
FPT155 and/or pembrolizumab ADA 
(serum) 
Plasma for PD (Day 28 visit) 
PaxGene for PD (Day 28 visit) 
ctDNA plasma for PD (Day 28 visit) 
PBMC for PD (Day 28 visit) 
Abbreviations: ADA = anti-drug antibody; ctDNA = circulating tumor deoxyribonucleic acid; EOT = end of 
treatment; PBMC = peripheral blood mononuclear cell; PD = pharmacodynamic; PK = pharmacokinetic. 
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Page 51 of 143 
Table 4: 
Dose Exploration/Expansion (Monotherapy and FPT155 + pembrolizumab): 
Schedule of Pharmacokinetic, Immunogenicity, and Pharmacodynamic 
Biomarker Specimens to be Submitted to Central Laboratory 
Study Cycle 
Study Day 
Time Point & Window 
Type of Sample 
Screening 
Screening  
Screening (Day-28) 
Archival tumor, as specified in Table 2 
Tumor biopsy, as specified in Table 2 
Plasma for PD 
PBMC for PD 
Cycle 1 
Day 1 
≤ 4 hours prior to infusion 
FPT155 and/or pembrolizumab PK 
(serum) 
FPT155 and/or pembrolizumab ADA 
(serum) 
Plasma for PD 
PaxGene for PD 
ctDNA plasma for PD 
PBMC for PD 
15 (± 10) minutes after end 
of infusion 
FPT155 and/or pembrolizumab PK 
(serum) 
1 hour (± 15 minutes) after 
end of infusion 
FPT155 PK (serum) 
Plasma for PD 
2 hours (± 30 min) after the 
end of infusion 
FPT155 PK (serum) 
6 hours (± 60 minutes) after 
end of infusion 
FPT155 PK (serum) 
Plasma for PD 
Day 2 
24 hours (± 2 hours) after 
end of infusion 
FPT155 PK (serum) 
Plasma for PD 
Day 4 
72 hours (± 1 day) after end 
of infusion 
FPT155 PK (serum) 
Plasma for PD 
Day 8 
168 hours (± 1 day) after 
infusion 
FPT155 PK (serum) 
Plasma for PD 
PaxGene for PD 
PBMC for PD 
Day 15 
336 hours (± 1 day) after 
infusion 
FPT155 PK (serum) 
Plasma for PD 
PaxGene for PD 
PBMC for PD 
 
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Page 52 of 143 
Table 4: 
Dose Exploration/Expansion (Monotherapy and FPT155 + pembrolizumab): 
Schedule of Pharmacokinetic, Immunogenicity, and Pharmacodynamic 
Biomarker Specimens to be Submitted to Central Laboratory (Contd) 
Study Cycle 
Study Day 
Time Point & Window 
Type of Sample 
Cycles 2-6 
Day 1 
≤ 4 hours prior to infusion 
Tumor Biopsy (prior to Cycle 3 Day 1 ± 1 
week), as specified in Table 2 
FPT155 PK (serum) 
Pembrolizumab PK (serum) (Cycle 2) 
FPT155 ADA (serum) (Cycles 2, 3, and 5) 
Pembrolizumab ADA (serum) (Cycles 2) 
Plasma for PD (Cycles 2, 3, and 5) 
PaxGene for PD (Cycles 2, 3, and 5) 
ctDNA plasma for PD (Cycle 3) 
PBMC for PD (Cycles 2, 3, and 5) 
15 (± 10) minutes after end 
of infusion  
FPT155 PK (serum) 
Cycles 9, 13, 
and 17 
Day 1 
≤ 4 hours prior to infusion 
FPT155 PK (serum) 
Pembrolizumab PK (serum) (Cycles 9) 
FPT155 ADA (serum) 
Pembrolizumab ADA (serum) (Cycles 9)  
15 (± 10) minutes after end 
of infusion 
FPT155 PK (serum) 
Every 8 Cycles 
starting from 
Cycle 17 
Day 1 
≤ 4 hours prior to infusion 
FPT155 PK (serum) 
FPT155 ADA (serum) 
15 (± 10) minutes after end 
of infusion 
FPT155 PK (serum) 
EOT  
Visit date  
(28 [±7] days 
and 100 [±7] 
days post-last 
dose) 
During visit 
Tumor Biopsy (Day 28 visit, as specified 
in Table 2 
FPT155 and/or pembrolizumab PK 
(serum) 
FPT155 and/or pembrolizumab ADA 
(serum) 
Plasma for PD (Day 28 visit) 
PaxGene for PD (Day 28 visit) 
ctDNA plasma for PD (Day 28 visit) 
PBMC for PD (Day 28 visit) 
Abbreviations: ADA = anti-drug antibody; ctDNA = circulating tumor deoxyribonucleic acid; EOT = end of 
treatment; PBMC = peripheral blood mononuclear cell; PD = pharmacodynamic; PK = pharmacokinetic.   
 
 
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2.0 
INTRODUCTION 
T cell regulation involves the integration of multiple signaling pathways: signaling via the T cell 
receptor (TCR) complex and through co-signaling receptors, both co-stimulatory and 
co-inhibitory.  CD80 (cluster of differentiation 80, also known as B7, B7.1, B7-1) is a 
well -characterized co-signaling ligand.  It is expressed on professional antigen-presenting cells 
(APCs) such as dendritic cells and activated macrophages.  Following TCR recognition of 
cognate peptide-major histocompatibility complex (MHC), CD80 acts as a co-stimulatory ligand 
via interactions with its receptor, cluster of differentiation 28 (CD28), expressed on T cells.  In 
addition to signaling via CD28, CD80 also interacts with co-inhibitory molecules cytotoxic 
T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-ligand 1 (PD-L1).  CD80 
interactions with CTLA-4 are central for dampening the T cell response once activated T cell 
responses are no longer needed, while the biological significance of the CD80 interaction with 
PD-L1 is not as well understood.  Together, the co-stimulatory and co-inhibitory ligands ensure 
both tolerance to self-antigens and the ability to mount an appropriate immune response to 
non-self antigens (Chen 2013). 
Although the immune system is often initially able to mount an effective immune response 
against tumor cells via TCR-dependent and -independent mechanisms, some tumors can evade 
the immune response.  Mechanisms by which this occurs include the upregulation of pathways 
that enforce peripheral tolerance to self-antigens (including CTLA-4 and PD-L1).  Recent 
immuno-oncology approaches have focused on reprogramming the immune system to mount an 
effective immune response against tumors that have evaded the initial immune response.  
Specifically, blocking antibodies against both the programmed cell death protein (PD-1)/PD-L1 
and CTLA-4 axes have been effective in anti-tumor immunity, including improved progression 
free survival (PFS) and overall survival (OS) in some patients (Postow 2015).  However, 
responses have only been observed in select tumor types, within which only a fraction of patients 
respond to checkpoint inhibitors.  Although some patients do achieve long term disease control 
with the use of blocking antibodies against the PD-1/PD-L1 and CTLA-4 axes, the majority of 
patients either do not respond or respond then subsequently relapse.  Therefore, a need exists for 
additional immuno-oncology approaches, and the CD80 signaling axis may provide additional 
opportunities for intervention. 
FPT155 (CD80-Fc) is a recombinant fusion protein composed of the extracellular domain (ECD) 
of human CD80 fused with the fragment crystallizable (Fc) domain of human immunoglobulin 
G1 (IgG1).  It is designed to act as a potent stimulator of anti-tumor immunity through 
2 mechanisms of action.  FPT155 exerts direct agonism, but not superagonism, of CD28, thereby 
co-stimulating T cell activation in response to TCR signaling.  FPT155 is also likely to prevent 
CTLA-4-mediated effector T cell inhibition.  FPT155 is being developed for the treatment of 
solid tumors that are predicted to be responsive to an immune-mediated therapeutic approach. 
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2.1 
Study Rationale 
Recently approved immune therapies, particularly inhibitors of immune checkpoints such as 
CTLA-4 and PD-1 have resulted in durable responses across many solid tumors (KEYTRUDA 
2018, OPDIVO 2018, Yervoy 2018).  Anti-PD(L)1 inhibitors have received regulatory approval 
across a range of solid tumors including melanoma and renal cell carcinoma (RCC).  The median 
objective response rate (ORR) in patients with advanced melanoma who received up to 1 prior 
therapy for metastatic disease ranged from 33-40% with a median PFS of approximately 
5 months (Robert 2015).  Ipilimumab, a CTLA-4 inhibitor, is approved as monotherapy in 
advanced melanoma with an ORR of 10% and median OS of 10 months (Hodi 2010).  The 
combination of nivolumab, an anti-PD-1 antibody, and ipilimumab has demonstrated superior 
efficacy in advanced melanoma compared to either agent alone with an ORR of 58% and a median 
PFS of 11.5 months compared to 44% and 6.5 months with nivolumab alone (Wolchok 2017).  In 
patients with advanced RCC who failed prior anti-angiogenic therapy, nivolumab resulted in an 
ORR of 25% and median PFS of 4.6 months (Motzer 2015).  In RCC the combination of 
ipilimumab and nivolumab was superior to sunitinib with an ORR 42% and median PFS of 
11.6 months (Motzer 2018).  Thus, even the combination of 2 checkpoint inhibitor therapies 
results in objective responses in < 60% of patients with a median PFS of less than 1 year.  
Efficacy of anti-PD(L)1 monotherapy in other solid tumors (eg squamous cell head and neck 
cancer and urothelial carcinoma) is even more limited compared to melanoma and RCC (Ferris 
2016, Bellmunt 2017).  Ipilimumab has shown limited activity in other solid tumors beyond 
melanoma and RCC.  While additional combination studies of anti-PD(L)1 and anti-CTLA4 
therapies with or without standard of care chemotherapy and targeted agents are ongoing, a novel 
immune therapy with a differentiated mechanism of action that results in improved response 
rates and durability across a broad range of solid tumors is necessary. 
This study is a Phase 1a/1b open-label, multicenter study to evaluate the dosing, safety, 
tolerability, pharmacokinetic (PK), pharmacodynamics (PD), and preliminary efficacy of 
FPT155 in patients with advanced solid tumors as monotherapy and in combination with 
pembrolizumab. 
2.2 
Background 
2.2.1 
FPT155, A CD80-Fc Fusion Protein  
FPT155 is a recombinant fusion protein composed of the ECD of human CD80 fused with 
human IgG1 wild type Fc.  FPT155 is designed to elicit immune responses in patients with 
advanced solid tumors via 2 key T cell regulators or modulators: CD28 and CTLA-4.  
Endogenous CD80 acts as an agonist but not superagonist of the CD28 receptor, and FPT155 is 
thought to engage CD28 similarly to endogenous CD80.  This engagement of CD28 
co-stimulates T cell responses only in the presence of TCR signaling.  FPT155 also binds to 
CTLA-4, preventing its ability to inhibit effector T cells via sequestration of endogenous CD80.  
FPT155 thus enhances CD28 signaling to promote T cell activation both directly, in the context 
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of Fc-mediated co-presentation with TCR stimulus in a cellular synapse, and indirectly, in the 
context of endogenous CD80 expression. 
2.2.2 
Nonclinical Pharmacology Studies with FPT155 
FPT155 promotes T cell activation through CD28 costimulation via 2 potential mechanisms: 
direct agonism of CD28 signaling, and prevention of CTLA-4-mediated inhibition of CD28 
activity.  Both of these mechanisms were explored in vitro and in vivo. 
2.2.2.1 
In Vitro Biology 
In vitro pharmacology studies focused on the binding of FPT155 to CD80 ligands and on the 
ability of FPT155 to co-stimulate T cell activation, as summarized below. 
CD80 has been reported to interact with 3 binding partners: CD28, CTLA-4, and PD-L1. 
Binding studies were performed to determine the relevant binding partners of FPT155 using 
surface plasmon resonance (SPR), enzyme-linked immunosorbent assay (ELISA), and flow 
cytometry.  The SPR studies demonstrated that FPT155 has the highest affinity for CTLA-4 
(1.8 nM), moderate affinity for PD-L1 (183 nM), and low affinity for CD28 (> 1 μM).  The low 
affinity of FPT155 for CD28 is consistent with literature reports (Greene 1996, Collins 2002).  
Results from an ELISA study also supported the strong affinity of FPT155 for CTLA-4, and flow 
cytometry studies showed engagement of FPT155 with cell surface CTLA-4 and CD28 but not 
PD-L1.  When FPT155 binding was tested on human peripheral blood mononuclear cells 
(PBMCs), FPT155 primarily bound to T cell subsets in a concentration-dependent manner.  
Potent binding was also demonstrated with in vitro-activated conventional CD4+ T cells and Treg.  
FPT155 binding to T cells was mediated via CD28 and CTLA-4; no binding to cell-surface PD-L1 
could be demonstrated. 
The costimulatory activity of FPT155 was assessed in 3 different cell-based in vitro assays.  
Two of these studies utilized an “artificial APC” (aAPC) in co-culture with a reporter cell line or 
primary human T cells.  The aAPC were generated by engineering HEK293T cells to stably co-
express a scFv derived from the anti-human CD3 antibody OKT3 and a form of CD64 (high 
affinity Fc gamma receptor 1).  These aAPC thus co-presented TCR stimulus and FPT155 
(captured by CD64) in the context of a cellular synapse.  The reporter cell line was generated by 
introducing a Luciferase reporter gene that requires the integration of TCR/CD3 and CD28 
signals into Jurkat cells, which express endogenous TCR/CD3 and CD28.  When aAPC and the 
Jurkat reporter cells were incubated together with increasing concentrations of FPT155, 
FPT155-mediated induction of IL-2 reporter activity was evident, indicating binding and 
signaling through CD28.  The aAPC were also capable of activating primary human T cells in a 
CD28-sensitive fashion.  FPT155 induced concentration-dependent enhancement of 
proliferation, cytokine, and activation marker responses when added to purified T cells 
co-cultured with aAPC.  Activity in these assays was dependent upon the presence of a TCR 
stimulus, and FPT155 alone did not induce T cell activation.  The potential for FPT155 to be 
CD28 superagonist was also examined by cytokine release experiments in vitro.  As in the 
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co-culture assays, FPT155 alone did not induce spontaneous cytokine release by primary human 
immune cells, in contrast to a CD28 superagonist antibody that exerts TCR stimulus-independent 
activity.  Based on these results, FPT155 likely does not pose the same risk to induce cytokine 
release syndrome (CRS) as a CD28 superagonist antibody. 
2.2.2.2 
In Vivo Pharmacology 
For preclinical studies in murine models, a surrogate molecule, was generated.  mFPT155 
(mCD80-Fc) composed of the ECD of murine CD80 fused with the Fc domain of murine IgG2a.  
Tumor efficacy studies demonstrated that FPT155 and mFPT155 significantly inhibited tumor 
growth in multiple models, including models that are typically refractive to I/O therapy.  Dose 
dependent antitumor activity was observed in the CT26, MC38, and EMT6 tumor models, and 
complete CT26 tumor rejections were observed following a single 0.3 mg/kg dose.  Mice that 
rejected tumors in response to mFPT155 treatment were resistant to subsequent rechallenge, 
indicating the formation of protective antitumor immunity.   
During primary CT26 tumor challenge, mFPT155 monotherapy treatment altered the tumor 
microenvironment to one that is favorable for a productive antitumor immune response.  This 
included increased frequency of effector T cell subsets, a shift towards an immune “memory” 
phenotype, enhanced CD4+ and CD8+ T cell activation, and the upregulation of downstream 
effectors of T cell cytolytic activity.  These findings were supported by the observation that 
tumor antigen AH1-specific T cells were increased in mice that rejected CT26 tumors in 
response to mFPT155 treatment.  This increase correlated with protection from other tumors that 
share the AH1 antigen (ie, Renca tumors). 
The combination of mFPT155 and anti-PD1 treatment was evaluated in the murine CT26 tumor 
model. At the anti-PD-1 dose evaluated, anti-PD--1 did not have activity but the combination of 
mFPT155 and anti-PD-1 resulted in synergistic activity and significant tumor growth reduction. 
The additional of anti-PD-1 to mFPT155 resulted in a higher number of complete tumor 
regressions than mFPT155 alone.  
2.2.3 
Nonclinical Pharmacokinetics 
The PK/toxicokinetics (TK) characteristics of FPT155 were investigated in mice, rats, and 
cynomolgus monkeys.  These studies included 1 single-dose PK study in mice that examined 
doses of FPT155 from 0.03 mg/kg to 3 mg/kg and 2 repeat-dose studies with 4-weekly dosing 
each in rats and cynomolgus monkeys that examined doses of FPT155 from 1 mg/kg to 
100 mg/kg.  Among 4 repeat-dose studies, there was 1 PK study in rats, 1 pilot toxicology study 
in cynomolgus monkeys, and 1 Good Laboratory Practice (GLP) toxicology study in each 
species.  In all studies FPT155 was administered by intravenous (IV) administration.  
Following single IV dose ranging from 0.03 to 3 mg/kg in mice, the maximum observed serum 
concentration (Cmax) increased more than dose proportionally from 0.03 mg/kg to 0.9 mg/kg and 
dose proportionally from 0.9 mg/kg to 3 mg/kg.  The area under serum concentration (AUC)-
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time curve from day 0 to day 4 increased in a dose-proportional manner from 0.03 mg/kg to 
3 mg/kg with estimated clearance of 18.0 to 26.3 mL/day/kg and terminal half-life of 1-2 days.  
Following 4-weekly doses in rats or cynomolgus monkeys, following the first and fourth doses 
both Cmax and the AUC-time curve from day 0 to day 7 increased approximately in proportion 
with dose level in the dose range from 1 mg/kg to 100 mg/kg.  The estimated terminal half-life was 
4-6 days.  Following 4-weekly dosing, there was little to no accumulation.  Anti-drug antibodies 
(ADA) were present in the majority of rats (11/16 and 23/24 for the PK study and the GLP 
toxicology study, respectively).  Seven out of 12 and 2 out of 30 cynomolgus monkeys treated 
with FPT155 from the pilot toxicology study and the GLP toxicology study, respectively, were 
ADA positive.  The impact of ADA on FPT155 serum concentration was observed and highly 
variable in ADA positive animals. 
In summary, FPT155 has linear clearance for the dose range tested from 0.03 mg/kg to 3 mg/kg 
in mice and from 1 mg/kg to 100 mg/kg in rats and cynomolgus monkeys.  FPT155 has faster 
clearance and shorter half-life than a typical monoclonal antibody (mAb) in animals. 
2.2.4 
Toxicology 
Toxicology studies performed with FPT155 include a pilot repeat-dose toxicity study in 
cynomolgus monkeys and Investigational New Drug (IND)-enabling GLP repeat-dose toxicity 
studies in rats and cynomolgus monkeys. 
Repeat Dose GLP Toxicology Study in Rats 
In the repeat-dose GLP toxicology studies in rats, FPT155 was administered at dose levels of 
0 (vehicle), 1, 10, or 100 mg/kg/dose for 4 weekly doses.  Reversibility of toxicity was evaluated 
during a 7-week recovery period following the final administration.   
FPT155 was clinically well tolerated in rats up to 100 mg/kg. At the 100 mg/kg dose, changes in 
hematologic parameters were observed including increases in neutrophils, lymphocytes, and 
monocytes; slight decrease in red blood cells (RBCs) and an increase in reticulocytes.  Changes 
in clinical chemistry parameters were mostly seen at 100 mg/kg, and including a decrease in 
triglycerides, increase in alanine aminotransferase (ALT) and alkaline phosphatase (ALP), a 
decrease in albumin and an increase in globulins, with an associated decrease in the 
albumin/globulin ratio.  Microscopic changes were observed in male and female rats at doses of 
10 and 100 mg/kg consisting of mononuclear cell inflammation in multiple tissues, changes in 
lymphoid tissue, hepatic changes, and mononuclear cell infiltrates in the thyroid gland and 
kidney.  Mononuclear cell inflammation was seen in the stomach, intestine, pancreas, salivary 
gland, and Harderian gland and was primarily observed at 100 mg/kg with only rare and minimal 
findings at 10 mg/kg.  Increased lymphoid cellularity was observed in lymph nodes, spleen, and 
gut-associated lymphoid tissue (GALT) and was also primarily observed at 100 mg/kg, with 
lower frequency and less extensive changes observed at 10 mg/kg.  Hepatic changes observed at 
100 mg/kg included increased cellularity, hepatocellular hypertrophy, extramedullary 
hematopoiesis, mononuclear cell infiltrates, lymphoid/histiocytic aggregates, and necrosis with 
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mixed cell infiltrates.  In conclusion, the no-observed-adverse-effect level (NOAEL) in the 
pivotal rat study was determined to be 10 mg/kg for 4 weekly doses due to the treatment related 
effects of the more severe mononuclear cell inflammation in the pancreas, gastrointestinal tract, 
salivary, and Harderian glands observed at 100 mg/kg. 
Repeat Dose Pilot Toxicology Study in Cynomolgus Monkeys 
In the pilot repeat-dose toxicology study, cynomolgus monkeys received 4 weekly IV doses of 
0 (vehicle), 1, 10 and 50 mg/kg FPT155.  All dose levels were well tolerated by cynomolgus 
monkeys.  Immunophenotyping analysis showed FPT155-related dose-dependent expansion and 
proliferation of central memory T cells in the 10 mg/kg and 50 mg/kg dose groups but not at 
1 mg/kg.  Histopathologically, at terminal necropsy, increased numbers of mononuclear cell 
infiltrates were seen in the liver, follicular hypertrophy was seen in the spleen and mesenteric 
lymph node, and increased cellularity of the bone marrow was seen at all dose levels.  These 
findings resolved following the 6-week recovery period. 
Repeat Dose GLP Toxicology Study in Cynomolgus Monkeys  
In the repeat-dose GLP toxicology studies in cynomolgus monkeys, FPT155 was administered at 
dose levels of 0 (vehicle), 1, 10, or 100 mg/kg/dose for 4 weekly doses.  Reversibility of toxicity 
was evaluated during a 6-week recovery period following administration of the last dose. 
FPT155 was well tolerated and no clinical or pathological changes were identified at 1 mg/kg 
when given as 4 weekly doses, but FPT155 was not tolerated at doses of 10 and 100 mg/kg, 
necessitating unscheduled sacrifice and necropsy of 6/10 and 4/10 animals, respectively, between 
study days 14 and 30. 
The affected animals displayed weight loss and lethargy, had signs consistent with dehydration, 
and were cold to the touch.  Some monkey had sporadic diarrhea.  Significant body weight loss 
was observed several days prior to euthanasia.  Affected animals showed significant electrolyte 
imbalance, including hyponatremia, blood urea nitrogen (BUN) and creatinine elevation, and 
signs of acute phase reaction (increased fibrinogen, increased globulin, increased C-reactive 
protein [CRP], and decreased albumin).  Aldosterone and cortisol level were increased and 
adrenocorticotropic hormone (ACTH) decreased.  No urinalysis was performed.  Hematologic 
analysis showed a severe reduction of reticulocytes in 5 animals.  No coagulation changes were 
observed.  Serum cytokine measurements (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ, TNF-α, 
and granulocyte-macrophage colony-stimulating factor [GM-CSF]) on the day of unscheduled 
euthanasia showed signs of acute stress responses (TNF-α and IL8 increases) but the pattern of 
affected cytokines as well as the magnitude of changes did not indicate an acute cytokine release 
syndrome (no increase in IL2 or IL6). 
Treatment related pathological findings in the unscheduled necropsy animals were 
predominantly seen in large intestine and lymphoid tissues, with possible treatment related 
microscopic changes in the kidneys and adrenals.  In the digestive tract, mucosal erosion, crypt 
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dilatation, and/or infiltration of mononuclear cells in the lamina propria of the large intestine, 
specifically the rectum, were observed.  The observed changes in the lymphoid system include 
changes in the lymphoid cellularity (increases and decreases) of the inguinal, mandibular, and 
mesenteric lymph nodes.  Decreased lymphoid cellularity was observed in the spleen and 
thymus.  Findings of uncertain relationship to FPT155 included an increased incidence of tubular 
dilatation with tubular casts and mineralization in the kidney, and an increased incidence of 
adrenal hypertrophy (zona fasciculata) in the adrenal. 
In the surviving animals in the 10 and 100 mg/kg group, the clinical observations of reduced 
body weight and decreased activity that were common with unscheduled euthanasia animals 
were also seen in 2 animals that reached scheduled euthanasia.  Sporadic minimal to mild 
diarrhea was seen with higher incidence in animals administered 10 mg/kg and 100 mg/kg.  
FPT155-related changes in clinical chemistry parameters in the 10 and 100 mg/kg group 
included a mild reduction in albumin and a mild increase in globulin at 10 and 100 mg/kg. 
These changes were accompanied by increased fibrinogen, suggestive of an acute phase 
response. These changes returned to baseline at the end of recovery period.  No signs indicative 
of CRS, such as fever or cytokine increases consistent with CRS events, were observed. 
Ophthalmic examination and cardiac evaluation did not show any FPT155 related changes at any 
dose level. Histopathological mucosal erosion and crypt dilatation was seen in the large intestine 
of animals given 100 mg/kg with sporadic findings in animals given 10 mg/kg.  Increased 
lymphoid cellularity was observed in the lymph nodes, whereas decreased lymphoid cellularity 
was observed in the spleen and thymus. 
Overall, the histopathological changes were not of a magnitude that would explain the observed 
moribundity at doses of ≥ 10 mg/kg.  The changes observed in the intestine were minimal to 
mild, and the diarrhea was sporadic among the affected animals.  The timing and magnitude of 
changes in cytokine levels were not consistent with acute cytokine release syndrome and were 
more consistent with a stress response.  Hyponatremia combined with the elevated BUN and 
creatinine could be indicative of renal or adrenal/pituitary effects; however, the histopathological 
findings in the kidney and adrenal were minimal and no histopathological findings were detected 
in the pituitary gland.  The observed dehydration could be indicative of primary renal toxicity, 
however only minimal histopathological kidney damage was identified, and the lack of urinalysis 
at the time of euthanasia limits interpretation.  Changes in ACTH, aldosterone, and cortisol 
hormone levels could indicate underlying endocrinopathy, however, these changes could also be 
explained by fluid loss and a compensatory stress response. 
In summary, FPT155 was clinically well tolerated in rat and the NOAEL in rats is considered 
10 mg/kg for 4-weekly doses.  In cynomolgus monkeys, based on the GLP-toxicology study, 
doses of 10 and 100 mg/kg were not tolerated and the NOAEL in cynomolgus monkeys is 
1 mg/kg for 4 weekly doses.  No explanation has been found for the difference in tolerability 
between the pilot toxicology study and the pivotal GLP toxicology study in cynomolgus 
monkeys, though the small number of animals used in the pilot toxicology study and the lack of 
full penetrance in the affected study groups in the pivotal study could be contributing factors. 
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2.3 
Clinical Experience with FPT155 
This is a first in human clinical study and there is no prior clinical experience with FPT155 in 
any setting.  In dose escalation with FPT155, no dose limiting toxicities have been identified 
through the 560mg dose level. As of September 1, 2020, patients have enrolled in dose 
exploration cohorts at 280mg and 560mg. Cumulative safety results include evidence of 
immune-related adverse events that have been manageable with standard of care treatment.  To 
date, with the exception of one patient with an unconfirmed partial response, the investigator-
assessed best overall response has been stable disease.  Enrollment of expansion cohorts are 
ongoing with additional dose escalation proposed if cumulative safety results continue to 
demonstrate favorable tolerability.  
Please reference the FPT155 Investigator’s Brochure for more detailed information. 
2.4 
Benefit/Risk Assessment 
This first in human study is planned to evaluate the safety and tolerability of FPT155 and to 
determine a recommended dose (RD) for further clinical evaluation as monotherapy and in 
combination with pembrolizumab. 
Despite recent advances in immunotherapy, an unmet need remains in patients with advanced 
solid tumors since a majority of patients are either refractory to currently available therapies or 
eventually relapse.  A novel immune therapy with a differentiated mechanism of action that 
results in improved response rates and durability across a broad range of solid tumors is 
necessary.  FPT155 is designed to act as a potent stimulator of anti-tumor immunity that acts 
through CD28 to co-stimulate T cell responses only in the presence of antigenic TCR signaling.  
FPT155 also blocks CTLA-4 from competing for endogenous CD80, allowing CD28 signaling to 
prevail in T cell activation.  Potential benefit for humans is based on data that a murine surrogate 
of FPT155 (mFPT155) is a potent inhibitor of tumor growth in multiple tumor models (ie, CT26, 
MC38, and EMT6) and results in complete tumor regressions in a majority of animals in the 
highly responsive CT26 model.  Moreover, in the CT26 tumor model, mice that reject tumors 
after treatment with mFPT155 remain tumor free and have durable T cell immunity to 
subsequent CT26 re-challenge.  FPT155 therefore has the potential to demonstrate durable anti-
tumor immune responses in patients with advanced solid tumors by acting through 2 key T cell 
regulators or modulators: CD28 and CTLA-4. 
Risks of FPT155 are anticipated to be related to possible overstimulation of T cell function and 
subsequent auto-immune adverse events similar to those reported by approved immunotherapies 
such as CTLA-4 antagonists.  Pre-clinical toxicology studies showed that FPT155 was clinically 
well tolerated in rats with no adverse clinical findings or treatment-related changes in most major 
organ systems.  The NOAEL in rats was determined to be 10 mg/kg when administered to 
animals once per week for 4 weekly doses.  FPT155 was not well tolerated in cynomolgus 
monkeys at doses ≥ 10 mg/kg.  Some monkeys at the 10 mg/kg dose had sporadic diarrhea, 
dehydration, lethargy, and were cold to the touch, although due to the method of conduct of the 
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study it isn’t clear that the same monkeys who had diarrhea also became moribund.  Intravenous 
hydration only temporarily improved the symptoms.  Diffuse lymphocytic and monocytic 
infiltrates were observed in a variety of organs, however, the mechanism of this toxicity is 
undetermined.  No clinical observations or adverse findings were seen in the low dose group of 
1 mg/kg which was, therefore, determined to be the NOAEL.  The starting dose of 0.07 mg 
(0.001 mg/kg for a 70 kg human) has been calculated based on the minimum anticipated biologic 
effect level (MABEL) approach and is approximately 1000-fold below the NOAEL.  Significant 
antitumor activity is evident even at doses as low as 0.1 mg/kg in the CT26 tumor model, which 
is approximately 10-fold below the NOAEL in both rats and monkeys.  Therefore, a potential 
therapeutic window for FPT155 exists. 
Based on the underlying mechanism of action, immune-related adverse events (irAEs; e.g., 
endocrinopathies, colitis, hepatitis, dermatitis) associated with the anti-CTLA-4 class of drugs 
(eg, ipilimumab) may potentially be observed with FPT155.  Since anti-CTLA-4 therapies have 
been in clinical use for several years, the toxicities associated with these agents are well 
characterized.  The protocol also includes specific guidelines for monitoring and managing these 
toxicities.  As immune-oncology agents are associated with delayed immune-mediated toxicities, 
the RD will consider toxicities observed both during and beyond the 21-day dose limiting 
toxicity (DLT) evaluation period. 
The CD28 pathway has been a target for investigational drugs in the clinic but no agents are 
approved.  TeGenero 1412 (TGN1412) is a humanized IgG4 kappa anti-CD28 superagonist 
antibody that activates T cell activation independently of TCR ligation, in contrast with 
physiological CD80 signaling which activates T cells via CD28 only when there is also TCR 
recognition of cognate peptide-MHC.  TGN1412 was initially dosed in 6 healthy male 
volunteers at doses of 0.1 mg/kg.  Each of these patients developed a severe inflammatory 
reaction characterized by rapid production of circulating cytokines (CRS) within 60 minutes 
after the infusion of TGN1412, leading to multi-organ failure within 24 hours of dosing 
(Suntharalingam 2006).  Follow up analysis of the trial revealed that the dose of TGN1412 given 
to patients was sufficient to occupy 90% of all CD28 receptors in the body (Duff 2006, Kenter 
2015).  TGN1412, now renamed TAB08, has subsequently been given in lower doses to healthy 
volunteers, patients with rheumatoid arthritis, and patients with solid tumors (Cabo 2017). 
FPT155 activates T cells in a TCR-dependent manner and therefore is not expected to have 
TCR-independent superagonist activity.  However, given the history of CRS associated with 
TGN1412, the Sponsor has performed in vitro cytokine release assays on human PBMCs and 
confirmed that FPT155 does not activate CD28 signaling in the absence of TCR signaling 
supporting the hypothesis that FPT155 should not induce CRS.  Nonetheless a conservative 
approach is being used with a low starting dose of FPT155 where the pharmacological activity 
(PA) for CD28 is expected to be <1% (Section 4.6).  As a further precaution, 48-hour inpatient 
admission following the first infusion of the first dose cohort to monitor for signs of CRS is 
mandated, and a 6-hour post infusion observation period is required for all patients in all cohorts. 
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As this is the first clinical study of FPT155, the safety profile in humans has not been 
established, unanticipated side effects may occur, and efficacy in humans remains unproven. 
Accordingly, Phase 1a enrollment is limited to patients with late stage tumor types without other 
efficacious treatment options. 
In summary, a conservative starting dose based on the MABEL approach, close patient 
monitoring, staggered enrollment, and cautious dose escalation is designed to limit the risk to 
patients during FPT155 dose escalation. 
For the combination of FPT155 with pembrolizumab, preclinical results suggest the potential for 
synergistic activity. However, the combination of both agents may lead to an increase in immune 
related adverse events. Preclinical results are consistent with the hypothesis that an 
approximately 4-fold reduction in FPT155 dose will decrease the combined effect with anti-PD-1 
directed therapy and to mitigate the risk of potential autoimmune toxicity, dose escalation with 
FPT155 in combination with pembrolizumab will start a minimum of 2 dose levels below the 
MTD for FPT155 monotherapy. Careful surveillance for immune related adverse events is 
specified in the protocol including consensus guidelines for diagnosis and management of these 
adverse events (Appendix 8). 
 
 
 
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3.0 
OBJECTIVES AND ENDPOINTS 
Objectives and Endpoints – Phase 1a Dose Escalation/Exploration – FPT155 Monotherapy:  
Objectives 
Endpoints 
Primary 
Safety 
• 
To assess the safety and tolerability of FPT155 as 
monotherapy in patients with advanced solid 
tumors 
• 
To determine the RD of FPT155 as monotherapy 
Safety 
• 
The incidence of adverse events (AEs), serious 
adverse events (SAEs), clinical laboratory 
abnormalities, and electrocardiogram (ECG) 
abnormalities 
• 
The incidence of AEs defined as dose limiting 
toxicities (DLTs), clinical laboratory 
abnormalities defined as DLTs, and overall 
assessment of pharmacokinetics (PK) and 
pharmacodynamics (PD) 
Secondary 
Pharmacokinetics 
• 
To characterize the PK profile of FPT155 as 
monotherapy in patients with advanced solid 
tumors 
Pharmacokinetics 
The following PK parameters will be derived from 
concentration-time data for FPT155 when appropriate 
and applicable.  
• 
Area under serum concentration-time curve 
(AUC) 
• 
Maximum observed serum concentration (Cmax) 
• 
Trough observed serum concentration at the end 
of each dose interval (Ctrough) 
• 
Clearance (CL) 
• 
Terminal half-life (t1/2) 
• 
Volume of distribution at steady state (Vss) 
Other parameters, such as dose proportionality, 
accumulation ratio, and attainment of steady state, will 
also be calculated if the data are available. 
Immunogenicity 
• 
To characterize the immunogenicity of FPT155 as 
monotherapy in patients with advanced solid 
tumors 
Immunogenicity 
• 
Incidence of treatment emergent anti-FPT155 
antibody response 
Exploratory 
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Efficacy 
• 
To evaluate the clinical benefit of FPT155 as 
monotherapy in patients with advanced solid 
tumors  
Efficacy 
• 
Objective Response Rate (ORR), defined as the 
total number of patients with confirmed responses 
of either complete response (CR) or partial 
response (PR), as determined by the investigator 
per RECIST v1.1, divided by the total number of 
patients who are evaluable for a response 
• 
Duration of Response (DOR) defined as the time 
from first response (CR or PR determined by the 
investigator per RECIST v1.1) that is 
subsequently confirmed until the onset of 
progressive disease or death from any cause, 
whichever comes first 
• 
Progression Free Survival (PFS) defined as the 
total number of patients with confirmed responses 
of either CR or PR, as determined by the 
investigator per Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1 
Objectives and Endpoints – Phase 1b Dose Expansion – FPT155 Monotherapy:  
Objectives 
Endpoints 
Primary 
Safety 
• 
To evaluate the safety and tolerability of FPT155 
as monotherapy in patients with selected advanced 
solid tumors treated at the RD 
Safety 
• 
The incidence of AEs, SAEs, clinical laboratory 
abnormalities, and ECG abnormalities 
• 
The incidence of treatment discontinuations, 
modifications, and interruptions due to AEs 
Secondary 
Efficacy  
• 
To evaluate the clinical benefit of FPT155 as 
monotherapy in patients with selected advanced 
solid tumors treated at the RD through the analysis 
of ORR, DOR, PFS, and DCR 
Efficacy  
• 
ORR, DOR, and PFS  
• 
Disease Control Rate (DCR) defined as total 
number of patients with confirmed responses of 
either CR, PR, or stable disease as determined by 
the investigator per RECIST v1.1, divided by the 
total number of patients who are evaluable for a 
response 
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Objectives 
Endpoints 
Pharmacokinetics 
• 
To characterize the PK profile of FPT155 as 
monotherapy in patients with selected advanced 
solid tumors treated at the RD 
Pharmacokinetics 
The following PK parameters will be derived from 
concentration-time data for FPT155 when appropriate 
and applicable.   
• 
AUC 
• 
Cmax 
• 
Ctrough 
• 
CL 
• 
t1/2 
• 
Vss 
Other parameters, such as dose proportionality, 
accumulation ratio, attainment of steady state, will also 
be calculated if the data are available.  Assessment of 
time-dependence of PK, the effect of body weight as 
well as other covariates on PK, and the exposure-
response relationship, when the data allow, will be 
conducted to determine the appropriate dosing 
approach (eg, body weight-based or fixed dosing) for 
future trials. 
Immunogenicity 
• 
To characterize the immunogenicity of FPT155 as 
monotherapy in patients with selected advanced 
solid tumors treated at the RD 
Immunogenicity 
• 
Incidence of treatment emergent anti-FPT155 
antibody response 
Exploratory 
 
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Objectives and Endpoints – Phase 1a Dose Escalation/Exploration – FPT155 + 
Pembrolizumab:  
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the safety and tolerability 
of FPT155 in combination with 
pembrolizumab in patients with 
advanced non-small cell lung cancer 
• 
To determine the RD of FPT155 in 
combination with pembrolizumab in 
patients with advanced non-small cell 
lung cancer. 
• 
The incidence of adverse events (AEs), serious adverse events 
(SAEs), clinical laboratory abnormalities, and 
electrocardiogram (ECG) abnormalities 
• 
The incidence of dose limiting toxicities (DLTs) 
Secondary 
 
• 
To evaluate the preliminary clinical 
response rate of FPT155 in 
combination with pembrolizumab in 
patients with non-small cell lung cancer 
• 
Objective Response Rate (ORR), defined as the total number 
of patients with responses of either CR or PR, as determined 
by the investigator per RECIST v1.1, divided by the total 
number of patients who are evaluable for a response 
Exploratory  
 
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4.0 
STUDY DESIGN 
4.1 
Overall Design 
This study is a Phase 1a/1b open-label, multicenter, dose escalation, dose exploration, and dose 
expansion study to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of FPT155  
in patients with advanced solid tumors.  FPT155 is a recombinant fusion protein composed of the 
ECD of human CD80 fused with the Fc domain of IgG1.  It is designed to act as a potent 
stimulator of antitumor immunity.  FPT155 as monotherapy and in combination with 
pembrolizumab will be evaluated.  The combination portion of the study will be conducted in 
Australia and South Korea. 
FPT155 Monotherapy 
FPT155 will be administered once every 3 weeks (Q3W) over approximately 60 minutes by IV 
infusion.  
• The monotherapy part of the study will initiate with Phase 1a dose escalation consisting of 
approximately 13 planned dose escalation cohorts, with the starting dose of 0.07 mg. 
• Phase 1a dose exploration consists of up to approximately 50 patients in total who may be 
enrolled at one or more dose levels to further evaluate safety, PK, PD, and clinical activity 
(conditional upon the dose level clearing dose escalation criteria). 
• Phase 1b dose expansion consists of up to 8 tumor-specific expansion cohorts, enrolling 
approximately 30 patients each.  Patients in Phase 1b will be treated with FPT155 at an RD 
selected after assessment of data obtained in Phase 1a. (See Appendix 11). 
Treatment will continue until disease progression, unacceptable toxicity, consent withdrawal, or 
if any of the specified withdrawal criteria listed in Section 7.0 of the protocol are met. 
4.1.1 
Phase 1a Dose Escalation 
FPT155 Monotherapy 
The Phase 1a dose escalation will include an initial accelerated titration design enrolling at least 
1 patient at lower doses followed by a standard 3+3 design until the RD for Phase 1b is 
determined.  Eligible patients with advanced solid tumors (except primary central nervous 
system [CNS] tumors) who are refractory to all standard therapy for their malignancy or for 
whom standard therapies would not be appropriate will be enrolled.   
All dose escalation decisions will be based on the assessment of DLTs, overall safety and 
tolerability, and will be made after the last patient enrolled in each cohort has completed the 
21-day DLT evaluation interval.  Dose escalation decisions will be agreed upon by the Cohort 
Review Committee (CRC) after all available laboratory and clinical information is reviewed. 
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Patients enrolled into the first FPT155 monotherapy dose cohort will have 48 hours of inpatient 
monitoring from the start of infusion of FPT155 at Cycle 1 Day 1 to evaluate for any signs or 
symptoms of CRS.  There will be an interval of at least 48 hours between administration of the 
first dose in each patient in the first dose cohort, if more than one patient is enrolled.  For the 
second infusion of FPT155, patients in the first dose cohort will undergo intensive monitoring in 
the outpatient setting, including a minimum 6-hour observation window. 
For subsequent dose cohorts, intensive monitoring will occur in the outpatient setting and include 
a minimum 6-hour observation window following completion of the first and second infusions.  
There will be an interval of at least 24 hours between administration of the first dose in each 
patient in subsequent dose cohorts.  Inpatient hospitalization will not be required for the first 
dose in subsequent dose cohorts unless there is evidence of CRS ≥ Grade 2 at the previous dose 
level. 
If any patient reports a Grade 2 or higher drug-related toxicity in the first 24 hours after 
completion of their first dose, enrollment of subsequent patients will be delayed until the toxicity 
for that patient returns to baseline or ≤ Grade 1, or the CRC determines that it is safe to continue 
enrollment.  In this setting, the CRC will review all available data to determine if enrollment 
should continue at the same or a lower dose level, or with a less frequent dosing schedule, or if 
enrollment should be discontinued. 
FPT155+pembrolizumab 
FPT155 will be administered once every 3 weeks (Q3W) over approximately 60 minutes by 
intravenous IV infusion followed by 200 mg of pembrolizumab administered by intravenous (IV) 
infusion after the completion of FPT155. Eligible patients with advanced non-small cell lung 
cancer will be enrolled,  
Combination dose escalation will start with a FPT155 dose that is a minimum of two dose levels 
lower than the highest dose cleared in FPT155 monotherapy. 
Combination dose exploration will include up to 30 patients who may be enrolled at one or more 
dose levels to further evaluate safety, PK, PD, and clinical activity (conditional upon the dose 
level clearing dose escalation criteria). 
For patients enrolled for treatment with FPT155 and pembrolizumab, treatment will be 
administered Q3W until disease progression, unacceptable toxicity or consent withdrawal; if one 
study drug is discontinued, the other may be continued for up to an additional 12 months. 
4.1.1.1 
Cohort Review Committee 
Safety will be monitored throughout the study by the Sponsor’s CRC, comprised of, but not 
limited to, Phase 1a study investigators, the Sponsor’s medical monitor, and the Sponsor’s safety 
representative.  The CRC will meet routinely to review the emerging safety, PK, PD, and 
efficacy data, and to make dose escalation decisions.  The CRC may recommend further 
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evaluation of the safety at a given dose.  The CRC will also review cumulative safety data in 
order to identify safety concerns that may emerge due to cumulative exposure beyond the DLT 
window.  The process for dose escalation decisions, dose interval recommendations, and the 
roles and responsibilities of the CRC will be detailed in the CRC Charter. 
4.1.1.2 
Proposed FPT155 Dose Levels 
FPT155 will be initially administered Q3W, on Day 1 of each 21-day cycle.   
The anticipated dose levels are outlined in Table 5. 
Table 5: 
Anticipated Dose Levels 
Design 
Dose 
Regimen 
Accelerated titration design 
0.07 mg FPT155 
Q3W 
0.21 mg FPT155 
Q3W 
0.70 mg FPT155 
Q3W 
2.1 mg FPT155 
Q3W 
3+3 design 
7 mg FPT155 
Q3W 
21 mg FPT155 
Q3W 
42 mg FPT155 
Q3W 
70 mg FPT155 
Q3W 
140 mg FPT155 
Q3W 
280 mg FPT155 
Q3W 
560 mg FPT155 
Q3W 
 840 mg FPT155 
Q3W 
 
1260 mg FPT155 
Q3W 
Abbreviations: Q3W = once every 3 weeks. 
Planned dosing increments take into account conservative estimates of RO and PA through both 
CD28 and CTLA-4.  Fixed 3-fold escalation increments are proposed while projected 
engagement of CD28 is low; more conservative increments (2-fold or less) are proposed at 
higher CD28 occupancy levels. 
The Sponsor may add cohorts with alternative dose levels or dose regimens (e.g., different 
dosing frequency, intermediate dose levels) upon review of safety, PK, and PD profiles to 
achieve optimal target exposure with acceptable tolerability.  The dose level of 700mg was 
replaced by 840mg based on preliminary PK showing dose-proportional increases in exposure 
and approximately 30-50% interpatient variability in exposure at a given dose level – the range 
of exposures from FPT155 560mg and from FPT155 700mg (25% increase in dose) were 
predicted not to be significantly different.  A 1.5-fold increment in dose levels has been selected 
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above 560mg based on early safety results showing an absence of DLTs or cytokine release 
syndrome through the 560mg dose level with the presence of immune-related toxicity 
manageable with standard of care treatment for irAEs.  Following clearance of a dose at the 
Q3W schedule, more frequent (eg Q2W) dosing at the same dose level may be evaluated using 
the 3+3 framework. 
4.1.1.3 
Dose Limiting Toxicity Definitions 
The DLT evaluation interval begins on the first day of treatment upon start of infusion and 
continues for 21 days.  Patients who receive at least 1 dose of study treatment and remain on 
study for the 21-day DLT evaluation interval or patients who discontinue study treatment for 
drug-related AEs before clearing the 21-day DLT evaluation interval will be considered 
evaluable for DLT determination. 
DLTs during Phase 1a dose escalation are defined as any of the following deemed by the 
investigator as related to FPT155: 
• Absolute neutrophil count (ANC) < 1.0 x 109/L for > 5 days duration or Grade 3 febrile 
neutropenia (eg, ANC < 1.0 x 109/L with a single temperature of > 38.3°C or fever > 38°C 
for more than 1 hour) 
• Platelets < 25 x 109/L or platelets < 50 x 109/L with clinically significant hemorrhage 
• Aspartate aminotransferase (AST) or ALT > 3 x upper limit of normal (ULN) with 
concomitant total bilirubin > 2 x ULN not related to liver involvement with cancer 
• Grade 3-4 non-hematological toxicity except: 
• Grade 3 fatigue < 7 days 
• Grade 3 nausea and Grade 3-4 vomiting and diarrhea lasting < 72 hours in patients who 
have not received optimal anti-emetic and/or anti-diarrheal therapy 
• Grade 3 endocrinopathy that is adequately treated by hormone replacement 
• Laboratory value that may be corrected through replacement within 48 hours 
• Grade 2 neurological toxicity except headache and peripheral neuropathy in patients with 
Grade 1-2 peripheral neuropathy at entry 
Additional DLT Considerations for FPT155 in combination with pembrolizumab 
Because pembrolizumab is a known immune checkpoint inhibitor and one of the proposed 
mechanisms of action of FPT155 is immune checkpoint blockade, immune-related adverse 
events (irAEs) are anticipated with this combination. An irAE is defined as a clinically 
significant AE that is associated with study drug exposure, without a clear alternate cause, and 
consistent with an immune-mediated mechanism. Based on that background, the first occurrence 
of the following irAEs will not be considered a DLT because they may occur with immune 
therapy and are likely to be fully reversable per Appendix 8:  
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• Grade 3 tumor flare (defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor) 
• Grade 3 non-skin immune-related adverse event (irAE) that resolve to a Grade 1 or less 
within 14 days with management per Appendix 8 
• Transient (resolving within 6 hours of onset) Grade 3 infusion-related AEs 
• Grade 3 drug-related bronchospasm or anaphylactic or anaphylactoid reactions 
Dose escalation may be paused prior to determining an MTD based on observed safety, 
tolerability, or emerging PK or PD results. 
4.1.1.4 
Dose Escalation Decisions in Phase 1a FPT155 Monotherapy 
An initial accelerated titration design enrolling at least 1 patient at each dose level is planned for 
FPT155 dose levels 0.07, 0.21, 0.70, and 2.1 mg.  Dose escalation to the next dose level may 
proceed after at least 1 patient completes the 21-day DLT evaluation interval. 
If a single patient experiences a DLT during the 21-day DLT evaluation interval, standard 
3+3 dose escalation criteria will apply for that cohort with enrollment of additional patients.  
All subsequent dosing cohorts will then follow standard 3+3 dose escalation criteria. 
Alternatively, if 2 patients experience moderate AEs (at any planned accelerated titration dose 
level), standard 3+3 dose escalation criteria will apply for the highest dose level at which a 
moderate AE was experienced, with enrollment of additional patients.  All subsequent dosing 
cohorts will then follow standard 3+3 dose escalation criteria.  Moderate AEs are defined as 
≥ Grade 2 AEs deemed by the investigator as related to FPT155.  Grade 2 laboratory values will 
not be considered as moderate AEs for this purpose unless accompanied by clinical sequalae. 
If not already applied at a lower dose level according to the criteria stated above, enrollment at 
all dose levels ≥ 7.0 mg will follow a standard 3+3 dose escalation design. 
The algorithm outlined in Table 6 below will be used for all dose escalation decisions. 
Table 6: 
Algorithm for 3+3 Dose Escalation Decisions  
Number of Patients with DLT at a 
Given Dose Level 
Dose Escalation Decision Rule 
0/3 or 1/6 
Enroll 3 patients at next dose level (next/higher cohort) 
1/3 
Enroll 3 additional patients at current dose level (current cohort) 
≥2 
Stop enrollment.  If at the starting dose level, the study will be stopped.  
If at any other dose level, enroll 3 more patients at the previous dose 
level (previous/lower cohort) if only 3 were previously enrolled, or at an 
intermediate dose level 
Abbreviations: DLT = dose limiting toxicity. 
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4.1.1.5 
Dose Escalation Within a Cohort 
In Phase 1a dose escalation, intra-patient dose escalation will be permitted in patients enrolled at 
dose levels below 70 mg, provided: 
• The patient did not experience a DLT 
• All other AEs have recovered to Grade 1 or lower prior to dose escalation 
• The patient may only dose escalate by a maximum of 1 dose level every 21 days and only 
after that dose level has cleared DLT review by the CRC (eg, a patient enrolled at 0.07 mg 
may escalate to 0.21 mg only after the 0.21 mg dose level has been cleared by the CRC). 
• The patient cannot dose escalate beyond the 70 mg dose level  
Intra-patient dose escalation will only be permitted after a discussion between the Sponsor and 
investigator, taking into account the overall safety experience, PK, and PD data available at the 
time of the request.  Safety data from such patients will be reviewed as part of the overall safety 
and tolerability of FPT155. 
4.1.1.6 
Determination of Recommended Dose and Maximum Tolerated Dose 
The maximum tolerated dose (MTD) will be defined as the dose level below that in which ≥2 
DLTs are identified.  If dose escalation completes without the identification of 2 DLTs at a given 
dose level, no MTD will have been identified.  The Sponsor may discontinue dose escalation 
prior to determining a MTD based on the available observed safety, tolerability, PK and PD.  
The RD of FPT155 will be identified based on an evaluation of all available safety, tolerability, 
PK, and PD data.  The determination of RD will consider toxicities observed both during and 
beyond the DLT evaluation period as well as dose reductions and discontinuations due to toxicity 
that do not meet the DLT criteria.  The RD, therefore, may or may not be the same as the MTD 
but cannot be higher than the MTD.   
4.1.2 
Phase 1a FPT155 Monotherapy Dose Exploration 
Phase 1a dose exploration consists of up to approximately 50 patients in total who may be 
enrolled at one or more dose levels to further evaluate safety, PK, PD, and clinical activity 
(conditional upon the dose level clearing dose escalation criteria).  Toxicities observed in these 
patients will contribute to the overall assessments of safety and tolerability, and may inform 
selection of the RD.  The Sponsor may choose to evaluate clinical activity in specific tumor 
types based on emerging safety, PK, PD, and efficacy data. 
Intensive monitoring will occur in the outpatient setting and include a minimum 6-hour 
observation window following completion of the first and second infusions.  There will be an 
interval of at least 24 hours between administration of the first dose in each patient. 
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4.1.3 
Phase 1b FPT155 Monotherapy Dose Expansion 
Enrollment in Phase 1b dose expansion will begin when the MTD and/or RD has been identified 
by the CRC.  If additional cumulative safety or preliminary efficacy results from dose escalation 
or exploration suggest that an alternate dose or schedule may improve the benefit relative to risk 
in treatment with FPT155, more than one dose or schedule may be evaluated in the phase 1b 
cohorts. 
Up to 8 tumor-specific cohorts consisting of approximately 30 patients each will evaluate the 
safety, efficacy, PK, and PD of FPT155 at a RD (see Appendix 11).  Patients with advanced 
RCC and melanoma who have failed prior anti-PD(L)1 therapy will be enrolled in 2 of the 8 
cohorts. 
Additional tumor types for the remaining Phase 1b cohorts will be determined based on 
emerging safety, translational, and clinical data for FPT155, as well as any potential new safety 
signals from other immunotherapies, such as significant changes to prescribing information for 
approved immunotherapies. 
Intensive monitoring will occur in the outpatient setting and include a minimum 6-hour 
observation window following completion of the first and second infusions.  Additional 
monitoring requirements may be implemented based on emerging safety data from Phase 1a dose 
escalation. 
Table 7: 
Phase 1b Monotherapy Dose Expansion Cohorts and Tumor Types 
Cohort 
Tumor Type 
1 
Renal cell carcinoma 
2 
Melanoma 
3-8 
Cohorts to be determined based on emerging safety, translational, and clinical data for 
FPT155, as well as any potential new safety signals from other immunotherapies, such as 
significant changes to prescribing information for approved immunotherapies (see 
Appendix 11) 
4.1.4 
Phase 1a FPT155+Pembrolizumab Dose Escalation 
FPT155 will start at a dose level a minimum of 2 levels below that cleared in dose escalation 
with FPT155 monotherapy.  
Dose escalation decisions will follow the standard 3+3 algorithm described above and continue 
up to the dose level established as the MTD for FPT155 monotherapy. Additional intermediate 
dose levels or dose regimens may be considered upon review of emerging safety, PK and PD 
results. 
4.1.5 
FPT155 + Pembrolizumab Dose Exploration  
Enrollment in combination dose exploration may occur at one more dose levels that have been 
cleared during combination dose escalation. 
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4.1.6 
Requirements for Archival Tumor Tissue and Fresh Biopsies 
Dose Escalation (Monotherapy and FPT155 + pembrolizumab):  
• Archival tumor tissue is required.  If archival tumor tissue is not available, a fresh biopsy is 
required prior to treatment for retrospective biomarker analysis. 
• Optional pre- and on-treatment biopsies will be requested during screening (prior to 
treatment) and during treatment (prior to the Cycle 3 Day 1 dose) to explore the relationship 
between baseline tumor immune phenotype and PD response. 
• An additional optional biopsy will be requested at disease progression. 
Dose Exploration/Expansion (Monotherapy and FPT155 + pembrolizumab): 
• Archival tumor tissue is required for retrospective biomarker analysis.  The fresh biopsy 
required at screening will be accepted in lieu of archival tumor tissue if archival tissue is not 
available. 
• Pre- and on-treatment biopsies will be mandatory during screening (prior to treatment) and 
during treatment (prior to the Cycle 3 Day 1 dose) to explore the relationship between 
baseline tumor immune phenotype and PD response. 
• An additional optional biopsy will be requested at disease progression. 
4.2 
Study Treatment and Duration 
FPT155 will be administered Q3W over approximately 60 minutes by IV infusion. 
In combination with FPT155 and pembrolizumab, pembrolizumab will be administered a 
minimum of 30 minutes following completion of the FPT155 infusion.  Pembrolizumab should 
be administered per the pembrolizumab Product Information. 
Treatment is administered Q3W until disease progression, unacceptable toxicity, or patient 
withdrawal.  If one drug is discontinued, treatment may continue with the other alone for up to 
an additional 12 months.  Treatment beyond disease progression may be allowed in patients with 
initial RECIST v1.1 defined progressive disease if the criteria in Section 4.3 are met. 
Patients should have end of treatment (EOT) follow-up visits approximately 28 days and 
100 days after the last dose of treatment on study.  In addition, patients enrolled in dose 
expansion will be followed for survival. 
4.3 
Treatment Beyond Disease Progression 
For patients in all cohorts, if progressive disease (based on RECIST v1.1) occurs, then the 
patient may continue to be treated with the scheduled regimen assigned after study enrollment 
until one of the following criteria is met: 
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• Confirmed disease progression: The assessment of disease progression by RECIST v1.1 
(baseline disease progression assessment) will be confirmed by a repeat evaluation at the 
next tumor assessment time point, but no sooner than 4 weeks later.  If any subsequent tumor 
assessment time point demonstrates disease progression by RECIST v1.1 or demonstrates 
further increase in the overall tumor burden (the sum of diameters of target lesions and new 
lesions), when compared to the baseline disease progression assessment (the sum of 
diameters of target lesions or the presence of a new lesion), then the subject would be 
deemed as having confirmed disease progression. 
• Meets any of the investigational product discontinuation criteria. 
• Clinical symptoms or signs indicating clinically significant disease progression such that the 
benefit-risk ratio of continuing therapy is no longer justified. 
• Rapid disease progression or threat to vital organs/critical anatomical sites (eg, spinal cord 
compression) requiring urgent alternative medical intervention, and/or continuation of study 
therapy would prevent institution of such intervention. 
4.4 
End of Study Definition 
The EOT follow-up visit approximately 100 days after the last dose of treatment on study will be 
considered the end of the study in Phase 1a. 
In the Phase 1b portion of the study, patients will also be followed for survival by clinic visit or 
by telephone approximately every 3 months after the Day 100 EOT visit.  Death, loss to follow-
up, or withdrawal of consent of the last study subject, or study termination by the Sponsor 
(whichever occurs first), will be considered the end of the study in Phase 1b. 
4.5 
Scientific Rationale for Study Design 
The study is designed as an initial accelerated titration followed by a standard 3+3 dose 
escalation.  The initial accelerated titration component may reduce the number of patients 
receiving potentially subtherapeutic doses of the study drug.  The 3+3 design is chosen to avoid 
selection of a Phase 2 clinical trial dose that causes a treatment-limiting toxicity in more than 
17% of patients, which is a standard that has been considered acceptable as an outpatient 
therapeutic for patients with limited options and life-threatening disease.  This design has the 
advantage of being rule-based, allocates the lowest dose level to the first cohort, and adaptively 
escalates/de-escalates based on observed DLTs.  Its execution is straightforward and generally 
well understood by clinicians and investigators, decreasing the potential for deviations from 
protocol. 
Phase 1a dose exploration with mandatory pre- and on-treatment biopsies at doses ≤ MTD will 
provide additional insight into the safety, PK, PD and mechanism of action of FPT155 and may 
help in determining the RD for Phase 1b. 
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Phase 1b for FPT155 monotherapy includes up to 8 tumor-specific cohorts.  Patients with 
advanced RCC and melanoma that have failed prior anti-PD(L)1 therapy will be enrolled in 2 of 
the 8 cohorts.  These patients have a poor prognosis and enrolling them will enable evaluation of 
the clinical activity of FPT155 in these typically immune-competent tumors that have progressed 
on a checkpoint inhibitor.  Additional tumor types for the remaining 6 Phase 1b cohorts 
(Appendix 11) will be determined based on emerging safety, translational, and clinical data for 
FPT155, as well as any potential new safety signals from other immunotherapies, such as 
significant changes to prescribing information for approved immunotherapies. 
Combination dose escalation with FPT155 and pembrolizumab will start with a FPT155 dose 
that is a minimum of two dose levels lower than the highest dose cleared during evaluation of 
FPT155 monotherapy as outlined below in Table 8.  Additional patients may be added in 
combination dose exploration at one or more dose levels that are cleared during combination 
dose escalation to better characterize the safety profile and preliminary clinical activity. The 
combination will be limited to patients with non-small cell lung cancer to maximize on the 
ability to interpret results from the limited enrollment that is planned. 
4.6 
Justification for Dose 
The MABEL approach was used to determine a safe first in human starting dose for FPT155.  
This approach was used because FPT155 functions through 2 key T cell regulators or 
modulators, including co-stimulation of CD28 on T cells after T cell receptor engagement, and 
blocking CTLA-4 from competing for endogenous CD80. 
The FPT155 starting dose was based on the established guidelines for MABEL dosing and 
relevant literature (Saber 2016).  Based on these guidelines, RO and PA between 20-80% are 
appropriate for selecting starting doses.  For FPT155, assessments of RO and PA through both 
CTLA-4 and CD28 were considered.  To project the human dose based on Cmax, assumptions of 
a plasma volume of distribution of central compartment of 2800 mL and a 70 kg average patient 
weight were used in calculating the percent RO and PA.  
Integrating the assessments of RO and PA through both CTLA-4 and CD28, a starting dose of 
0.07 mg was selected.  Among the PA assays examined, CTLA-4 ELISA was thought to be both 
biologically relevant and sensitive.  Using this ELISA assay, 50% PA leads to a predicted 
starting dose, when rounded down, of 0.07 mg.  Several PA assays for CD28 activity were 
considered, however these assays were either thought to be not biologically relevant or predicted 
a much higher starting dose. 
The Sponsor has selected a Q3W dosing interval.  Although the half-life of FPT155 in patients is 
predicted to be less than 10 days, preclinical evidence suggests that the total exposure, not Ctrough, 
may be an important driver of efficacy.  A Q3W interval between was thought to be appropriate 
because no target trough concentration has been identified to achieve between dose interval from 
nonclinical efficacy studies.   
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The Phase 1a dose escalation portion of the study will use an initial accelerated titration design 
followed by a standard 3+3 design, with patients enrolled across approximately 13 planned dose 
levels.  The starting dose of 0.07 mg is predicted to attain a nominal (< 1%) PA for CD28 using 
the binding assay of Chinese hamster ovary (CHO) cells overexpressing CD28.  The proposed 
dosing increments also take into consideration PA through both CD28 and CTLA-4.  Fixed 
3-fold escalation increments are proposed while PA of CD28 is low, with more conservative 
increments proposed at higher expected CD28 activity levels. Two fold or smaller increments in 
dose were used in dose escalation from 21mg to 560mg. During dose escalation, FPT155 is 
projected to achieve 99% PA for CTLA-4 at Cmax for doses ≥ 7 mg.  Based on the KD and 
observed Cmax, ipilimumab, an anti-CTLA4 antibody, was projected to achieve 99% RO for 
CTLA-4 at the clinically approved dose of 3 mg/kg (BMS 2011, He 2017, Yervoy 2018). 
Preliminary pharmacokinetic results are consistent with dose-proportional increases in exposure 
with an absence of dose-limiting toxicities through the 560 mg dose level. As immune-related 
adverse events have been manageable in accordance with consensus guidelines and no MTD has 
been identified, dose escalation above 560mg uses 1.5-fold increments.  The dose escalation 
cohorts are summarized below (Table 8).   
Table 8: 
FPT155 Phase 1 Dose Escalation Cohorts 
Cohort 
Dose Level (mg) 
1aM1 
0.07 
1aM2 
0.21 
1aM3 
0.7 
1aM4 
2.1 
1aM5 
7 
1aM6 
21 
1aM7 
42 
1aM8 
70 
1aM9 
140 
1aM10 
280 
1aM11 
560 
1aM12 
840 
1aM13 
1260 
Given many practical advantages, such as decreased operational difficulty, decreased compound 
waste, and reduced dosing errors, flat dosing will be used for this Phase 1 trial.  PK variability 
introduced by either body weight-based or fixed dosing regimens is moderate relative to the 
variability generally observed in PD, efficacy, and safety (Bai 2012).  Therefore, testing either 
body weight-based or fixed dosing regimens in phase 1 can achieve the goal of characterizing 
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PK.  Assessment of the effect of body weight on PK will be conducted to determine the 
appropriate dosing approach and to support the proposed dose and dose regimen(s) for future 
trials using PK data collected from Phase 1. 
Preclinical results show the potential for synergistic benefit from the combination of FPT155 and 
pembrolizumab.  Pembrolizumab will be administered at the approved dose and schedule – 
200mg IV Q3W.  To mitigate the risk of increased immune-related toxicity, FPT155 dose 
escalation in combination with pembrolizumab will start at least two dose levels below the 
highest cleared FPT155 monotherapy dose level reflecting a four-fold reduction in FPT155 dose. 
Preclinical animal models demonstrated a reduction in the activity of the FPT155 and 
pembrolizumab combination with a three-fold reduction in FPT155 dose. 
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5.0 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria  
Patients are eligible to be included in the study only if all of the following criteria apply: 
Age 
1.01) Patient must be 18 years of age or older at the time of signing the informed consent. 
Type of Patient and Disease Characteristics 
2.01) Histologically confirmed solid tumors (except primary CNS tumors).  For patients 
enrolled for treatment with FPT155+pembrolizumab: histologically confirmed non-small 
cell lung cancer not eligible for curative therapy. 
2.02) For patients in Phase 1a dose escalation (all) and Phase 1a dose exploration (FPT155 
monotherapy) only: Disease that is unresectable, locally advanced, or metastatic and has 
progressed following all standard treatments or is not appropriate for standard treatments.  
2.03) All patients must have at least one measurable lesion at baseline according to RECIST 
v1.1.  Tumor sites situated in a previously irradiated area, or in an area subjected to other 
loco-reginal therapy, are not considered measurable unless there has been demonstrated 
progression in the lesion. 
2.04) Availability of archival tumor tissue and consent to provide archival tumor for 
retrospective biomarker analysis, or consent to undergo a fresh tumor biopsy during 
screening 
2.05) For patients participating in Phase 1a dose exploration cohorts and Phase 1b dose 
expansion: consent to undergo a mandatory fresh tumor biopsy during screening and on 
treatment 
2.06) ECOG performance status of 0 or 1 
2.07) Life expectancy of at least 3 months in the opinion of the investigator 
2.08) Willing and able to comply with all study procedures 
2.09) Prior radiotherapy must be completed at least 2 weeks before first dose of study treatment 
administration.  No radiopharmaceuticals (eg, strontium, samarium) within 8 weeks 
before first dose of study treatment administration 
2.10) Prior surgery that requires general anesthesia must be completed at least 14 days before 
first dose of study treatment administration unless patients have recovered, and it is 
considered safe after discussion with medical monitor.  Surgery requiring local/epidural 
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anesthesia must be completed at least 72 hours before first dose of study treatment 
administration and patients must have recovered. 
2.11) Screening laboratory values must meet the following criteria: 
Hematologic 
a. Neutrophils ≥ 1.2 x 109/L 
b. Platelets ≥ 75 x 109/L 
c. Hemoglobin ≥ 9.0 g/dL 
d. Serum creatinine < 1.5 x ULN or creatinine clearance of ≥ 40 mL/minute (using 
Cockcroft/Gault Formula) 
Female creatinine clearance 
(CrCl) = 
(140 – age in years) × (weight in kg) × 0.85 
 
72 × (serum creatinine in mg/dL) 
Male CrCl =  
(140 – age in years) × (weight in kg) 
 
72 × (serum creatinine in mg/dL) 
e. Prothrombin time (PT)/International normalized ratio (INR) < 1.5x ULN and partial 
thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5x 
ULN except for patients receiving anticoagulation, who must be on a stable dose of 
warfarin for 6 weeks prior to enrollment 
Hepatic 
f. AST or ALT < 3x ULN  
g. Bilirubin < 1.5x ULN (except patients with Gilbert's syndrome, who must have total 
bilirubin < 3 mg/dL) 
h. Albumin ≥ 3.0 g/dL (patients with pancreatic cancer only) 
Sex 
3.01) Male or female 
General Inclusion Criteria 
Reproductive Status 
Male patients: 
4.01) A male patient must agree to use contraception as detailed in Appendix 3 of this protocol 
during the treatment period and at least 2 months or 5 half-lives, whichever is longer, 
after the last dose of study treatment and refrain from donating sperm during this period. 
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Female patients:  
5.01) A female patient is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, and at least one of the following conditions applies: 
• Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 
OR 
• A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least 2 months or 5 half-lives, whichever is longer, after the 
last dose of study treatment.  
Informed Consent 
6.01) Capable of giving signed informed consent as described in Section 10.3 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol  
5.2 
Additional Inclusion Criteria - Monotherapy (Phase 1b Only) 
Cohort 1b1: Renal Cell Carcinoma 
7.01) Patients with histologically or cytologically confirmed advanced or metastatic renal cell 
carcinoma with a clear-cell component. 
7.02) Must have received at least one prior anti-angiogenic therapy regimen (eg, sunitinib, 
sorafenib, pazopanib, axitinib, tivozanib, or bevacizumab) in the advanced or metastatic 
setting 
7.03) Must have received at least one anti-PD(L1) therapy (eg, nivolumab, pembrolizumab, 
atezolizumab, durvalumab, or avelumab) in the advanced or metastatic setting.  Prior 
cytokine therapy (eg, IL-2, IFN-α) and anti-CTLA-4 therapy (eg, ipilimumab) is allowed 
but not required. 
Cohort 1b2: Melanoma 
8.01) Patients with histologically- or cytologically-confirmed unresectable stage III or stage IV 
cutaneous melanoma not amenable to local therapy 
8.02) Must have received at least one anti-PD(L1) therapy (including but not limited to 
nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab) in the advanced 
or metastatic setting.  Prior cytokine therapy (eg, IL-2, IFN-α) and anti-CTLA-4 therapy 
(eg, ipilimumab) is also allowed. 
8.03) Patients with BRAF mutations must have received prior BRAF inhibitor therapy 
(eg vemurafenib and dabrafenib) in the advanced or metastatic setting. 
9.01) Inclusion Criteria for Additional Phase 1b Cohorts are included in Appendix 11. 
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5.3 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1.01) Decreased cardiac function with New York Heart Association (NYHA) > Class 2 
1.02) Uncontrolled or significant heart disorder such as unstable angina 
1.03) Current unresolved infection or history of chronic, active, clinically significant infection 
(viral, bacterial, fungal, or other) which, in the opinion of the investigator, would 
preclude the patient from exposure to a biologic agent or pose a risk to patient safety 
1.04) Any uncontrolled medical condition or psychiatric disorder which, in the opinion of the 
investigator, would pose a risk to patient safety or interfere with study participation or 
interpretation of individual patient results 
1.05) Active autoimmune disease, history of clinically significant autoimmune disease, or 
suspected autoimmune disease.  Patients with type I diabetes mellitus, hypothyroidism 
requiring only hormone replacement, 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 
1.06) Symptomatic interstitial lung disease or inflammatory pneumonitis 
1.07) Untreated or active CNS or leptomeningeal metastases.  Patients are eligible if metastases 
have been treated and patients are neurologically returned to baseline or neurologically 
stable (except for residual signs or symptoms related to the CNS treatment) for at least 
2 weeks prior to the first dose of study treatment  
1.08) Evidence of coagulopathy or bleeding diathesis 
Prior/Concomitant Therapy 
2.01)  Treatment with any anti-cancer therapy or participation in another investigational drug or 
biologics trial within 28 days or ≤ 5 half-lives (whichever is shorter) prior to first dose of 
study treatment administration or while on this study 
2.02)  For patients participating in Phase 1a dose escalation and exploration cohorts: Prior 
treatment with a CTLA-4 antagonist, including ipilimumab and tremelimumab 
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2.03)  Patients who have received prior immune-modulating therapies (including regimens 
containing an immune agonist or a PD-L1/PD-1 antagonist) are NOT permitted to enroll 
unless all the following apply: 
a. Must not have experienced a drug-related toxicity that led to permanent 
discontinuation of prior immunotherapy 
b. Last treatment was administered 5 half-lives or 90 days (whichever is shorter) prior to 
first dose of study treatment 
2.04)  Ongoing adverse effects from prior treatment > National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Grade 1 (with the exception of 
Grade 2 alopecia or peripheral neuropathy) 
Other Exclusions 
3.01)  Immunosuppressive doses of systemic medications, such as steroids or absorbed topical 
steroids (doses > 10 mg/day prednisone or equivalent daily) must be discontinued at least 
2 weeks before study treatment administration 
3.02) QTcF > 450 msec for males or > 470 msec for females at screening 
3.03)  Severe allergic, anaphylactic, or other infusion-related reaction to a previous biologic 
agent 
3.04)  Known history of sensitivity to infusions containing Tween 20 (polysorbate 20), 
L histidine, and sucrose 
3.05)  Vaccines (eg, human papillomavirus [HPV] vaccine) within 4 weeks of study treatment 
administration.  The inactivated seasonal influenza vaccine can be given to patients 
before treatment and while on therapy without restriction.  Influenza vaccines containing 
live virus or other clinically indicated vaccinations for infectious diseases (eg, 
pneumovax, varicella) may be permitted, but must be discussed with the Sponsor’s 
medical monitor and may require a study treatment washout period prior to and after 
administration of vaccine 
3.06)  Patients with abnormal serum chemistry values that in the opinion of the investigator are 
considered to be clinically significant.  This will include patients who show clinical signs 
and symptoms related to their abnormal serum chemistry values as well as patients whose 
serum chemistry values are asymptomatic but clinically significant per investigator 
(eg, hypokalemia or hyponatremia). 
3.07)  Pregnant or breastfeeding 
3.08)  Known history of testing positive for human immunodeficiency virus (HIV) 1 or 2 or 
known acquired immunodeficiency syndrome (AIDS) 
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3.09) Positive test for hepatitis B virus surface antigen (HBsAg) or detectable hepatitis C virus 
ribonucleic acid (HCV RNA) indicating acute or chronic infection 
3.10) Transfusion of blood or platelets or granulocyte-colony stimulating factor (G-CSF) 
administration completed within 72 hours prior to first dose of study treatment 
No waivers of these inclusion or exclusion criteria will be granted. 
5.4 
Lifestyle Considerations 
There is not enough information currently available to make any specific recommendations. 
5.5 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study and enter 
the screening period but are not subsequently enrolled.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients 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 after discussion with the Sponsor.  Patients who screen fail may repeat screening 
procedures one time, within the 28-day screening window, inclusive of informed consent.  
A patient who is rescreened is not required to sign another ICF is the rescreening occurs within 
the 28-day screening window. 
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6.0 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study patient according to the 
study protocol.  For patients enrolled for evaluation of FPT155 monotherapy, the study 
intervention administered is FPT155.  For patients enrolled for evaluation of combination 
treatment, the study interventions administered are FPT155 and pembrolizumab. 
6.1 
FPT155 Identity 
FPT155 drug product is supplied for IV administration as a sterile, aqueous, colorless to slightly 
yellow, pyrogen-free solution supplied in single-use glass vials.  The composition of the drug 
product contains 10 mg/mL active ingredient, 20 mM L-histidine, 270 mM sucrose, 0.05% (w/v) 
polysorbate 20 at pH 6.7.  The drug product is providedin two configurations consisting of 20 
mg/vial or 140 mg/vial.  The container-closure systems consist of either an ISO 2R Type I glass 
vial, sealed with a 13 mm bromobutyl rubber stopper, and an orange flip-off cap containing a 
nominal volume of 2 mL or an ISO 20R Type I glass vial, sealed with a 20 mm bromobutyl 
rubber stopper, and a white flip-off cap containing a nominal volume of 14 mL.  The final drug 
product will be provided as 2ºC to 8ºC refrigerated liquid which is diluted for administration per 
instructions provided in a separate Pharmacy Manual. 
FPT155 will be supplied in a sterile vial for dilution into an IV container for administration by 
the study center. 
6.2 
Pembrolizumab Identity  
Pembrolizumab for injection is a sterile, preservative-free, clear to slightly opalescent, colorless 
to slightly yellow solution that requires dilution for intravenous infusion. Each vial contains 100 
mg of pembrolizumab in 4 mL solution. Each 1 mL solution contains 25 mg of pembrolizumab 
and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg) and Water 
for Injection. For additional information, refer to the local Keytruda® (pembrolizumab) 
Prescribing Information.  FPT155 + pembrolizumab combination cohorts will enroll in Australia 
and South Korea. 
Pembrolizumab is available for injection as a 50 mg lyophilized powder in single-use vial for 
reconstitution and in 100 mg/4 mL (25 mg/mL) solution in single use vial.   
The injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly 
yellow solution that requires dilution for intravenous infusion. Each 1 mL of solution contains 
25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), 
sucrose (70 mg) and water for Injection.  Please refer to local pembrolizumab package insert.  
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6.3 
Handling, Storage, and Accountability  
6.3.1 
FPT155 
1. 
FPT155 should be stored under refrigerated temperature of 2-8ºC.  Shaking and long-term 
exposure to light should be avoided. 
2. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment. 
3. 
Only patients enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment.  All study treatments 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. 
4. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
5. 
The Investigator is responsible for returning all unused study treatment to the Sponsor 
(or designee) and must verify that no remaining supplies are in the Investigator’s possession.  
The study site is permitted to destroy used or partially used study treatment vials according 
to the site policy once Sponsor approval of their documented destruction procedure has been 
obtained.  On completion of the study, the number of FPT155 vials shipped, destroyed, and 
returned must be reconciled. 
6. 
Further guidance and information for the final disposition of unused study treatment are 
provided in the pharmacy manual. 
6.3.2 
Pembrolizumab 
For the combination cohorts pembrolizumab packaging, labelling, and storage of pembrolizumab 
should be in accordance with the local Keytruda® package insert, the Pharmacy Manual, and 
relevant local guidelines.    
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6.4 
Administration  
6.4.1 
FPT155 
FPT155 will be administered as a 60 minute IV infusion Q3W in 21-day cycles.  Proposed dose 
levels to be studied are outlined in Section 4.1.1.2.  
There is no pre-specified maximum number of doses of FPT155.   
A pharmacist (or other responsible person) will prepare FPT155 for administration.  Doses in 
different cohorts should be prepared and administered according to the instructions provided in 
the Pharmacy Manual. 
Infusion of FPT155 must be stopped, reduced, interrupted, or discontinued according to 
Section 6.9.3 (Dose Modification and Delay Criteria) and Section 6.9.6 (Dose Interruptions 
During Study Treatment Administration).  If a patient experiences an infusion reaction, the 
patient’s vital signs (temperature, blood pressure, pulse, and respiration rate) should be 
monitored during the infusion as well as every 30 minutes after the infusion for a minimum of 
2 hours and until resolution of the infusion reaction. 
6.4.2 
Pembrolizumab 
Pembrolizumab should be prepared and administered according to the pembrolizumab Product 
Information.   
6.5 
Method of Treatment Assignment 
An Interactive Voice/Web Response System (IVRS/IWRS) will be used to assign patients to 
study treatment. 
Patients in Phase 1a dose escalation will be sequentially assigned to dose levels at the time of 
enrollment, as described in Section 4.1.1.2.  Patients in Phase 1a dose exploration will be 
assigned to the dose level and schedule selected based on the results of the Phase 1a dose 
escalation, as described in Section 4.2.  Patients in Phase 1b dose expansion will be assigned to 
the dose level and schedule selected based on the results of Phase 1a, as described in Section 4.3. 
6.6 
Measures to Minimize Bias: Randomization and Blinding 
This is an open label study.  There is no randomization or blinding.  
6.7 
Study Intervention Compliance 
Only qualified study center personnel may administer FPT155 or pembrolizumab.  Pharmacy 
personnel trained in the study requirements will monitor compliance with the treatment 
assignments.  Records of study medication administered (date, time, and dose administered 
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relative to time of preparation) will be recorded on the patient’s electronic case report form 
(eCRF). 
6.8 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrollment or receives 
during the study 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. 
6.8.1 
Permitted Concomitant Medications 
Supportive care (e.g., antiemetics, analgesics, bisphosphonates, and RANK-L inhibitors) may be 
used at the investigator’s discretion and in accordance with institutional procedures.  Patients 
should receive antiemetic and other prophylactic treatments according to the local standard of 
care and manufacturer’s instruction.  Patients should receive full supportive care, transfusions of 
blood and blood products, antibiotics, antiemetics, etc., when appropriate.  Hematopoietic 
stimulating agents may be used if indicated.  Short course of focal radiation for palliation of 
symptoms is allowed.  Patients are permitted to use topical, ocular, intra-articular, intranasal, and 
inhaled corticosteroids (with minimal systemic absorption).  Adrenal replacement steroid doses 
> 10 mg daily prednisone are permitted.  A brief (approximately less than 3 weeks) course of 
corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune 
conditions (e.g., delayed-type hypersensitivity reaction caused by a contact allergen) and for the 
treatment of tumor-related AEs is permitted. 
6.8.2 
Prohibited Concomitant Medications 
Concomitant anticancer therapies of any kind including extensive non-palliative radiation are not 
permitted.  Immunosuppressive doses of systemic corticosteroids are prohibited (unless utilized 
to treat a drug-related AE). 
6.8.3 
Imaging Restrictions and Precautions 
Tumor evaluation by CT or MRI will be conducted according to RECIST v1.1 in accordance 
with the schedule of assessments.  Patients with a heart pacemaker, brain aneurysm clips, and 
some implanted metallic or electrical devices should not have an MRI.  Patients with known 
allergies or discomfort from contrast agents may have imaging without contrast.  
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6.9 
Dose Modifications 
6.9.1 
Dose Escalation 
The algorithm for dose escalations is described in Table 6.  Intra-patient dose escalation will be 
permitted in patients enrolled at dose levels below 70 mg provided the criteria in Section 4.1.1.5 
are met. 
Safety will be monitored throughout the study by the Sponsor’s CRC, comprised of Phase 1a 
study investigators, the Sponsor’s medical monitor, and the Sponsor’s safety representative.  
The CRC will meet routinely to review the emerging safety, PK, pharmacodynamics, and 
efficacy data, and to make dose escalation decisions. 
In Phase 1a dose exploration, patients will be enrolled at one or more dose levels from Phase 1a, 
and dose escalation will not be permitted. 
In Phase 1b, patients will be treated at the MTD and/or RD as determined from Phase 1a dose 
escalation, and dose escalation will not be permitted.  
6.9.2 
Toxicity at Lowest Dose Level 
If the MTD is unexpectedly exceeded at the first dose level of FPT155 (0.07 mg), dosing will be 
suspended.  Decisions on how to next proceed including decision on evaluating a lower dose will 
be based on safety, tolerability, and PK data, and will be determined by the CRC (refer to 
Section 4.1.1). 
6.9.3 
Dose Modification and Delay Criteria 
Dose reductions or delays for FPT155 may be permitted for patients on treatment beyond the 
DLT evaluation interval in Phase 1a dose escalation, any patients in the Phase 1a dose 
exploration, or any patients in Phase 1b per the guidelines in Table 9.  Dose reductions can be 
assessed using local laboratories.  If a patient in Phase 1a dose escalation requires a dose 
reduction of FPT155 during the DLT period, they will be considered a DLT and be permanently 
discontinued from FPT155. 
Dose reductions and delays for FPT155-related AEs or laboratory abnormalities should follow 
the guidelines outlined in Table 9.  Refer to Section 6.9.4 and Appendix 10 for additional 
specific guidelines for irAEs and CRS.  Any variations from these guidelines must be discussed 
with the Sponsor prior to dosing and must take into consideration the overall benefit and risks for 
the patient of continued participation in the study.  
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Table 9: 
Dose Modification and Delay Criteria for FPT155 (Non-Infusion Toxicity) 
FPT155-related Toxicity Grade 
Dose Schedule 
New FPT155 Dose 
Grade 1  
No delay or missed dose 
required 
100% of dose 
Grade 2 
Delay or miss dose until 
recovery to Grade 1 for 
suspected irAEsa and CRSb  
No delay or missed dose 
required for other AEs 
100% of dose 
Grade 3 (first occurrence) 
Delay or miss dose until 
recovery to baseline or Grade 1  
If recovery to baseline or Grade 1 within 
14 days, may resume at 100% of starting 
dose or 1 dose lowerc 
Grade 3 (second occurrence) 
Delay or miss dose until 
recovery to baseline or Grade 1  
If recovery to baseline or Grade 1 within 
14 days, may resume at 1 level lowerb than 
previous dose or discontinue  
Grade 3 (third occurrence) 
Grade 3 which does not recover to 
baseline or Grade 1 within 14 days 
Any Grade 4 
Permanently Discontinue 
N/A 
a Refer to Section 6.9.4 and Appendix 8 for additional guidance regarding irAEs 
b Refer to Section 6.9.5 and Appendix 10 for additional guidance regarding CRS 
c E.g., 1 dose level lower for patients treated at 70.0 mg is 42.0 mg; 1 dose level lower for patients treated at 
42.0 mg is 21.0 mg. 
Abbreviations: AE = adverse event; irAEs = immune-related adverse events; CRS = cytokine release syndrome. 
The first dose of each cycle is considered Day 1 of each cycle.  Cycles will repeat every 21 days 
unless there is a treatment delay.  A treatment delay of longer than 4 weeks should be discussed 
with the medical monitor prior to continuation of that subject on study. Treatment is 
administered Q3W until disease progression, unacceptable toxicity, or until the patient meets any 
of the other protocol-specified withdrawal criteria.  
6.9.4 
Management of irAEs  
Based on the underlying mechanism action, irAEs associated with the anti-CTLA-4 class of 
drugs (eg, ipilimumab) may potentially be observed with FPT155.  Given the differentiated 
mechanism of action of FPT155 and the absence of any clinical data, the actual timing, incidence 
and severity of these AEs may differ significantly from anti-CTLA-4 therapies.  General 
guidelines for management of suspected irAEs are provided here.  These may be supplemented 
by discussions with the Sponsor as well as institutional guidelines on management of these 
toxicities. 
In all instances, patients should be thoroughly evaluated to rule out a non-inflammatory etiology 
(eg, disease progression, concomitant medication, infections etc.).  Symptomatic or topical 
therapy should be considered for most Grade 1 or 2 events unless otherwise specified in 
Appendix 8.  Corticosteroids are the primary therapy for irAEs.  Corticosteroids should be 
tapered over at least 2-4 weeks in patients experiencing Grade 2 AEs and at least 4-8 weeks in 
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patients experiencing Grade 3/4 AEs.  Appropriate antiviral, antifungal (e.g. pneumocystis) and 
antibacterial prophylaxis must be considered in patients receiving corticosteroids for prolonged 
durations to reduce the risk of opportunistic infections.  More potent immunosuppressive agents 
such as TNF inhibitors (eg, infliximab) should be considered for events not responding to 
systemic steroids.  Refer to Appendix 8 for additional specific guidelines for individual irAEs. 
6.9.5 
Management of CRS 
Refer to Appendix 10 for specific guidelines for grading and management of CRS. 
6.9.6 
Dose Interruptions During Study Treatment Administration 
6.9.6.1 
FPT155 
Infusion of FPT155 must be stopped if any AE ≥ Grade 3 occurs during the infusion.  
If bronchospasm or dyspnea occurs in a patient during the infusion, the infusion must be stopped. 
In addition, at the investigator’s discretion, the infusion rate for FPT155 may be reduced or 
stopped if a less severe AE (Grade 1 or 2) occurs during the infusion.  If a Grade 3 or less severe 
AE resolves within 4 hours, the infusion may be restarted at half the previous rate and promptly 
managed according to the discretion of the Investigator.  If the same AE appears again with the 
same severity at any time during the restarted infusion, the infusion should be discontinued, and 
no further dosing of FPT155 will occur without consultation with the Sponsor or Sponsor’s 
designee. 
If a patient experiences an infusion reaction prior to completion of the infusion, the infusion must 
be stopped, and the patient should be promptly managed and monitored according to signs and 
symptoms, and local clinical protocol until there is a complete resolution of the event.  
Symptoms of infusion reactions may include: fever, chills, rigors, urticaria, hypotension and 
hypertension with headache, wheeze, breathlessness, hypoxia, and pulmonary infiltrates.  For 
patients whose infusion-associated events were either Grade 1 or 2, and completely resolved on 
the day of the infusion, the infusion may be resumed at the discretion of the Investigator at a 
slower rate with premedication.  All subsequent infusions for that patient should then be 
administered at the reduced rate of infusion with pre-medications.  Pre-medications may include 
medications such as corticosteroids, diphenhydramine, acetaminophen and/or bronchodilators as 
indicated.  FPT155 will be permanently discontinued for patients who have experienced Grade 3 
(lasting longer than 4 hours) or above infusion -associated AEs, and for patients who have 
recurrent infusion-associated reactions after restarting the infusion despite pre-medications and 
slower infusion. 
If a patient experiences an infusion reaction, the patient’s vital signs (temperature, blood 
pressure, pulse, and respiration rate) should be monitored during the infusion, as well as every 
30 minutes after the infusion for a minimum of 2 hours and until resolution of the infusion 
reaction. 
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6.9.6.2 
Pembrolizumab 
Dose modifications for pembrolizumab will be allowed in accordance with the local Keytruda® 
package insert.  Dose reductions for pembrolizumab are not permitted.   
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion.  Dose 
modification and toxicity management for infusion reactions associated with pembrolizumab 
should be in accordance with the guidelines provided in the Keytruda® USPI. 
AEs associated with pembrolizumab exposure may represent an immunologic etiology.  
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously.  irAEs 
may be managed with interruptions of pembrolizumab, administration of corticosteroids and/or 
other supportive care.  Dose modification and toxicity management for irAEs associated with 
pembrolizumab should be done in accordance with the guidelines provided in the local 
Keytruda® package insert. 
6.10 
Treatment After the End of the Study 
At the end of the study, the Sponsor will not continue to provide Sponsor-supplied study 
intervention to patients/investigators unless the Sponsor extends the study.  The investigator 
should ensure that the patient receives appropriate standard of care to treat the condition under 
study. 
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7.0 
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL  
7.1 
Discontinuation of Study Intervention  
See the Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4) for data to be collected 
at the time of treatment discontinuation and for any further evaluations that need to be 
completed. 
Study treatment may be discontinued for any of the following reasons: 
• Consent withdrawal at the request of the patient or their legally authorized representative 
• Progressive disease as assessed by the investigator.  Treatment beyond disease progression 
may be allowed in select patients in accordance with Section 4.3. 
• Any event that would pose an unacceptable safety risk to the patient 
• A concurrent illness that would affect assessments of the clinical status to a significant 
degree 
• A positive pregnancy test at any time during the study 
• Specific request of the Sponsor or its authorized representative (e.g., if the study is 
terminated for reasons of patient safety) 
• AE  
• Investigator decision 
• Patient decision, non-AE 
• Other 
7.2 
Patient Discontinuation/Withdrawal from the Study 
See the Schedule of Assessments (Table 1, Table 2, Table 3, and Table 4) for data to be collected 
at the time of study discontinuation and for any further evaluations that need to be completed. 
The Sponsor or its designee must be notified if a patient is withdrawn from study treatment or 
from the study.  The reason(s) for withdrawal must be documented in the patient’s medical 
records and eCRF. 
Any patient may be discontinued from the study for any of the following reasons:  
• Consent withdrawal at the request of the patient or their legally authorized representative 
• AE 
• Death 
• Investigator decision 
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• Lost to follow-up 
• Significant noncompliance to protocol  
• Study termination by Sponsor 
• Other 
If the patient withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the site study records. 
7.3 
Lost to Follow Up 
A patient 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 patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the patient wishes to and/or should continue in the study. 
• Before a patient is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the patient (where possible, 3 telephone calls and, if necessary, a 
certified letter to the patient’s last known mailing address or local equivalent methods).  
These contact attempts should be documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
Discontinuation of specific sites or of the study as a whole are described in Section 10.0. 
7.4 
Replacement of Patients 
Patients in Phase 1a dose escalation will be replaced if they are unevaluable for DLT (refer to 
Section 4.1.1.3).   
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8.0 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the Schedule of Assessments (Table 1, 
Table 2, Table 3, and Table 4).  Protocol waivers or exemptions are not allowed. 
• Specific clinical laboratory tests to be conducted: Appendix 1 
• Guidance for ECOG assessment: Appendix 5 
• RECIST v1.1: Appendix 6 
• NYHA Classification: Appendix 7 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
intervention. 
• Adherence to the study design requirements, including those specified in the Schedule of 
Assessments, is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria.  The investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
• Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the Schedule of Assessments. 
8.1 
Efficacy Assessments  
8.1.1 
Tumor Assessment for the Study 
Tumor assessments consist of clinical examination and appropriate imaging techniques 
(preferably CT scans with appropriate slice thickness per RECIST v 1.1; MRI is acceptable).  
Assessments should be performed as outlined in the Schedule of Assessments.  The same 
methods used to detect lesions at baseline are to be used to follow the same lesions throughout 
the clinical study. 
Tumor response assessment will be performed by the investigator per RECIST v 1.1 guidelines 
(Eisenhauer 2009). 
Tumor assessments will be performed at screening, then every 6 weeks from the first dose for 
24 weeks, and then every 12 weeks thereafter.  Once an initial CR or PR is reported by the 
investigator, confirmatory scans must be performed 4–6 weeks later. 
If patient terminates study treatment prior to scheduled CT/MRI scans, patient should have scans 
done at the EOT visits (does not need to be repeated if performed within 8 weeks prior to the end 
of treatment visits, or if tumor progression was previously determined). 
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After discontinuation of study treatment for reasons other than progressive disease, withdrawal 
of consent, or initiation of additional anti-cancer therapy, tumor assessments will continue every 
12 weeks until disease progression, withdrawal of consent or start of new anti-cancer therapy. 
In the Phase 1b portion of the study, patients in LTFU for survival must have tumor scans every 
12 weeks if tumor progression was not previously determined and/or use of alternative anti-
cancer therapy has not been initiated. 
8.1.2 
Methods of Measurement 
Every attempt should be made to image each patient using an identical acquisition protocol on 
the same scanner for all imaging time points.  Tumor measurements should be made by the same 
investigator or radiologist for each assessment whenever possible.  Change in tumor 
measurements and tumor response to guide ongoing study treatment decisions will be assessed 
by the investigator. 
Bone scan or PET scan is not adequate for assessment of RECIST v1.1 response in target lesions.  
In selected circumstances where such modalities are the sole modality used to assess certain 
nontarget organs, those non-target organs may be evaluated less frequently.  For example, bone 
scans may need to be repeated only when complete response is identified in target disease or 
when progression in bone is suspected. 
Bone scans may be collected per local standards, as clinically indicated. 
Screening assessments are to be performed within 28 days prior to treatment assignment.  
In addition to the chest, abdomen, pelvis, and brain (if brain metastases are suspected at 
baseline), all known sites of disease should be assessed at baseline.  Subsequent assessments 
should include chest, abdomen, pelvis, and all known sites of disease using the same imaging 
method and technique as was used at baseline. 
In addition, subjects receiving study treatment beyond progression must continue tumor 
assessments until such treatment has been discontinued.  Treatment beyond disease progression 
is detailed in Section 4.3. 
8.2 
Informed Consent, Screening, and Enrollment 
Patients must be able to provide written informed consent and meet all eligibility criteria prior to 
enrollment. 
Only patients who meet all eligibility criteria outlined in Section 5.0 will be enrolled in this 
study.  No waivers of inclusion or exclusion criteria will be granted by the Investigator and 
Sponsor or its designee for any patient enrolled in the study.  Patients who qualify for Phase 1a 
of the study will be enrolled into the first available cohort.  A patient may be enrolled into either 
Phase 1a or Phase 1b of the study, but not both. 
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8.3 
Safety Assessments 
Planned time points for all safety assessments are provided in the Schedule of Assessments. 
Only data for the procedures and assessments specified in this protocol should be submitted to 
the Sponsor on eCRF.  Additional procedures and assessments may be performed as part of 
standard of care; however, data for these assessments should remain in the patient’s medical 
record and should not be provided to the Sponsor, unless specifically requested. 
8.3.1 
Medical History and Demographics 
Patient medical and surgical history includes a thorough review of significant past medical and 
surgical history, current conditions, concomitant therapies, alcohol and smoking history, and 
smoking status.  Demographics including age, gender, race, and ethnicity will be recorded. 
8.3.2 
Physical Examinations 
A complete physical examination including height and weight will be performed at screening.  
A limited physical examination (eg, symptom-directed examination of specific organ systems/ 
body area) should be conducted at the specified time points after screening in accordance with 
the Schedule of Assessments.  Investigators should pay special attention to clinical signs related 
to previous serious illnesses.  
8.3.3 
Vital Signs 
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
patient in a quiet setting. 
8.3.4 
Electrocardiograms 
Twelve-lead ECG will be obtained as outlined in the Schedule of Assessments.  ECGs for each 
patient should be obtained from the same machine whenever possible.  To minimize variability, 
it is important that patients be in a resting position for at least 5 minutes prior to each ECG 
evaluation.  Body position should be consistently maintained for each ECG evaluation to prevent 
changes in heart rate.  Environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording. 
The exact time of ECG should be recorded.  The ECGs should be reviewed promptly by a 
qualified physician and any clinically important finding should be recorded on the appropriate 
eCRF.  The Investigator is responsible for providing the interpretation of all ECGs.  The results 
will include heart rate, PR interval, QRS interval, QT interval, and QTc interval. 
Additional ECGs may be obtained at any time if clinically indicated.  If abnormal (excluding 
sinus tachycardia), ECGs should be obtained as clinically indicated until the abnormality is 
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resolved or clinically stable.  Any clinically significant changes in ECG that occur during the 
study should be reported as an AE in the eCRF. 
8.3.5 
Eastern Cooperative Oncology Group Performance Status  
ECOG performance status will be assessed in all patients in accordance with the Schedule of 
Assessments.  The ECOG performance scale is provided in Appendix 5.  The ECOG 
performance status is a scale used to assess how a patient's disease is progressing, assess how the 
disease affects the daily living abilities of the patient, and determine appropriate treatment and 
prognosis. 
8.3.6 
Clinical Safety Laboratory Assessments 
See Appendix 1 for the list of clinical laboratory tests to be performed and the Schedule of 
Assessments for the timing and frequency. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF.  The 
laboratory reports must be filed with the source documents. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. 
All protocol-required laboratory assessments, as defined in Appendix 1, must be conducted in 
accordance with the laboratory manual and the Schedule of Assessments. 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in patient management or are considered clinically 
significant by the investigator (eg, SAE or AE or dose modification), then the results must be 
recorded in the eCRF. 
8.4 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 2. 
Assessment of AEs will follow the guidelines provided in the NCI CTCAE version 4.03. 
Abnormal laboratory results that lead to a change in patient treatment management (e.g., dose 
delay, requirement for additional medication or monitoring) are considered clinically significant 
for the purposes of this study and will be recorded on the AE page of the eCRF. 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative). 
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The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs to 
resolution. 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information  
All SAEs will be collected from the start of study treatment (Cycle 1 Day 1).  In addition, any 
SAE occurring between signing of ICF and start of treatment will be recorded if it is due to a 
study related procedure.  The SAEs will be collected through the Day 100 EOT visit. 
All AEs will be collected from the start of study treatment (Cycle 1 Day 1) through completion 
of study, at the time points specified in the Schedule of Assessments.  AEs ascribed to study 
treatment and SAEs should be assessed through the Day 100 EOT visit. 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the Medical History section of the eCRF, not the AE section, unless 
they directly correlate to a study-related procedure, in which case they will be reported on the 
AE eCRF page. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 2.  The investigator will submit any updated SAE data to the sponsor or designee 
within 24 hours of it being available. 
SAEs occurring after the Day 100 EOT visit should be reported to the Sponsor by the 
Investigator only if the Investigator considers the event reasonable related to FPT155.  SAEs 
should always be recorded on the AE eCRF. 
Investigators are not obligated to actively seek AE or SAE in former study patients.  However, if 
the investigator learns of any SAE, including a death, at any time after a patient has been 
discharged from the study, and he/she considers the event to be reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 2. 
8.4.2 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 2. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
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8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts.  All SAEs, will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3).  Further 
information on follow-up procedures is given in Appendix 2. 
8.4.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor or designee of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of patients and the safety of a 
study treatment under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. 
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 a safety report describing a SAE or other specific safety 
information (eg, 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. 
Details of all pregnancies in female patients and female partners of male patients will be 
collected after the start of study treatment and until the Day 100 EOT visit. 
If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 3. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.4.5 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Disease progression is an expected event in patients with advanced cancer.  Therefore, disease 
progression itself diagnosed clinically or based on laboratory/testing should not be considered as 
an AE.  
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Since disease progression is an efficacy endpoint of this study it should be recorded separately in 
the appropriate eCRFs intended to capture tumor response assessment. 
8.5 
Treatment of Overdose 
There are no clinical data with FPT155.  In the event of a medical emergency due to suspected 
FPT155 overdose the Sponsor should be contacted as soon as possible.  Monitoring and 
reporting a suspected treatment overdose should follow guidelines for AEs and SAEs.  
No specific antidote is available for treating overdose with FPT155.  Management of any AEs 
due to overdose should be managed per Institutional practice. 
8.6 
Tumor Tissue 
Tumor tissue should be collected in accordance with the Schedule of Assessments (Table 1, 
Table 2, Table 3, and Table 4) and Section 4.1.4. 
8.6.1 
Archival Tumor Tissue 
Archival tumor tissue from an excisional, incisional or core needle biopsy, as fine needle 
aspirates or other cytology specimens are insufficient for downstream biomarker analyses. 
Patients must consent to undergo a fresh tumor biopsy during screening if archival tumor tissue 
is not available. Archival tissue will be collected as follows: 
8.6.2 
Tumor Tissue Biopsy 
The following guidelines apply to patients who consent for tumor biopsy: 
• All patients that consent to a pre-treatment biopsy must have at least one tumor site that can 
be biopsied and be willing to have pre-treatment and on-treatment biopsies, from the same 
lesion where feasible. 
• Biopsies will be performed according to the treating institution’s own guidelines.  These 
biopsies must be excisional, incisional or core needle biopsies, as fine needle aspirates or 
other cytology specimens are insufficient for downstream biomarker analyses. 
• If a pre-treatment biopsy has been performed as part of the patient’s standard of care within 
28 days prior Cycle 1 Day 1, if the sample is available to study Sponsor and has sufficient 
evaluable tumor content, the pre-treatment biopsy does not need to be repeated. 
• Sites for biopsy must be distinct from target lesions used for efficacy assessment 
• Patient must have recovered from any acute adverse effects of the biopsy procedure prior to 
dosing 
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Patients may also have an (optional) biopsy upon documented disease progression.  If available, 
tumor tissue obtained from post-treatment procedures such as surgery may also be collected. 
8.7 
Pharmacokinetics 
PK parameters are evaluated in this study in accordance with the Schedule of Assessments 
(Table 3 and Table 4). 
Serum samples will be collected for measurement of concentrations of FPT155 and 
pembrolizumab as specified in the Schedule of Assessments.  Instructions for the collection and 
handling of biological samples are in the laboratory manual.  The actual date and time (24-hour 
clock time) of each sample will be recorded.  The measurement of serum FPT155 and 
pembrolizumab concentration will be performed using validated ELISAs. 
8.8 
Pharmacodynamics 
Pharmacodynamic parameters will be evaluated in this study in accordance with the Schedule of 
Assessments (Table 3 and Table 4). 
Venous blood samples will be collected for measurement of immune phenotype changes due to 
study intervention by (including but not limited to) flowcytometry or cytokine or ribonucleic 
acid (RNA) analysis.  Specific time points are listed in the Schedule of Assessments. 
Tumor biopsy samples at screening and prior to Cycle 3 Day 1 will be collected from select 
patients for measurement of immune phenotype changes due to study intervention by (including 
but not limited to) immune histochemistry or RNA analysis.  Specific time points are listed in the 
Schedule of Assessments. 
8.9 
Biomarkers 
Samples for predictive and pharmacodynamic biomarker assessment will be collected and 
processed according to instructions provided in a separate laboratory manual.  Additional 
guidance for sampling and procedures is provided in the following sections: 
• Specific timing requirements for study assessments and procedures are outlined in the 
Schedule of Assessments. 
• Guidance for the specific timing and sample collection of PK, immunogenicity, and 
pharmacodynamic sample collection: Table 3 and Table 4 Schedule of Pharmacokinetic, 
Immunogenicity, and Pharmacodynamic Blood Sample Collection. 
A variety of endpoints that could monitor drug activity or potentially predict clinical response to 
study intervention may be investigated in peripheral blood and archival and/or fresh tumor 
specimens, collected from patients prior to and during treatment.  Data from these analyses will 
be evaluated for association with response and/or safety data. 
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Samples will be stored in a secure storage space with adequate measures to protect 
confidentiality. 
8.9.1 
Immunogenicity Assessments 
Antibodies to FPT155 and pembrolizumab will be evaluated in serum samples collected from all 
patients according to the Schedule of Assessments.  
Serum samples will be screened for antibodies binding to FPT155 and pembrolizumab and the 
titer of confirmed positive samples will be reported.  Other analyses may be performed to further 
characterize ADAs to FPT155 and pembrolizumab. 
The detection and characterization of antibodies to FPT155 will be performed using a validated 
ligand binding assay.  Samples collected for detection of antibodies to FPT155 will also be 
evaluated with concurrent FPT155 serum concentration samples to enable interpretation of the 
effect of the antibody on serum concentration and other pharmacokinetic parameters.  Antibodies 
may be further characterized and/or evaluated for their ability to neutralize the activity of 
FPT155.  Samples may be stored until the Clinical Study Report (CSR) is written and approved 
or up to the stability date established during assay validation (typically this will be the stability 
period established for serum drug concentration samples) to enable further analysis of immune 
responses to FPT155 if needed. 
8.9.2 
RNA Expression Research  
Transcriptome studies may be conducted using RNA sequencing or alternative equivalent 
technologies, which facilitates the simultaneous measurement of the relative abundances of 
thousands of RNA species resulting in a transcriptome profile for each blood and tumor sample.  
Alternatively, targeted RNA expression analysis may be performed using targeted RNA 
sequencing assays and/or alternative equivalent technologies.  This will enable the evaluation of 
baseline correlates, or changes in transcriptome profiles that may correlate with biological 
response relating to study intervention. 
The samples may also be used to confirm findings by application of alternative technologies. 
8.9.3 
Immunohistochemistry/Immunofluorescence 
Immunohistochemistry (IHC) or immunofluorescence (IF) studies may be conducted using 
archival tumor and fresh biopsy samples.  This will enable the evaluation of baseline correlates, 
or changes in tumor immune profiles that may correlate with biological response relating to 
study intervention. 
The samples may also be used to confirm findings by application of alternative technologies. 
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8.9.4 
PBMC Collection  
PBMCs will be isolated from peripheral blood samples at various time points.  Flow cytometry 
and/or alternative equivalent technologies may be performed to understand baseline correlates of 
immune phenotype, and/or changes in immune phenotype due to study intervention. 
The samples may also be used to confirm findings by application of alternative technologies. 
8.9.5 
Cytokine Analysis 
Cytokine analysis by ELISA based and/or alternative equivalent technologies may be performed 
to understand baseline correlates, and/or changes in cytokine profile due to study intervention. 
The samples may also be used to confirm findings by application of alternative technologies. 
8.9.6 
Circulating Tumor DNA Blood Assay 
Circulating tumor DNA-containing plasma will be isolated from peripheral blood samples at 
various time points.  Targeted deoxyribonucleic acid (DNA) sequencing and/or alternative 
equivalent technologies may be performed to identify tumor driver mutations and/or estimate 
tumor mutation burden and understand their association with biological response relating to 
study intervention. 
The samples may also be used to confirm findings by application of alternative technologies. 
8.10 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 
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9.0 
STATISTICAL CONSIDERATIONS  
All analyses will be descriptive and will be presented by phase, dose group, cohort and overall as 
appropriate.  In addition, all patients dosed at the MTD and/or RD will also be summarized as 
appropriate.  Data collected in this study will be presented using summary tables and patient data 
listings.  Continuous variables will be summarized using descriptive statistics, specifically the 
number of subjects, mean, median, standard deviation (SD), minimum, and maximum.  
Categorical variables will be summarized by frequencies and percentages. 
A change to the data analysis methods described in the protocol will require a protocol 
amendment only if it alters a principal feature of the protocol.  The statistical analysis plan (SAP) 
will be finalized prior to database lock.  Any changes to the methods described in the final SAP 
will be described and justified in the clinical study report. 
9.1 
Statistical Hypotheses 
Not applicable. 
9.2 
Sample Size Determination 
This study is designed as a dose escalation, dose exploration, and dose expansion study with 
objectives that include determination of an MTD and/or RD and assessments of the safety and 
tolerability of FPT155 as monotherapy and in combination with pembrolizumab.  The sample 
size of this study was not determined by strict statistical considerations.  The total number of 
patients planned for this study is estimated to be approximately 408. 
The sample size of Phase 1a is defined by the requirements of the accelerated titration and 3+3 
dose escalation design.  Approximately up to 108 patients will participate in Phase 1a 
monotherapy, depending on the number of dose levels evaluated and the incidence of DLTs; this 
includes up to 58 patients in the Phase 1a monotherapy dose escalation portion and allows for up 
to approximately 50 patients in the Phase 1a monotherapy dose exploration to further explore 
safety, PK, PD, and clinical activity at one or more dose levels (conditional upon the dose level 
clearing dose escalation criteria).  Approximately up to 60 patients will participate in Phase 1a 
combination, depending on the number of dose levels evaluated and the incidence of DLTs; this 
includes up to 30 patients in the Phase 1a combination dose escalation, and up to 30 patients in 
the Phase 1a combination dose exploration. 
For the objective of estimating the ORR of FPT155 in Phase 1b monotherapy, it is estimated that 
up to 30 patients will be enrolled to ensure 25 evaluable patients in each cohort.  Table 10 
displays the corresponding 2-sided 90% confidence interval (CI) and the precision for the 
various observed response rates (Agresti 1998) based on 25 evaluable patients.  The sample size 
of 25 is chosen to ensure that it will allow to exclude 10% when the observed ORR is 24% or 
higher in each cohort. 
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Approximately 240 patients will participate in Phase 1b monotherapy.  Phase 1b monotherapy 
will consist of up to 8 cohorts of approximately 30 patients each. 
Table 10: 
Two-Sided 90% Confidence Intervals of the Observed Response Rates 
Sample Size 
Observed Response Rate 
90% CI 
Precision (longest one-sided CI length*) 
25 
5/25 (20%) 
(8%, 38%) 
18% 
6/25 (24%) 
(11%, 42%) 
18% 
7/25 (28%) 
(14%, 46%) 
18% 
8/25 (32%) 
(17%, 50%) 
18% 
9/25 (36%) 
(20%, 54%) 
18% 
10/25 (40%) 
(24%, 58%) 
18% 
Abbreviations: CI = confidence interval. 
*Distance from the observed response rate to the lower or upper CI boundary. 
9.3 
Populations for Analyses 
The following analysis populations are defined for the study as follows: 
Population 
Description 
Enrolled  
All patients who sign informed consent and are registered as enrolled in 
IVRS/IWRS. 
Efficacy Population 
All patients who have received any portion of at least one dose of study drug. 
DLT-Evaluable Population 
All patients enrolled into Phase 1a dose escalation portion of the study who 
received at least 1 dose of all assigned study drug(s) and remain on study for 
the 21-day DLT evaluation, or who experienced a DLT before clearing the 
21-day DLT evaluation interval.  
Safety Population 
All patients who have received any portion of at least one dose of any study 
drug. 
Response-Evaluable Population 
All patients who met eligibility criteria, received at least one dose of any study 
drug, have measurable tumor lesions at baseline, and have at least 
one post-baseline disease assessment unless the death and clinical progressive 
disease occurred prior to the first post baseline disease assessment. 
PK-Evaluable Population 
All patients who have received at least one dose of study drug and have had 
sufficient PK sample for the calculation of at least one PK parameter on at 
least one Study Day. 
9.4 
Statistical Analyses 
The SAP will be developed and finalized before database lock and will describe the patient 
populations to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data.  This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints. 
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9.4.1 
Efficacy Analyses 
The primary efficacy analyses (Table 11) will be performed on the efficacy population.  Efficacy 
analyses based on the response-evaluable population may be performed as a sensitivity analysis.  
Details of the censoring scheme on time-to-event endpoints such as DOR and PFS will be 
described in the SAP. 
Table 11:  
Efficacy – Statistical Analyses 
Endpoint 
Statistical Analysis Methods 
ORR is defined as the proportion of patients whose BOR is either 
confirmed CR or PR per RECIST v1.1 in the population of 
interest. 
BOR for a patient will be assessed per RECIST v1.1 by the 
investigator, unless otherwise specified. 
DCR defined as total number of patients with confirmed 
responses of either CR, PR, or stable disease as determined by 
the investigator per RECIST v1.1, divided by the total number of 
patients who are evaluable for a response 
Estimate of ORR and corresponding 2-sided 
exact 90% CI using the Clopper-Pearson 
method 
Estimate of DCR and corresponding 2-sided 
exact 90% CI using the Clopper-Pearson 
method 
DOR  
DOR for a patient with a BOR of confirmed CR or PR is defined 
as the time between the date of first response and the date of the 
first objectively documented tumor progression per RECIST v1.1 
or death, whichever occurs first. 
Estimate by the Kaplan-Meier method and 
corresponding 2-sided 90% CI using 
Brookmeyer and Crowley methodology 
(using log-log transformation) 
PFS  
PFS for a patient is defined as the time from the first dosing date 
to the date of first objectively documented disease progression or 
death due to any cause, whichever occurs first.  
Estimate by the Kaplan-Meier method and 
corresponding 2-sided 90% CI using 
Brookmeyer and Crowley methodology 
(using log-log transformation) 
OS 
OS for a patient is defined as the time from the first dose of study 
treatment until death from any cause. 
Estimate by the Kaplan-Meier method and 
corresponding 2-sided 90% CI using 
Brookmeyer and Crowley methodology 
(using log-log transformation) 
Abbreviations: BOR = best overall response; CI = confidence interval; CR = complete response; DOR = duration of 
response; DCR= disease control rate; PFS = progression free survival; OS = overall survival; PR = partial response; 
RECIST v1.1  = Response Evaluation Criteria in Solid Tumors version 1.1. 
9.4.2 
Safety Analyses 
All safety analyses will be performed on the Safety Population. 
Safety analyses will be performed separately within both phases of the study and for all patients 
combined.  In addition, the incidence of DLTs in Phase 1a will be summarized for the DLT-
Evaluable Population. 
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Table 12:  
Safety – Statistical Analyses 
Endpoint 
Statistical Analysis Methods 
Incidence of DLTs, AEs, SAEs, and AEs leading 
to discontinuation, modifications, and 
interruptions, and death 
AEs will be graded according to CTCAE v4.03. 
Frequency distribution of treated patients with AE using the 
worst CTC grade.  Patients will only be counted (1) once at 
the preferred term level, (2) once at the SOC level, and 
(3) once in the “Total subject” row at their worst CTC grade, 
regardless of SOC or preferred term. 
Laboratory abnormalities 
Laboratory values will be graded according to 
CTCAE v4.03. 
Laboratory shift table using the worst CTC grade on 
treatment per patient. 
ECG abnormality 
Frequency distribution of treated patients with post baseline 
ECG abnormality by visit. 
Abbreviations: AE = adverse event; CTCAE = common terminology criteria for adverse events; DLT = dose 
limiting toxicity; ECG = electrocardiogram; SOC = system organ class. 
9.4.3 
Pharmacokinetic Analyses 
The following PK parameters of FPT155 will be summarized. 
Endpoint 
Statistical Analysis Methods 
The following PK parameters will be derived from 
concentration-time data for FPT155 when appropriate 
and applicable to characterize single-dose/multiple 
dose PK.   
• 
AUC 
• 
Cmax 
• 
Ctrough 
• 
CL 
• 
t1/2 
• 
Vss 
• 
Cmax and Ctrough as well as the accumulation ratio of 
Cmax and Ctrough for pembrolizumab may be 
calculated if the data are available 
Other parameters, such as dose proportionality, 
accumulation ratio, attainment of steady state, will also 
be estimated if the data are available.  
Individual and mean (± SD) serum FPT155 and 
pembrolizumab concentration-time data will be 
tabulated and plotted by dose level, respectively.  PK 
parameters of FPT155 and pembrolizumab will be 
tabulated and summarized by dose level when 
appropriate and applicable, respectively.  The impact 
of immunogenicity on FPT155 and pembrolizumab 
exposure will be assessed, tabulated, and summarized 
by dose level as data allow.  
Assessments of time-dependence of PK, the effect of 
body weight as well as other covariates on PK, and 
exposure-response relationship for FPT155 will be 
conducted, when the data allow, to determine the 
appropriate dosing approach (eg, body weight-based or 
fixed dosing) for future trials. 
The effect of body size on PK and correlation of 
exposure with clinical outcomes and toxicity will be 
assessed for FPT155 when data allow.  These analyses 
will be used to determine the appropriate dosing 
approach (eg, body size-based or fixed dosing) to 
support the proposed dose and dose regimen(s) for 
further trials. 
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9.4.4 
Immunogenicity Analyses 
Endpoint 
Statistical Analysis Methods 
Incidence of ADA to 
FPT155 and pembrolizumab 
Frequency distribution of baseline ADA-positive subjects for FPT155 and 
pembrolizumab and FPT155 and pembrolizumab treatment induced ADA-positive 
subjects after initiation of the treatment; titer (titer range), respectively.  May 
characterize ADA as either transient or persistent ADA. 
9.4.5 
Other Analyses  
 
 
9.5 
Interim Analyses  
There is no planned interim analysis in this study. 
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10.0 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1 
Regulatory and Ethical Considerations 
10.1.1 
Good Clinical Practice 
The procedures set forth in this study protocol are designed to ensure that the Sponsor and 
investigator abide by all applicable laws, regulations and guidelines, including ICH Good 
Clinical Practice (GCP) guidelines and international guidelines for ethical practices, including 
the Declaration of Helsinki (1989) and the Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
Before the first patient is screened, the study protocol, including any amendments thereto, the 
form ICF, the Investigator Brochure and any other relevant documents must be approved by the 
IRB/IEC, in accordance with applicable laws, regulations and guidelines.  The Sponsor, 
Sponsor’s agents, and investigator must ensure that all ethical and legal requirements have been 
met before the first patient is enrolled in the study. 
If a significant safety issue is identified by the Sponsor, either from an individual case report or 
review of aggregate data, the Sponsor will promptly notify the applicable regulatory authorities 
and investigators.  Investigators will then notify local IRB/IECs as deemed appropriate based on 
individual IRB/IEC policy.  A significant safety issue is one that has a significant impact on the 
course of the clinical trial or program (including the potential for suspension of the trial program 
or amendments to protocols) or warrants immediate update of informed consent. 
All potential serious breaches must be reported to the Sponsor or designee immediately.  
A serious breach is a breach of the conditions and principles of GCP in connection with the study 
or the protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study. 
The investigator will also be responsible for providing oversight of the conduct of the study at 
the site, including oversight of all personnel involved in the study, and adherence to all 
applicable laws and regulations, as set forth in the Clinical Trial Agreement. 
Personnel involved in conducting this study will be qualified by education, training, and 
experience prior to performing their respective tasks. 
The study will not use the services of study personnel against whom sanctions have been 
invoked or who have engaged in scientific misconduct or fraud (e.g., loss of medical licensure, 
debarment). 
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10.1.2 
Institutional Review Board/Independent Ethics Committee 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
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 patients. 
The investigator will be responsible for 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. 
The investigator should notify the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures. 
10.1.3 
Compliance with the Protocol and Protocol Revisions 
This protocol is to be followed exactly.  The investigator may not implement any deviation or 
change to the protocol, except where necessary to eliminate an immediate hazard to study 
subjects. 
Any amendments to the protocol must be written and receive approval from the appropriate 
personnel and the IRB/IEC (and, if applicable, also by the local health authority) prior to 
implementation.  Following approval, the protocol amendment will be submitted to the IND 
application / Clinical Trial Application under which the study is being conducted.  If an 
amendment substantially alters the study design or increases the potential risk to patients: (1) the 
informed consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form of informed consent must be used to obtain 
consent from subjects currently enrolled in the study if they are affected by the amendment; and 
(3) the new form of informed consent must be used to obtain consent from new subjects prior to 
enrollment. 
If a deviation or change to a protocol is implemented by an investigator to eliminate an 
immediate hazard to a study subject, the investigator must report such the deviation or change as 
soon as possible to: 
• the IRB/IEC; and 
• any applicable Regulatory Authority(ies), if required by local regulations. 
Investigator must send to Sponsor documentation of approval/favorable opinion of such 
deviation or change, signed by the chairperson or designee of the IRB(s)/IEC(s) and, if 
applicable, also by the local health authority. 
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If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s). 
10.2 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with complete and accurate 
information required by Part 54 of Title 21 of the Code of Federal Regulations about such 
investigators’ and sub-investigators’ financial interests, as requested by Sponsor, to allow the 
Sponsor to submit financial certifications or disclosure statements to the appropriate regulatory 
authorities, as required by Part 54 of Title 21 of the Code of Federal Regulations.  Investigators 
are responsible for providing such information during the course of the study and for one year 
after completion of the study. 
10.3 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the patient and 
answer all questions regarding the study.  Patients must be informed that their participation in the 
study is voluntary.  If a patient cannot provide his or her consent, the investigator must ensure 
that the patient’s legally authorized or other legally acceptable (as per country-specific 
guidelines) representatives are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding the study. 
Investigator, with the assistance of Sponsor, will prepare forms of written statements of informed 
consent (each, an ICF) for use in the study that meet the requirements of Part 50 of Title 21 of 
the Code of Federal Regulations, local regulations, ICH guidelines, the Health Insurance 
Portability and Accountability Act (“HIPAA”), where applicable, and the IRB/IEC or study 
center.  Each form ICF must be approved by the IEC/IRB and the Sponsor before any patients 
are enrolled in the study. 
Patients or their legally authorized representatives will be required to sign the appropriate forms 
of ICF to provide their consent prior to their enrollment in the study.  The authorized person that 
obtained the patient’s informed consent must also sign the ICF.  The original ICFs will be filed 
in the investigator’s study center file, unless otherwise agreed by the Sponsor and the study 
center.  A copy of each patient’s signed ICFs will be provided to such patient or such patient’s 
legally authorized representative. 
The investigator will not undertake any investigation with respect to a patient specifically 
required only for the study until valid consent has been obtained from such patient.  The terms of 
the consent and when it was obtained must be documented in the source documents and in the 
eCRF. 
Patients must always be consented to the most current approved version of the ICF during their 
participation in the study.  If a protocol amendment is required, the ICFs may need to be revised 
to reflect the changes to the protocol.  If any ICF form is revised, it must be reviewed and 
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approved by the appropriate IRB/IEC and signed by all patients subsequently enrolled in the 
study as well as those currently enrolled in the study. 
Each patient’s medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the study and the date the written consent was 
obtained. 
10.4 
Data Protection 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other pertinent data for each study patient.  All 
information recorded in the case histories or eCRFs for this study must be consistent with the 
patients’ source documentation (ie, medical records). 
Investigator and study center must maintain the anonymity of participating patients.  Each patient 
will be assigned a unique patient identifier by the Sponsor that may consist of one or more of the 
following: the patient’s patient number, initials, and/or birth date.  Investigator and study center 
will include only such patient identifier on any eCRFs or other patient records, datasets or other 
documents that are transferred or submitted to the Sponsor or Sponsor’s designee during the 
course of the study and will redact patient’s name and all other personally-identifiable patient 
information from such documents.  In addition, investigator must maintain in confidence any 
documents that include personally-identifiable patient information (e.g., the signed ICF) and take 
all reasonable precautions to prevent the disclosure of any personally identifiable patient 
information by any employee or agent of the study center to any third party or otherwise into the 
public domain. 
The investigator or study center must inform study patients that their personal study-related data 
will be used by the Sponsor in accordance with local data protection law and must explain the 
level of disclosure to patients.  In addition, each patient must be informed that his/her medical 
records may be examined by Clinical Quality Assurance auditors or other authorized personnel 
appointed by the Sponsor, by IRB/IEC members of the study center, and by inspectors from 
regulatory authorities. 
The Sponsor (or designee) may conduct a site visit prior to study initiation at a site to verify the 
qualifications of each investigator, inspect the site facilities, and inform the investigator of 
investigator’s responsibilities for ensuring study compliance and procedures for preparing and 
maintaining adequate and correct eCRFs. 
10.5 
Clinical Study Data and Publication Policy 
A signatory investigator must be selected to sign the clinical study report. 
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For this protocol, the signatory investigator will be selected as appropriate based on the 
following factors: 
• Role of investigator in study, including role as  
• External principal investigator designated at protocol development 
• National coordinating investigator 
• Investigator’s success in patient recruitment (e.g., among the top quartile of enrollers) 
• Investigator’s involvement in the study design 
• Investigator’s regional representation (e.g., among the top quartile of enrollers from a 
specified region or country) 
• Other factors (as determined by the study team) 
All data obtained during this study are confidential information of the Sponsor.  The investigator 
and members of his/her research team must not disclose such information without prior written 
approval from the Sponsor, in accordance with the Clinical Trial Agreement.  Any publications 
or abstracts arising from this study require approval by the Sponsor prior to publication or 
presentation and must adhere to the Sponsor’s publication requirements as set forth in the 
Clinical Trial Agreement. 
10.6 
Data Quality Assurance 
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
All data obtained during the study should be entered in the eCRFs promptly.  All source 
documents from which eCRF entries are derived should be placed in the patient’s medical 
records.  eCRF fields for which source documents will typically be needed include laboratory 
assessments, physical examination reports, nursing notes, ECG recordings, hospital records, CT 
scans, and/or MRI reports. 
During the study, study monitors will perform routine site monitoring visits and ongoing source 
data verification to confirm that data entered into the eCRF by authorized site personnel are 
accurate, complete, and verifiable from source documents; that the safety and rights of patients 
are being protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements.  Instances of missing or uninterpretable data will be discussed with the investigator 
for resolution.  The review of medical records will be performed in a manner to ensure that 
patient confidentiality is maintained. 
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In accordance with ICH GCP guidelines, the investigator must ensure provision of sufficient 
time, reasonable space, and adequate qualified personnel and other support for study monitoring 
visits.  Moreover, regulatory authorities, IRBs, IECs, and/or the Sponsor’s Quality Assurance 
group may wish to carry out additional source data checks and/or on-site audit inspections.  The 
investigator must provide direct access to source data documents upon request during 
study-related monitoring visits, audits, IRB/IEC review, and regulatory agency inspections, 
provided that such visits, audits, reviews and inspections must be carried out giving due 
consideration to data protection and medical confidentiality.  In addition, investigator will ensure 
that the Sponsor and/or Sponsor’s designee will receive the necessary support to complete these 
activities. 
The Data Management Plan, to be developed during the initiation phase of the study, will include 
specifications for consistency and plausibility checks on data and will also include data-handling 
rules for obvious data errors.  All processes for data processing and query handling will be 
described in the Data Management Plan. 
Each study site will maintain a study file, which should contain, at minimum, the IB, the protocol 
and any amendments thereto, the protocol for tissue sampling, drug accountability records, any 
material correspondence with the IEC/IRB and the Sponsor (or its designee), and other 
study-related documents. 
The investigator agrees to keep records and those documents that include (but are not limited to) 
the identification of all participating patients, medical records, study-specific source documents, 
source worksheets, all original signed and dated ICFs, copies of all eCRFs, query responses, and 
detailed records of drug disposition to enable evaluations or audits from regulatory authorities 
and the Sponsor or its designees.  The investigator must maintain accurate documentation 
(source data) that supports the information entered in the CRF. 
The investigator shall retain records related to the study, including patient medical records, in 
accordance with the requirements set forth in the Clinical Trial Agreement. 
No data should be destroyed without the agreement of the Sponsor.  Should the investigator wish 
to assign the study records to another party or move them to another location, the Sponsor must 
be notified in writing of the new responsible person and/or the new location.  Patients’ medical 
records and other original data will be archived in accordance with the archiving regulations or 
facilities of the investigational site. 
10.7 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected.  Source documents are filed at the investigator’s site. 
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Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents, and any discrepancies must be explained.  The 
investigator may need to request a patient’s previous medical records or transfer records, 
depending on the study.  Also, each patient’s current medical records must be available. 
All participating centers should take particular care in ensuring that original imaging source data 
(CT images, MRI images, echo images, etc.) are maintained and accessible for monitoring, and 
that these original source data are then archived on a long-term basis in compliance with ICH 
GCP Section 8.  These images must be stored in a secure location until the Sponsor or Sponsor’s 
designee authorizes their destruction and must be retrievable by study patient number in the 
event of an audit. 
10.8 
Study and Site Closure 
The Sponsor may close the study site or terminate the study at any time for any reason at its sole 
discretion. 
The study may also be terminated if an investigator, Sponsor, or Sponsor’s designee becomes 
aware of conditions or events that suggest a possible hazard to patients if the study continues. 
Conditions that may warrant termination of the study site or the study include, but are not limited 
to: 
• 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 
• Discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in the 
study 
• Failure of a study site to enroll patients at an acceptable rate 
• Decision on the part of the Sponsor to suspend or discontinue development of the study 
intervention 
Study sites will be closed upon study completion.  A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed. 
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REFERENCES 
Agresti, A. and B. Coull (1998). "Approximate is Better than "Exact" for Interval Estimation of Binomial 
Proportions." The American Statistician 52(2): 119-126. 
Bai, S., K. Jorga, Y. Xin, et al. (2012). "A guide to rational dosing of monoclonal antibodies." Clin 
Pharmacokinet 51(2): 119-135. 
Bellmunt, J., R. de Wit, D. Vaughn, et al. (2017). "Pembrolizumab as Second-Line Therapy for Advanced 
Urothelial Carcinoma." The New England Journal of Medicine 376(11): 1015-1026. 
BMS (2011). "Australian Public Assessement Report for Ipilimumab." 
Cabo, M., R. Offringa, L. Zitvogel, et al. (2017). "Trial Watch: Immunostimulatory monoclonal 
antibodies for oncological indications." Oncolmmunology 6(12): 16. 
Chen, L. (2013). "Molecular Mechanisms of T Cell Co-Stimulation and Co-Inhibition." Nature Reviews 
Immunology 13: 227-242. 
Collins, A., D. Brodie, R. Gilbert, et al. (2002). "The Interaction Properties of Costimulatory Molecules 
Revisited " Immunity 17: 201-210. 
Duff, G. (2006). Expert Scientific Group on Phase One Clinical Trials : final report : 30th November 
2006. London, TSO. 
Eisenhauer, E. A., P. Bogaerts, L. H. Schwartz, et al. (2009). "New Response Evaluation Criteria in Solid 
Tumours: Revised RECIST Guideline (version 1.1)." European Journal of Cancer 45: 228-247. 
Ferris, R. L., G. Blumenschein Jr, J. Fayette, et al. (2016). "Nivolumab for Recurrent Squamous-Cell 
Carcinoma of the Head and Neck." The New England Journal of Medicine 375: 1856-1867. 
Greene, J., G. Leytze, J. Emswiler, et al. (1996). "Covalent Dimerization of CD28/CTLA-4 and 
Oligomerization of CD80/CD86 Regulate T Cell Costimulatory Interactions " The Journal of Biological 
Chemistry 271(43): 26762-26771. 
Haanen, J., F. Carbonnel, C. Robert, et al. (2018). "Management of Toxicities from immunotherapy: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up." Annals of Oncology 28(4): 
119-142. 
He, M., Y. Chai, J. Qi, et al. (2017). "Remarkably Similar CTLA-4 Binding Properties of Therapeutic 
Ipilimumab and Tremelimumab Antibodies." Impact Journals 8(40): 67129-67139. 
Hodi, F., S. O'Day, D. McDermott, et al. (2010). "Improved Survival with Ipilimumab in Patients with 
Metastatic Melanoma." The New England Journal of Medicine 363(8): 711-723. 
Kenter, M. and A. Cohen (2015). "The Return of the Prodigal Son and the Extraordinary Development 
Route of Antibody TGN1412-Lessons for Drug Development and Clinical Pharmacology." British 
Journal of Clinical Pharmacology 79(4): 545-547. 
KEYTRUDA (2018). "KEYTRUDA® (pembrolizumab) US Prescribing Information, 2019." 
Lee, D., R. Gardner, D. Porter, et al. (2014). "Current Concepts in the Diagnosis and Management of 
Cytokine Release Syndrome " Blood 124(2): 188-195. 
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Motzer, R., B. Escudier, M. F. McDermott, et al. (2015). "Nivolumab versus Everolimus in Advanced 
Renal-Cell Carcinoma." The New England Journal of Medicine 373(19): 1803-1813. 
Motzer, R. J., N. M. Tannir, D. McDermott, et al. (2018). "Nivolumab plus Ipilimumab versus Sunitinib 
in Advanced Renal-Cell Carcinoma." The New England Journal of Medicine 378(14): 1277-1290. 
OPDIVO (2018). "OPDIVO (nivolumab) US Prescribing Information 2019." 
Postow, M., M. Callahan and J. Wolchok (2015). "Immune Checkpoint Blockade in Cancer Therapy." 
Journal of Clinical Oncology 33(17): 1974-1982. 
Robert, C., J. Schachter, G. Long, et al. (2015). "Pembrolizumab versus Ipilimumab in Advanced 
Melanoma." The New England Journal of Medicine 372: 2521-2532. 
Saber, H., R. Gudi, M. Manning, et al. (2016). "An FDA Oncology Analysis of Immune Activating 
Products and First-In-Human Dose Selection." Regulatory Toxicology and Pharmacology 81: 448-456. 
Suntharalingam, G., M. Perry, S. Ward, et al. (2006). "Cytokine Storm in a Phase 1 Trial of the Anti-
CD28 Monoclonal Antibody TGN1412." The New England Journal of Medicine 355(10): 1018-1028. 
Wolchok, J., V. Chiarion-Sileni, R. Gonzalez, et al. (2017). "Overall Survival with Combined Nivolumab 
and Ipilimumab in Advanced Melanoma." The New England Journal of Medicine 377: 1345-1356. 
Yervoy ( 2019). "Highlights of Prescribing Information-Yervoy." 
 
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APPENDICES 
APPENDIX 1: 
PHASE 1A AND PHASE 1B CLINICAL LABORATORY TESTS 
• The laboratory parameters outlined in Table 13 will be determined in accordance with the 
Schedule of Assessments and assessed locally. 
• The results of each test must be entered into the eCRF. 
• Investigators must document their review of each laboratory safety report. 
• Protocol-specific requirements for inclusion or exclusion of patients are detailed in 
Section 5.0 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations. 
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Table 13: 
Protocol-Required Clinical Laboratory Assessments 
Hematology: CBC with differential: 
ANC 
ALC 
basophils (%) 
eosinophils (%) 
hemoglobin 
hematocrit 
 
lymphocytes (%) 
monocytes (%) 
neutrophils (%) 
platelets  
RBC 
WBC 
Clinical Chemistry*: 
Albumin 
alkaline phosphatase 
ALT (SGPT) 
AST (SGOT) 
BUN or Urea 
calcium 
chloride 
CO2 (bicarbonate) 
creatinine 
CRP 
direct bilirubin  
 
Glucose 
LDH 
magnesium 
phosphate 
potassium 
sodium 
total bilirubin 
total cholesterol 
total protein 
uric acid  
TSH 
Free T4 
ACTH 
Coagulation:  
INR, PT, PTT and APTT 
Urinalysis: 
Dipstick (appearance, color, pH, specific gravity, ketones, protein, glucose, bilirubin, nitrite, urobilinogen, and 
occult blood).  If dipstick is positive (2+ or greater) for blood or protein, perform a microscopic examination. 
At Screening Only:  
Serology for Hepatitis B (HBsAg), and Hepatitis C (HCV RNA) 
 
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Table 13: 
Protocol-Required Clinical Laboratory Assessments (Contd) 
Hematology: CBC with differential: 
ANC 
ALC 
basophils (%) 
eosinophils (%) 
hemoglobin 
hematocrit 
 
lymphocytes (%) 
monocytes (%) 
neutrophils (%) 
platelets  
RBC 
WBC 
NOTES:  
• 
If either AST or ALT is elevated, obtain total serum bilirubin and alkaline phosphatase; repeat daily or other 
interval, as clinically indicated, until resolved or stable 
• 
Additional tests to rule out drug-induced liver injury (eg, abdominal ultrasound, serum GGT, hepatitis 
serology) may be obtained at any time, if clinically indicated 
• 
For WOCBP, a serum pregnancy test will be performed at screening and pregnancy testing will be performed 
at each subsequent cycle of treatment prior to dosing.  Additional serum pregnancy testing may be performed if 
there is a concern with pregnancy, the patient missed a menstrual period, or did not follow the contraceptive 
guidance in Appendix 3. 
• 
Phase 1a: Additional labs may be performed locally as clinically indicated for patients in the first dose cohort 
that are hospitalized for the initial infusion or for any patients showing evidence of ≥ Grade 2 CRS 
• 
Phase 1b: Additional labs may be performed locally as clinically indicated 
• 
Samples for PK, PD, and ADA analyses should be submitted to the central laboratory as listed in Table 3 and 
Table 4.  Cytokines will be assessed at a central and/or specialty laboratory, however, may also be performed 
locally for assessment of CRS.   
• 
During dose escalation, a chemistry and hematology panel will be drawn on Day 2, 8 and 15 of Cycles 2 and 3. 
Abbreviations: ALC = absolute lymphocyte count; ALT = alanine transaminase; ANC = absolute neutrophil count; 
APTT = activated partial thromboplastin time; AST = aspartate transaminase; BUN = blood urea nitrogen; 
CBC = complete blood count; CO2 = carbon dioxide; CRP = c-reactive protein; GGT = gamma-glutamyltransferase; 
INR = international normalized ratio; HBsAG = hepatitis B surface antigen; HCV RNA = hepatitis C virus 
ribonucleic acid; LDH = lactate dehydrogenase; PT = prothrombin time; PTT = partial thromboplastin time; 
RBC = red blood cell; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic 
transaminase; WBC = white blood cell. 
 
 
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APPENDIX 2: 
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
1. 
Definition of AE 
AE Definition 
An AE is any untoward medical occurrence in a patient or clinical study patient, temporally associated with the 
use of study treatment, whether or not considered related to the study treatment. 
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 study treatment. 
 
Events Meeting the AE Definition  
Any abnormal 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, considered 
clinically significant in the medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or 
intensity of the condition. 
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 treatment or a concomitant 
medication. 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or SAE.  
Such instances will be captured in the efficacy assessments.  However, the signs, symptoms, and/or clinical 
sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE or 
SAE.  
 
Events NOT Meeting the AE Definition  
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the investigator to be more severe than expected for the 
patient’s condition. 
Abnormal laboratory findings that are judged by the investigator to be not clinically significant.   
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. 
 
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2. 
Definition of SAE 
A SAE is defined as any 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 patient was at risk of death 
at the time of the event as it occurred. 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 patient has been admitted for at least 24 hours 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.  Complications that occur during hospitalization are AEs.  If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
d. 
Results in persistent 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 (e.g., 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 
f. 
Other situations: 
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 patient 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, 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. 
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3. 
Recording an AE and/or SAE 
AE and SAE Recording 
The investigator will record all available relevant AE/SAE information in the CRF and send it to the sponsor or 
designee within 24 hours of becoming aware of the event. 
There may be instances when copies of medical records for certain cases are requested by the Sponsor.  In this 
case, all patient identifiers, with the exception of the patient number, will be redacted on the copies of the medical 
records before submission. 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical 
information.  Whenever possible, the diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE. 
Assessment of Intensity 
Investigators need to assess the severity of AEs according to the guidelines provided in NCI-CTCAE, 
version 4.03.  CTCAE v 4.03 Severity Grades are: 
Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated; mild AE 
Grade 2:  Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental 
activities of daily living; moderate AE 
Grade 3:  Severe or medically significant but non-immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care activities of daily living; severe AE 
Grade 4:  Life-threatening consequences; urgent intervention indicated 
Grade 5:  Fatal AE 
If the AE is not specified in the CTCAE or the study protocol, the grading of severity will be assessed as mild 
(Grade 1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4), or death due to the AE (Grade 5) 
using the following definitions: 
Mild: The patient is aware of the event or symptom, but the event or symptom is easily tolerated. 
Moderate: The patient experiences sufficient discomfort to interfere with or reduce his or her usual level of 
activity. 
Severe: Significant impairment of functioning: the patient is unable to carry out usual activities. 
Very severe (life-threatening): The patient’s life is at risk from the event. 
 
Assessment of Causality 
The investigator is should assess the relationship between study treatment and each occurrence of each AE/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 clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study treatment administration will be considered and investigated. 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, for marketed 
products, in his/her assessment. 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the AE/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, all SAE data should be sent to the Sponsor or designee within 
24 hours of becoming aware of the event and should include an assessment of causality for every event. 
The investigator may change his/her opinion of causality in light of follow-up information and send a SAE 
follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
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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. 
• 
If a patient dies during participation in the study or during a recognized follow-up period, the investigator 
will try to obtain the cause of death and autopsy report if they are available and provide it to the Sponsor.  
New or updated information will be recorded in the originally completed CRF. 
The investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of the information. 
4. 
Reporting of SAEs 
SAE Reporting to Sponsor/Designee via Paper CRF 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this information to the 
Sponsor/designee/medical monitor or the SAE coordinator. 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is acceptable with a 
copy of the SAE data collection tool sent by overnight mail or courier service. 
Initial notification via telephone does not replace the need for the investigator to complete and sign the SAE CRF 
pages within the designated reporting time frames. 
Contacts for SAE reporting:  
Novotech (Australia) Safety Department 
Fax number: +61 2 85690970 
Email: fiveprime.safety@novotech-cro.com 
 
 
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APPENDIX 3:  
CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION 
1. 
Definitions 
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 
• Premenarchal 
• Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
• Note:  Documentation can come from the site personnel’s: review of the patient’s 
medical records, medical examination, or medical history interview. 
• Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
• A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT).  However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required.  
• Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-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. 
2. 
Contraception Guidance: 
Male patients 
Male patients with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following during the study and for up to 100 days after last dose of FPT155. 
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent 
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• Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 14 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant 
Men 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 study and 
for up to 100 days after last dose of FPT155. 
Male patients must refrain from donating sperm for the duration of the study and for up to 
100 days after last dose of FPT155. 
Female patients 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 14. 
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Table 14:  
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly. a  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb  
Oral  
Intravaginal  
Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
Oral  
Injectable  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
Intrauterine device (IUD)c 
Intrauterine hormone-releasing system (IHS) c 
Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed.  If not, an additional highly effective 
method of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment.  The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the patient.  
NOTES:  
a Typical-use failure rates may differ from those when used consistently and correctly.  Use should be consistent 
with local regulations regarding the use of contraceptive methods for patients participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous.  In this case, 
alternative methods of contraception should be utilized. 
c IUDs and IHSs are acceptable methods of contraception in the absence of definitive drug interaction studies 
when hormone exposures from IUDs do not alter contraception effectiveness. 
3. 
Pregnancy Testing 
WOCBP should only be included after a confirmed negative, highly sensitive serum pregnancy 
test. 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is 
otherwise suspected and at the times specified in the protocol. 
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4. 
Collection of Pregnancy Information  
Male patients with partners who become pregnant 
• The investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this study. 
• 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.  This 
information will reside in the site’s source documents and will be submitted to the sponsor as 
indicated but will not be captured within the clinical database.  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. 
Female Patients who become pregnant  
• The investigator will collect pregnancy information on any female patient 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 patient's pregnancy.  
• The patient will be followed to determine the outcome of the pregnancy.  The investigator 
will collect follow-up information on the patient 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 treatment by the 
investigator will be reported to the sponsor as described in Appendix 2.  While the 
investigator is not obligated to actively seek this information in former study patients, he or 
she may learn of an SAE through spontaneous reporting.  
• Any female patient who becomes pregnant while participating in the study will discontinue 
study treatment or be withdrawn from the study  
 
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APPENDIX 4:  
GENETICS 
Use/Analysis of DNA 
• Genetic variation (eg, mutations) in the tumor may impact a patient’s tumor response to 
study intervention, and these mutations might determine severity and progression of disease.  
To determine tumor genetic variations, comparison to the normal genome to the patient is 
necessary to computationally be able to identify tumor specific genetic alterations.  
Therefore, tumor and blood samples that will be collected for pharmacodynamic analysis 
such as immune phenotyping might be used to isolate tumor and normal DNA. 
• DNA samples might be used for research related to tumor mutation analysis and correlates of 
efficacy or safety. 
• The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
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APPENDIX 5:  
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
Grade 
Eastern Cooperative Oncology Group (ECOG) Performance Status Criteria 
0 
Fully active, able to carry on all pre-disease activities without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
sedentary nature (light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
 
 
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APPENDIX 6:  
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
VERSION 1.1
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New response evaluation criteria in solid tumours:
Revised RECIST guideline (version 1.1)
E.A. Eisenhauera,*, P. Therasseb, J. Bogaertsc, L.H. Schwartzd, D. Sargente, R. Fordf,
J. Danceyg, S. Arbuckh, S. Gwytheri, M. Mooneyg, L. Rubinsteing, L. Shankarg, L. Doddg,
R. Kaplanj, D. Lacombec, J. Verweijk
aNational Cancer Institute of Canada – Clinical Trials Group, 10 Stuart Street, Queen’s University, Kingston, ON, Canada
bGlaxoSmithKline Biologicals, Rixensart, Belgium
cEuropean Organisation for Research and Treatment of Cancer, Data Centre, Brussels, Belgium
dMemorial Sloan Kettering Cancer Center, New York, NY, USA
eMayo Clinic, Rochester, MN, USA
fRadPharm, Princeton, NJ, USA
gDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
hSchering-Plough, Kenilworth, NJ, USA
iEast Surrey Hospital, Redhill, Surrey, UK
jNational Cancer Research Network, Leeds, UK
kErasmus University Medical Center, Rotterdam, The Netherlands
A R T I C L E
I N F O
Article history:
Received 17 October 2008
Accepted 29 October 2008
Keywords:
Response criteria
Solid tumours
Guidelines
A B S T R A C T
Background: Assessment of the change in tumour burden is an important feature of the
clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response)
and disease progression are useful endpoints in clinical trials. Since RECIST was published
in 2000, many investigators, cooperative groups, industry and government authorities have
adopted these criteria in the assessment of treatment outcomes. However, a number of
questions and issues have arisen which have led to the development of a revised RECIST
guideline (version 1.1). Evidence for changes, summarised in separate papers in this special
issue, has come from assessment of a large data warehouse (>6500 patients), simulation
studies and literature reviews.
Highlights of revised RECIST 1.1: Major changes include: Number of lesions to be assessed: based
on evidence from numerous trial databases merged into a data warehouse for analysis pur-
poses, the number of lesions required to assess tumour burden for response determination
has been reduced from a maximum of 10 to a maximum of ﬁve total (and from ﬁve to two
per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes
with a short axis of P15 mm are considered measurable and assessable as target lesions.
The short axis measurement should be included in the sum of lesions in calculation of
tumour response. Nodes that shrink to <10 mm short axis are considered normal. Conﬁrma-
tion of response is required for trials with response primary endpoint but is no longer
required in randomised studies since the control arm serves as appropriate means of inter-
pretation of data. Disease progression is clariﬁed in several aspects: in addition to the previ-
ous deﬁnition of progression in target disease of 20% increase in sum, a 5 mm absolute
increase is now required as well to guard against over calling PD when the total sum is very
0959-8049/$ - see front matter  2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejca.2008.10.026
* Corresponding author: Tel.: +1 613 533 6430; fax: +1 613 533 2411.
E-mail address: eeisenhauer@ctg.queensu.ca (E.A. Eisenhauer).
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journal homepage: www.ejconline.com
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small. Furthermore, there is guidance offered on what constitutes ‘unequivocal progres-
sion’ of non-measurable/non-target disease, a source of confusion in the original RECIST
guideline. Finally, a section on detection of new lesions, including the interpretation of
FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a
new imaging appendix with updated recommendations on the optimal anatomical assess-
ment of lesions.
Future work: A key question considered by the RECIST Working Group in developing RECIST
1.1 was whether it was appropriate to move from anatomic unidimensional assessment of
tumour burden to either volumetric anatomical assessment or to functional assessment
with PET or MRI. It was concluded that, at present, there is not sufﬁcient standardisation
or evidence to abandon anatomical assessment of tumour burden. The only exception to
this is in the use of FDG-PET imaging as an adjunct to determination of progression. As
is detailed in the ﬁnal paper in this special issue, the use of these promising newer
approaches requires appropriate clinical validation studies.
 2008 Elsevier Ltd. All rights reserved.
1.
Background
1.1.
History of RECIST criteria
Assessment of the change in tumour burden is an important
feature of the clinical evaluation of cancer therapeutics. Both
tumour shrinkage (objective response) and time to the devel-
opment of disease progression are important endpoints in
cancer clinical trials. The use of tumour regression as the
endpoint for phase II trials screening new agents for evi-
dence of anti-tumour effect is supported by years of evi-
dence suggesting that, for many solid tumours, agents
which produce tumour shrinkage in a proportion of patients
have a reasonable (albeit imperfect) chance of subsequently
demonstrating an improvement in overall survival or other
time to event measures in randomised phase III studies (re-
viewed in [1–4]). At the current time objective response car-
ries with it a body of evidence greater than for any other
biomarker supporting its utility as a measure of promising
treatment effect in phase II screening trials. Furthermore,
at both the phase II and phase III stage of drug development,
clinical trials in advanced disease settings are increasingly
utilising time to progression (or progression-free survival)
as an endpoint upon which efﬁcacy conclusions are drawn,
which is also based on anatomical measurement of tumour
size.
However, both of these tumour endpoints, objective re-
sponse and time to disease progression, are useful only if
based on widely accepted and readily applied standard crite-
ria based on anatomical tumour burden. In 1981 the World
Health Organisation (WHO) ﬁrst published tumour response
criteria, mainly for use in trials where tumour response was
the primary endpoint. The WHO criteria introduced the con-
cept of an overall assessment of tumour burden by summing
the products of bidimensional lesion measurements and
determined response to therapy by evaluation of change from
baseline while on treatment.5 However, in the decades that
followed their publication, cooperative groups and pharma-
ceutical companies that used the WHO criteria often ‘modi-
ﬁed’ them to accommodate new technologies or to address
areas that were unclear in the original document. This led
to confusion in interpretation of trial results6 and in fact,
the application of varying response criteria was shown to lead
to very different conclusions about the efﬁcacy of the same
regimen.7 In response to these problems, an International
Working Party was formed in the mid 1990s to standardise
and simplify response criteria. New criteria, known as RECIST
(Response Evaluation Criteria in Solid Tumours), were pub-
lished in 2000.8 Key features of the original RECIST include
deﬁnitions of minimum size of measurable lesions, instruc-
tions on how many lesions to follow (up to 10; a maximum
ﬁve per organ site), and the use of unidimensional, rather
than bidimensional, measures for overall evaluation of tu-
mour burden. These criteria have subsequently been widely
adopted by academic institutions, cooperative groups, and
industry for trials where the primary endpoints are objective
response or progression. In addition, regulatory authorities
accept
RECIST
as
an
appropriate
guideline
for
these
assessments.
1.2.
Why update RECIST?
Since RECIST was published in 2000, many investigators have
conﬁrmed in prospective analyses the validity of substituting
unidimensional for bidimensional (and even three-dimen-
sional)-based criteria (reviewed in [9]). With rare exceptions
(e.g. mesothelioma), the use of unidimensional criteria seems
to perform well in solid tumour phase II studies.
However, a number of questions and issues have arisen
which merit answers and further clarity. Amongst these
are whether fewer than 10 lesions can be assessed without
affecting the overall assigned response for patients (or the
conclusion about activity in trials); how to apply RECIST in
randomised phase III trials where progression, not response,
is the primary endpoint particularly if not all patients have
measurable disease; whether or how to utilise newer imag-
ing technologies such as FDG-PET and MRI; how to handle
assessment of lymph nodes; whether response conﬁrmation
is truly needed; and, not least, the applicability of RECIST in
trials of targeted non-cytotoxic drugs. This revision of the
RECIST guidelines includes updates that touch on all these
points.
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1.3.
Process of RECIST 1.1 development
The RECIST Working Group, consisting of clinicians with
expertise in early drug development from academic research
organisations, government and industry, together with imag-
ing specialists and statisticians, has met regularly to set the
agenda for an update to RECIST, determine the evidence
needed to justify the various changes made, and to review
emerging evidence. A critical aspect of the revision process
was to create a database of prospectively documented solid
tumour measurement data obtained from industry and aca-
demic group trials. This database, assembled at the EORTC
Data Centre under the leadership of Jan Bogaerts and Patrick
Therasse (co-authors of this guideline), consists of >6500 pa-
tients with >18,000 target lesions and was utilised to investi-
gate the impact of a variety of questions (e.g. number of
target lesions required, the need for response conﬁrmation,
and lymph node measurement rules) on response and pro-
gression-free survival outcomes. The results of this work,
which after evaluation by the RECIST Working Group led to
most of the changes in this revised guideline, are reported
in detail in a separate paper in this special issue.10 Larry Sch-
wartz and Robert Ford (also co-authors of this guideline) also
provided key databases from which inferences have been
made that inform these revisions.11
The publication of this revised guideline is believed to be
timely since it incorporates changes to simplify, optimise
and standardise the assessment of tumour burden in clinical
trials. A summary of key changes is found in Appendix I. Be-
cause the fundamental approach to assessment remains
grounded in the anatomical, rather than functional, assess-
ment of disease, we have elected to name this version RECIST
1.1, rather than 2.0.
1.4.
What about volumetric or functional assessment?
This raises the question, frequently posed, about whether it is
‘time’ to move from anatomic unidimensional assessment of
tumour burden to either volumetric anatomical assessment
or to functional assessment (e.g. dynamic contrast enhanced
MRI or CT or (18)F-ﬂuorodeoxyglucose positron emission
tomographic (FDG-PET) techniques assessing tumour metab-
olism). As can be seen, the Working Group and particularly
those involved in imaging research, did not believe that there
is at present sufﬁcient standardisation and widespread avail-
ability to recommend adoption of these alternative assess-
ment methods. The only exception to this is in the use of
FDG-PET imaging as an adjunct to determination of progres-
sion, as described later in this guideline. As detailed in paper
in this special issue12, we believe that the use of these prom-
ising newer approaches (which could either add to or substitute
for anatomical assessment as described in RECIST) requires
appropriate and rigorous clinical validation studies. This pa-
per by Sargent et al. illustrates the type of data that will be
needed to be able to deﬁne ‘endpoints’ for these modalities
and how to determine where and when such criteria/modal-
ities can be used to improve the reliability with which truly
active new agents are identiﬁed and truly inactive new agents
are discarded in comparison to RECIST criteria in phase II
screening trials. The RECIST Working Group looks forward
to such data emerging in the next few years to allow the
appropriate changes to the next iteration of the RECIST
criteria.
2.
Purpose of this guideline
This guideline describes a standard approach to solid tumour
measurement and deﬁnitions for objective assessment of
change in tumour size for use in adult and paediatric cancer
clinical trials. It is expected these criteria will be useful in all
trials where objective response is the primary study endpoint,
as well as in trials where assessment of stable disease, tu-
mour progression or time to progression analyses are under-
taken, since all of these outcome measures are based on an
assessment of anatomical tumour burden and its change on
study. There are no assumptions in this paper about the pro-
portion of patients meeting the criteria for any of these end-
points which will signal that an agent or treatment regimen is
active: those deﬁnitions are dependent on type of cancer in
which a trial is being undertaken and the speciﬁc agent(s) un-
der study. Protocols must include appropriate statistical sec-
tions which deﬁne the efﬁcacy parameters upon which the
trial sample size and decision criteria are based. In addition
to providing deﬁnitions and criteria for assessment of tumour
response,
this
guideline
also
makes
recommendations
regarding standard reporting of the results of trials that utilise
tumour response as an endpoint.
While these guidelines may be applied in malignant brain
tumour studies, there are also separate criteria published for
response assessment in that setting.13 This guideline is not in-
tended for use for studies of malignant lymphoma since
international guidelines for response assessment in lym-
phoma are published separately.14
Finally, many oncologists in their daily clinical practice fol-
low their patients’ malignant disease by means of repeated
imaging studies and make decisions about continued therapy
on the basis of both objective and symptomatic criteria. It is
not intended that these RECIST guidelines play a role in that
decision making, except if determined appropriate by the
treating oncologist.
3.
Measurability of tumour at baseline
3.1.
Deﬁnitions
At baseline, tumour lesions/lymph nodes will be categorised
measurable or non-measurable as follows:
3.1.1.
Measurable
Tumour lesions: Must be accurately measured in at least one
dimension (longest diameter in the plane of measurement is
to be recorded) with a minimum size of:
• 10 mm by CT scan (CT scan slice thickness no greater than
5 mm; see Appendix II on imaging guidance).
• 10 mm caliper measurement by clinical exam (lesions
which cannot be accurately measured with calipers should
be recorded as non-measurable).
• 20 mm by chest X-ray.
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Malignant lymph nodes: To be considered pathologically en-
larged and measurable, a lymph node must be P15 mm in
short axis when assessed by CT scan (CT scan slice thickness
recommended to be no greater than 5 mm). At baseline and in
follow-up, only the short axis will be measured and followed
(see Schwartz et al. in this Special Issue15). See also notes be-
low on ‘Baseline documentation of target and non-target le-
sions’ for information on lymph node measurement.
3.1.2.
Non-measurable
All other lesions, including small lesions (longest diameter
<10 mm or pathological lymph nodes with P10 to <15 mm
short axis) as well as truly non-measurable lesions. Lesions
considered truly non-measurable include: leptomeningeal dis-
ease, ascites, pleural or pericardial effusion, inﬂammatory
breast disease, lymphangitic involvement of skin or lung,
abdominal masses/abdominal organomegaly identiﬁed by
physical exam that is not measurable by reproducible imaging
techniques.
3.1.3.
Special considerations regarding lesion measurability
Bone lesions, cystic lesions, and lesions previously treated
with local therapy require particular comment:
Bone lesions:.
• Bone scan, PET scan or plain ﬁlms are not considered ade-
quate imaging techniques to measure bone lesions. How-
ever,
these
techniques
can
be
used
to
conﬁrm
the
presence or disappearance of bone lesions.
• Lytic bone lesions or mixed lytic-blastic lesions, with identi-
ﬁable soft tissue components, that can be evaluated by cross
sectional imaging techniques such as CT or MRI can be con-
sidered as measurable lesions if the soft tissue component
meets the deﬁnition of measurability described above.
• Blastic bone lesions are non-measurable.
Cystic lesions:.
• Lesions that meet the criteria for radiographically deﬁned
simple cysts should not be considered as malignant lesions
(neither measurable nor non-measurable) since they are, by
deﬁnition, simple cysts.
• ‘Cystic lesions’ thought to represent cystic metastases can
be considered as measurable lesions, if they meet the deﬁ-
nition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are pre-
ferred for selection as target lesions.
Lesions with prior local treatment:.
• Tumour lesions situated in a previously irradiated area, or
in an area subjected to other loco-regional therapy, are usu-
ally not considered measurable unless there has been dem-
onstrated progression in the lesion. Study protocols should
detail the conditions under which such lesions would be
considered measurable.
3.2.
Speciﬁcations by methods of measurements
3.2.1.
Measurement of lesions
All measurements should be recorded in metric notation,
using calipers if clinically assessed. All baseline evaluations
should be performed as close as possible to the treatment
start and never more than 4 weeks before the beginning of
the treatment.
3.2.2.
Method of assessment
The same method of assessment and the same technique
should be used to characterise each identiﬁed and reported
lesion at baseline and during follow-up. Imaging based evalu-
ation should always be done rather than clinical examination
unless the lesion(s) being followed cannot be imaged but are
assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered mea-
surable when they are superﬁcial and P10 mm diameter as
assessed using calipers (e.g. skin nodules). For the case of skin
lesions, documentation by colour photography including a ru-
ler to estimate the size of the lesion is suggested. As noted
above, when lesions can be evaluated by both clinical exam
and imaging, imaging evaluation should be undertaken since
it is more objective and may also be reviewed at the end of the
study.
Chest X-ray: Chest CT is preferred over chest X-ray, particu-
larly when progression is an important endpoint, since CT is
more sensitive than X-ray, particularly in identifying new le-
sions. However, lesions on chest X-ray may be considered
measurable if they are clearly deﬁned and surrounded by aer-
ated lung. See Appendix II for more details.
CT, MRI: CT is the best currently available and reproducible
method to measure lesions selected for response assessment.
This guideline has deﬁned measurability of lesions on CT
scan based on the assumption that CT slice thickness is
5 mm or less. As is described in Appendix II, when CT scans
have slice thickness greater than 5 mm, the minimum size
for a measurable lesion should be twice the slice thickness.
MRI is also acceptable in certain situations (e.g. for body
scans). More details concerning the use of both CT and MRI
for assessment of objective tumour response evaluation are
provided in Appendix II.
Ultrasound: Ultrasound is not useful in assessment of lesion
size and should not be used as a method of measurement.
Ultrasound examinations cannot be reproduced in their en-
tirety for independent review at a later date and, because
they are operator dependent, it cannot be guaranteed that
the same technique and measurements will be taken from
one assessment to the next (described in greater detail in
Appendix II). If new lesions are identiﬁed by ultrasound in
the course of the study, conﬁrmation by CT or MRI is ad-
vised. If there is concern about radiation exposure at CT,
MRI may be used instead of CT in selected instances.
Endoscopy, laparoscopy: The utilisation of these techniques for
objective tumour evaluation is not advised. However, they
can be useful to conﬁrm complete pathological response
when biopsies are obtained or to determine relapse in trials
where recurrence following complete response or surgical
resection is an endpoint.
Tumour markers: Tumour markers alone cannot be used to as-
sess objective tumour response. If markers are initially above
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the upper normal limit, however, they must normalise for a
patient to be considered in complete response. Because
tumour markers are disease speciﬁc, instructions for their
measurement should be incorporated into protocols on a
disease speciﬁc basis. Speciﬁc guidelines for both CA-125
response (in recurrent ovarian cancer) and PSA response (in
recurrent prostate cancer), have been published.16–18 In addi-
tion, the Gynecologic Cancer Intergroup has developed CA125
progression criteria which are to be integrated with objective
tumour assessment for use in ﬁrst-line trials in ovarian
cancer.19
Cytology, histology: These techniques can be used to differenti-
ate between PR and CR in rare cases if required by protocol
(for example, residual lesions in tumour types such as germ
cell tumours, where known residual benign tumours can re-
main). When effusions are known to be a potential adverse
effect of treatment (e.g. with certain taxane compounds or
angiogenesis inhibitors), the cytological conﬁrmation of the
neoplastic origin of any effusion that appears or worsens dur-
ing treatment can be considered if the measurable tumour
has met criteria for response or stable disease in order to dif-
ferentiate between response (or stable disease) and progres-
sive disease.
4.
Tumour response evaluation
4.1.
Assessment of overall tumour burden and
measurable disease
To assess objective response or future progression, it is nec-
essary to estimate the overall tumour burden at baseline and
use this as a comparator for subsequent measurements.
Only patients with measurable disease at baseline should
be included in protocols where objective tumour response
is the primary endpoint. Measurable disease is deﬁned by
the presence of at least one measurable lesion (as detailed
above in Section 3). In studies where the primary endpoint
is tumour progression (either time to progression or propor-
tion with progression at a ﬁxed date), the protocol must
specify if entry is restricted to those with measurable disease
or whether patients having non-measurable disease only are
also eligible.
4.2.
Baseline documentation of ‘target’ and ‘non-target’
lesions
When more than one measurable lesion is present at baseline
all lesions up to a maximum of ﬁve lesions total (and a max-
imum of two lesions per organ) representative of all involved
organs should be identiﬁed as target lesions and will be re-
corded and measured at baseline (this means in instances
where patients have only one or two organ sites involved a
maximum of two and four lesions respectively will be re-
corded). For evidence to support the selection of only ﬁve tar-
get lesions, see analyses on a large prospective database in
the article by Bogaerts et al.10.
Target lesions should be selected on the basis of their size
(lesions with the longest diameter), be representative of all in-
volved organs, but in addition should be those that lend
themselves to reproducible repeated measurements. It may be
the case that, on occasion, the largest lesion does not lend it-
self to reproducible measurement in which circumstance the
next largest lesion which can be measured reproducibly
should be selected. To illustrate this point see the example
in Fig. 3 of Appendix II.
Lymph nodes merit special mention since they are normal
anatomical structures which may be visible by imaging even
if not involved by tumour. As noted in Section 3, pathological
nodes which are deﬁned as measurable and may be identi-
ﬁed as target lesions must meet the criterion of a short axis
of P15 mm by CT scan. Only the short axis of these nodes
will contribute to the baseline sum. The short axis of the
node is the diameter normally used by radiologists to judge
if a node is involved by solid tumour. Nodal size is normally
reported as two dimensions in the plane in which the image
is obtained (for CT scan this is almost always the axial plane;
for MRI the plane of acquisition may be axial, saggital or
coronal). The smaller of these measures is the short axis.
For example, an abdominal node which is reported as being
20 mm · 30 mm has a short axis of 20 mm and qualiﬁes as a
malignant, measurable node. In this example, 20 mm should
be recorded as the node measurement (See also the example
in Fig. 4 in Appendix II). All other pathological nodes (those
with short axis P10 mm but <15 mm) should be considered
non-target lesions. Nodes that have a short axis <10 mm
are considered non-pathological and should not be recorded
or followed.
A sum of the diameters (longest for non-nodal lesions, short
axis for nodal lesions) for all target lesions will be calculated
and reported as the baseline sum diameters. If lymph nodes
are to be included in the sum, then as noted above, only the
short axis is added into the sum. The baseline sum diameters
will be used as reference to further characterise any objective
tumour regression in the measurable dimension of the
disease.
All other lesions (or sites of disease) including pathological
lymph nodes should be identiﬁed as non-target lesions and
should also be recorded at baseline. Measurements are not re-
quired and these lesions should be followed as ‘present’, ‘ab-
sent’, or in rare cases ‘unequivocal progression’ (more details
to follow). In addition, it is possible to record multiple non-
target lesions involving the same organ as a single item on
the case record form (e.g. ‘multiple enlarged pelvic lymph
nodes’ or ‘multiple liver metastases’).
4.3.
Response criteria
This section provides the deﬁnitions of the criteria used to
determine objective tumour response for target lesions.
4.3.1.
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions.
Any pathological lymph nodes (whether target or
non-target) must have reduction in short axis to
<10 mm.
Partial Response (PR): At least a 30% decrease in the sum of
diameters of target lesions, taking as reference the
baseline sum diameters.
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Progressive Disease (PD): At least a 20% increase in the sum
of diameters of target lesions, taking as reference
the smallest sum on study (this includes the baseline
sum if that is the smallest on study). In addition to
the relative increase of 20%, the sum must also dem-
onstrate an absolute increase of at least 5 mm. (Note:
the appearance of one or more new lesions is also
considered progression).
Stable Disease (SD): Neither sufﬁcient shrinkage to qualify for
PR nor sufﬁcient increase to qualify for PD, taking as
reference the smallest sum diameters while on study.
4.3.2.
Special notes on the assessment of target lesions
Lymph nodes. Lymph nodes identiﬁed as target lesions should
always have the actual short axis measurement recorded (mea-
sured in the same anatomical plane as the baseline examina-
tion), even if the nodes regress to below 10 mm on study. This
means that when lymph nodes are included as target lesions,
the ‘sum’ of lesions may not be zero even if complete response
criteria are met, since a normal lymph node is deﬁned as having
a short axis of <10 mm. Case report forms or other data collec-
tion methods may therefore be designed to have target nodal le-
sions recorded in a separate section where, in order to qualify
for CR, each node must achieve a short axis <10 mm. For PR,
SD and PD, the actual short axis measurement of the nodes is
to be included in the sum of target lesions.
Target lesions that become ‘too small to measure’. While on
study, all lesions (nodal and non-nodal) recorded at baseline
should have their actual measurements recorded at each sub-
sequent evaluation, even when very small (e.g. 2 mm). How-
ever, sometimes lesions or lymph nodes which are recorded
as target lesions at baseline become so faint on CT scan that
the radiologist may not feel comfortable assigning an exact
measure and may report them as being ‘too small to measure’.
When this occurs it is important that a value be recorded on
the case report form. If it is the opinion of the radiologist that
the lesion has likely disappeared, the measurement should be
recorded as 0 mm. If the lesion is believed to be present and is
faintly seen but too small to measure, a default value of 5 mm
should be assigned (Note: It is less likely that this rule will be
used for lymph nodes since they usually have a deﬁnable size
when normal and are frequently surrounded by fat such as in
the retroperitoneum; however, if a lymph node is believed to
be present and is faintly seen but too small to measure, a de-
fault value of 5 mm should be assigned in this circumstance as
well). This default value is derived from the 5 mm CT slice
thickness (but should not be changed with varying CT slice
thickness). The measurement of these lesions is potentially
non-reproducible, therefore providing this default value will
prevent false responses or progressions based upon measure-
ment error. To reiterate, however, if the radiologist is able to
provide an actual measure, that should be recorded, even if
it is below 5 mm.
Lesions that split or coalesce on treatment. As noted in Appen-
dix II, when non-nodal lesions ‘fragment’, the longest diame-
ters of the fragmented portions should be added together to
calculate the target lesion sum. Similarly, as lesions coalesce,
a plane between them may be maintained that would aid in
obtaining maximal diameter measurements of each individ-
ual lesion. If the lesions have truly coalesced such that they
are no longer separable, the vector of the longest diameter
in this instance should be the maximal longest diameter for
the ‘coalesced lesion’.
4.3.3.
Evaluation of non-target lesions
Thissection provides the deﬁnitionsofthe criteriausedtodeter-
mine the tumour response for the group of non-target lesions.
While some non-target lesions may actually be measurable,
they need not be measured and instead should be assessed only
qualitatively at the time points speciﬁed in the protocol.
Complete Response (CR): Disappearance of all non-target le-
sions and normalisation of tumour marker level. All
lymph nodes must be non-pathological in size
(<10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target le-
sion(s) and/or maintenance of tumour marker level
above the normal limits.
Progressive Disease (PD): Unequivocal progression (see com-
ments below) of existing non-target lesions. (Note:
the appearance of one or more new lesions is also
considered progression).
4.3.4.
Special notes on assessment of progression of non-
target disease
The concept of progression of non-target disease requires
additional explanation as follows:
When the patient also has measurable disease. In this setting,
to achieve ‘unequivocal progression’ on the basis of the
non-target disease, there must be an overall level of substan-
tial worsening in non-target disease such that, even in pres-
ence of SD or PR in target disease, the overall tumour
burden has increased sufﬁciently to merit discontinuation
of therapy (see examples in Appendix II and further details
below). A modest ‘increase’ in the size of one or more non-tar-
get lesions is usually not sufﬁcient to quality for unequivocal
progression status. The designation of overall progression so-
lely on the basis of change in non-target disease in the face of
SD or PR of target disease will therefore be extremely rare.
When the patient has only non-measurable disease.This circum-
stance arises in some phase III trials when it is not a criterion of
study entry to have measurable disease. The same general con-
cepts apply here as noted above, however, in this instance there
is no measurable disease assessment to factor into the inter-
pretation of an increase in non-measurable disease burden.
Because worsening in non-target disease cannot be easily
quantiﬁed (by deﬁnition: if all lesions are truly non-measur-
able) a useful test that can be applied when assessing patients
for unequivocal progression is to consider if the increase in
overall disease burden based on the change in non-measurable
disease is comparable in magnitude to the increase that would
berequiredtodeclarePDformeasurabledisease: i.e.anincrease
in tumour burden representing an additional 73% increase in
‘volume’ (which is equivalent to a 20% increase diameter in a
measurable lesion). Examples include an increase in a pleural
effusion from ‘trace’ to ‘large’, an increase in lymphangitic
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disease from localised to widespread, or may be described in
protocols as ‘sufﬁcient to require a change in therapy’. Some
illustrative examples are shown in Figs. 5 and 6 in Appendix II.
If ‘unequivocal progression’ is seen, the patient should be con-
sidered to have had overall PD at that point. While it would be
ideal to have objective criteria to apply to non-measurable dis-
ease, the very nature of that disease makes it impossible to do
so, therefore the increase must be substantial.
4.3.5.
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 ﬁnd-
ing of a new lesion should be unequivocal: i.e. not attributable
to differences in scanning technique, change in imaging
modality or ﬁndings thought to represent something other
than tumour (for example, some ‘new’ bone lesions may be
simply healing or ﬂare of pre-existing lesions). This is partic-
ularly important when the patient’s baseline lesions show
partial or complete response. For example, necrosis of a liver
lesion may be reported on a CT scan report as a ‘new’ cystic
lesion, which it is not.
A lesion identiﬁed on a follow-up study in an anatomical
location that was not scanned at baseline is considered a new
lesion andwill indicate diseaseprogression. An example of this
is the patient who has visceral disease at baseline and while on
study has a CTor MRI brain ordered which reveals metastases.
The patient’s brain metastases are considered to be evidence of
PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its
small size, continued therapy and follow-up evaluation will
clarify if it represents truly new disease. If repeat scans con-
ﬁrm there is deﬁnitely a new lesion, then progression should
be declared using the date of the initial scan.
While FDG-PET response assessments need additional
study, it is sometimes reasonable to incorporate the use of
FDG-PET scanning to complement CT scanning in assessment
of progression (particularly possible ‘new’ disease). New le-
sions on the basis of FDG-PET imaging can be identiﬁed
according to the following algorithm:
a. Negative FDG-PET at baseline, with a positivel FDG-PET
at follow-up is a sign of PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at fol-
low-up:
If the positive FDG-PET at follow-up corresponds to a
new site of disease conﬁrmed by CT, this is PD.
If the positive FDG-PET at follow-up is not conﬁrmed as
a new site of disease on CT, additional follow-up CT
scans are needed to determine if there is truly progres-
sion occurring at that site (if so, the date of PD will be
the date of the initial abnormal FDG-PET scan).
If the positive FDG-PET at follow-up corresponds to a
pre-existing site of disease on CT that is not progress-
ing on the basis of the anatomic images, this is not PD.
4.4.
Evaluation of best overall response
The best overall response is the best response recorded from
the start of the study treatment until the end of treatment
taking into account any requirement for conﬁrmation. On oc-
casion a response may not be documented until after the end
of therapy so protocols should be clear if post-treatment
assessments are to be considered in determination of best
overall response. Protocols must specify how any new therapy
introduced before progression will affect best response desig-
nation. The patient’s best overall response assignment will
depend on the ﬁndings of both target and non-target disease
and will also take into consideration the appearance of new
lesions. Furthermore, depending on the nature of the study
and the protocol requirements, it may also require conﬁrma-
tory measurement (see Section 4.6). Speciﬁcally, in non-ran-
domised trials where response is the primary endpoint,
conﬁrmation of PR or CR is needed to deem either one the
‘best overall response’. This is described further below.
4.4.1.
Time point response
It is assumed that at each protocol speciﬁed time point, a re-
sponse assessment occurs. Table 1 on the next page provides
a summary of the overall response status calculation at each
time point for patients who have measurable disease at
baseline.
When patients have non-measurable (therefore non-tar-
get) disease only, Table 2 is to be used.
4.4.2.
Missing assessments and inevaluable designation
When no imaging/measurement is done at all at a particular
time point, the patient is not evaluable (NE) at that time point.
If only a subset of lesion measurements are made at an
assessment, usually the case is also considered NE at that
time point, unless a convincing argument can be made that
the contribution of the individual missing lesion(s) would
not change the assigned time point response. This would be
most likely to happen in the case of PD. For example, if a pa-
tient had a baseline sum of 50 mm with three measured le-
sions and at follow-up only two lesions were assessed, but
those gave a sum of 80 mm, the patient will have achieved
PD status, regardless of the contribution of the missing lesion.
4.4.3.
Best overall response: all time points
The best overall response is determined once all the data for the
patient is known.
Best response determination in trials where conﬁrmation of com-
plete or partial response IS NOT required: Best response in these
trials is deﬁned as the best response across all time points (for
example, a patient who has SD at ﬁrst assessment, PR at sec-
ond assessment, and PD on last assessment has a best overall
response of PR). When SD is believed to be best response, it
must also meet the protocol speciﬁed minimum time from
baseline. If the minimum time is not met when SD is other-
wise the best time point response, the patient’s best response
depends on the subsequent assessments. For example, a pa-
tient who has SD at ﬁrst assessment, PD at second and does
not meet minimum duration for SD, will have a best response
of PD. The same patient lost to follow-up after the ﬁrst SD
assessment would be considered inevaluable.
l A ‘positive’ FDG-PET scan lesion means one which is FDG avid
with an uptake greater than twice that of the surrounding tissue
on the attenuation corrected image.
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Best response determination in trials where conﬁrmation of com-
plete or partial response IS required: Complete or partial re-
sponses may be claimed only if the criteria for each are met
at a subsequent time point as speciﬁed in the protocol (gener-
ally 4 weeks later). In this circumstance, the best overall re-
sponse can be interpreted as in Table 3.
4.4.4.
Special notes on response assessment
When nodal disease is included in the sum of target lesions
and the nodes decrease to ‘normal’ size (<10 mm), they may
still have a measurement reported on scans. This measure-
ment should be recorded even though the nodes are normal
in order not to overstate progression should it be based on
increase in size of the nodes. As noted earlier, this means that
patients with CR may not have a total sum of ‘zero’ on the
case report form (CRF).
In trials where conﬁrmation of response is required, re-
peated ‘NE’ time point assessments may complicate best re-
sponse determination. The analysis plan for the trial must
address how missing data/assessments will be addressed in
determination of response and progression. For example, in
most trials it is reasonable to consider a patient with time
point responses of PR-NE-PR as a conﬁrmed response.
Patients with a global deterioration of health status requir-
ing discontinuation of treatment without objective evidence
of disease progression at that time should be reported as
‘symptomatic deterioration’. Every effort should be made to
document objective progression even after discontinuation
of treatment. Symptomatic deterioration is not a descriptor
of an objective response: it is a reason for stopping study ther-
apy. The objective response status of such patients is to be
determined by evaluation of target and non-target disease
as shown in Tables 1–3.
Conditions that deﬁne ‘early progression, early death and
inevaluability’ are study speciﬁc and should be clearly de-
scribed in each protocol (depending on treatment duration,
treatment periodicity).
In some circumstances it may be difﬁcult to distinguish
residual disease from normal tissue. When the evaluation of
complete response depends upon this determination, it is
recommended that the residual lesion be investigated (ﬁne
Table 3 – Best overall response when conﬁrmation of CR and PR required.
Overall response
Overall response
BEST overall response
First time point
Subsequent time point
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable.
a If a CR is truly met at ﬁrst time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to baseline,
makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether minimum duration
for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and in fact the
patient had PR, not CR at the ﬁrst time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
Table 1 – Time point response: patients with target (+/–
non-target) disease.
Target lesions
Non-target lesions
New
lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or
not all evaluated
No
PR
SD
Non-PD or
not all evaluated
No
SD
Not all
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease,
PD = progressive disease, and NE = inevaluable.
Table 2 – Time point response: patients with non-target
disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete
response,
PD = progressive
disease,
and
NE = inevaluable.
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target
disease since SD is increasingly used as endpoint for assessment
of efﬁcacy in some trials so to assign this category when no
lesions can be measured is not advised.
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needle aspirate/biopsy) before assigning a status of complete
response. FDG-PET may be used to upgrade a response to a CR
in a manner similar to a biopsy in cases where a residual
radiographic abnormality is thought to represent ﬁbrosis or
scarring. The use of FDG-PET in this circumstance should be
prospectively described in the protocol and supported by dis-
ease speciﬁc medical literature for the indication. However, it
must be acknowledged that both approaches may lead to
false positive CR due to limitations of FDG-PETand biopsy res-
olution/sensitivity.
For equivocal ﬁndings of progression (e.g. very small and
uncertain new lesions; cystic changes or necrosis in existing
lesions), treatment may continue until the next scheduled
assessment. If at the next scheduled assessment, progression
is conﬁrmed, the date of progression should be the earlier
date when progression was suspected.
4.5.
Frequency of tumour re-evaluation
Frequency
of
tumour
re-evaluation
while
on
treatment
should be protocol speciﬁc and adapted to the type and sche-
dule of treatment. However, in the context of phase II studies
where the beneﬁcial effect of therapy is not known, follow-up
every 6–8 weeks (timed to coincide with the end of a cycle) is
reasonable. Smaller or greater time intervals than these could
be justiﬁed in speciﬁc regimens or circumstances. The proto-
col should specify which organ sites are to be evaluated at
baseline (usually those most likely to be involved with meta-
static disease for the tumour type under study) and how often
evaluations are repeated. Normally, all target and non-target
sites are evaluated at each assessment. In selected circum-
stances certain non-target organs may be evaluated less fre-
quently. For example, bone scans may need to be repeated
only when complete response is identiﬁed in target disease
or when progression in bone is suspected.
After the end of the treatment, the need for repetitive tu-
mour evaluations depends on whether the trial has as a goal
the response rate or the time to an event (progression/death).
If ‘time to an event’ (e.g. time to progression, disease-free
survival, progression-free survival) is the main endpoint of
the study, then routine scheduled re-evaluation of protocol
speciﬁed sites of disease is warranted. In randomised com-
parative trials in particular, the scheduled assessments
should be performed as identiﬁed on a calendar schedule
(for example: every 6–8 weeks on treatment or every 3–4
months after treatment) and should not be affected by delays
in therapy, drug holidays or any other events that might lead
to imbalance in a treatment arm in the timing of disease
assessment.
4.6.
Conﬁrmatory measurement/duration of response
4.6.1.
Conﬁrmation
In non-randomised trials where response is the primary end-
point, conﬁrmation of PR and CR is required to ensure re-
sponses identiﬁed are not the result of measurement error.
This will also permit appropriate interpretation of results in
the context of historical data where response has traditionally
required conﬁrmation in such trials (see the paper by Bogaerts
et al. in this Special Issue10). However, in all other circum-
stances, i.e. in randomised trials (phase II or III) or studies
where stable disease or progression are the primary endpoints,
conﬁrmation ofresponseis notrequiredsince itwillnotaddva-
lue to theinterpretationoftrial results.However, eliminationof
the requirement for response conﬁrmation may increase the
importance of central review to protect against bias, in partic-
ular in studies which are not blinded.
In the case of SD, measurements must have met the SD
criteria at least once after study entry at a minimum interval
(in general not less than 6–8 weeks) that is deﬁned in the
study protocol.
4.6.2.
Duration of overall response
The duration of overall response is measured from the time
measurement criteria are ﬁrst met for CR/PR (whichever is ﬁrst
recorded) until the ﬁrst date that recurrent or progressive dis-
ease is objectively documented (taking as reference for progres-
sive disease the smallest measurements recorded on study).
The duration of overall complete response is measured
from the time measurement criteria are ﬁrst met for CR until
the ﬁrst date that recurrent disease is objectively documented.
4.6.3.
Duration of stable disease
Stable disease is measured from the start of the treatment (in
randomised trials, from date of randomisation) until the crite-
ria for progression are met, taking as reference the smallest
sum on study (if the baseline sum is the smallest, this is the
reference for calculation of PD).
The clinical relevance of the duration of stable disease var-
ies in different studies and diseases. If the proportion of pa-
tients achieving stable disease for a minimum period of time
is an endpoint of importance in a particular trial, the protocol
should specify the minimal time interval required between
two measurements for determination of stable disease.
Note: The duration of response and stable disease as well as
theprogression-free survivalareinﬂuenced by thefrequencyof
follow-up after baseline evaluation. It is not in the scope of this
guideline to deﬁne a standard follow-up frequency. The fre-
quency should take into account many parameters including
disease types and stages, treatment periodicity and standard
practice. However, these limitations of the precision of the
measured endpoint should be taken into account if compari-
sons between trials are to be made.
4.7.
Progression-free survival/proportion progression-free
4.7.1.
Phase II trials
This guideline is focused primarily on the use of objective re-
sponse endpoints for phase II trials. In some circumstances, ‘re-
sponse rate’ may not be the optimal method to assess the
potential anticancer activity of new agents/regimens. In such
cases ‘progression-free survival’ (PFS) or the ‘proportion pro-
gression-free’ at landmark time points, might be considered
appropriate alternatives to provide an initial signal of biologic
effect of new agents. It is clear, however, that in an uncontrolled
trial, these measures are subject to criticism since an appar-
ently promising observation may be related to biological factors
such as patient selectionand not theimpactof theintervention.
Thus, phase II screening trials utilising these endpoints are best
designed with a randomised control. Exceptions may exist
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where the behaviour patterns of certain cancers are so consis-
tent (and usually consistently poor), that a non-randomised
trial is justiﬁable (see for example van Glabbeke et al.20). How-
ever, in these cases it will be essential to document with care
the basis for estimating the expected PFS or proportion progres-
sion-free in the absence of a treatment effect.
4.7.2.
Phase III trials
Phase III trials in advanced cancers are increasingly designed
to evaluate progression-free survival or time to progression as
the primary outcome of interest. Assessment of progression
is relatively straightforward if the protocol requires all pa-
tients to have measurable disease. However, restricting entry
to this subset of patients is subject to criticism: it may result
in a trial where the results are less likely to be generalisable if,
in the disease under study, a substantial proportion of pa-
tients would be excluded. Moreover, the restriction to entry
will slow recruitment to the study. Increasingly, therefore, tri-
als allow entry of both patients with measurable disease as
well as those with non-measurable disease only. In this cir-
cumstance, care must be taken to explicitly describe the ﬁnd-
ings which would qualify for progressive disease for those
patients without measurable lesions. Furthermore, in this set-
ting, protocols must indicate if the maximum number of re-
corded target lesions for those patients with measurable
disease may be relaxed from ﬁve to three (based on the data
found in Bogaerts et al.10 and Moskowitz et al.11). As found in
the ‘special notes on assessment of progression’, these guide-
lines offer recommendations for assessment of progression
in this setting. Furthermore, if available, validated tumour mar-
ker measures of progression (as has been proposed for ovarian
cancer) may be useful to integrate into the deﬁnition of pro-
gression. Centralised blinded review of imaging studies or of
source imaging reports to verify ‘unequivocal progression’
may be needed if important drug development or drug ap-
proval decisions are to be based on the study outcome. Finally,
as noted earlier, because the date of progression is subject to
ascertainment bias, timing of investigations in study arms
should be the same. The article by Dancey et al. in this special
issue21 provides a more detailed discussion of the assessment
of progression in randomised trials.
4.8.
Independent review of response and progression
For trials where objective response (CR + PR) is the primary end-
point, and in particular where key drug development deci-
sions are based on the observation of a minimum number of
responders, it is recommended that all claimed responses be
reviewed by an expert(s) independent of the study. If the study
is a randomised trial, ideally reviewers should be blinded to
treatment assignment. Simultaneous review of the patients’
ﬁles and radiological images is the best approach.
Independent review of progression presents some more
complex issues: for example, there are statistical problems
with the use of central-review-based progression time in
place of investigator-based progression time due to the poten-
tial introduction of informative censoring when the former
precedes the latter. An overview of these factors and other
lessons learned from independent review is provided in an
article by Ford et al. in this special issue.22
4.9.
Reporting best response results
4.9.1.
Phase II trials
When response is the primary endpoint, and thus all patients
must have measurable disease to enter the trial, all patients
included in the study must be accounted for in the report of
the results, even if there are major protocol treatment devia-
tions or if they are not evaluable. Each patient will be assigned
one of the following categories:
1. Complete response
2. Partial response
3. Stable disease
4. Progression
5. Inevaluable for response: specify reasons (for example: early
death, malignant disease; early death, toxicity; tumour
assessments not repeated/incomplete; other (specify)).
Normally, all eligible patients should be included in the
denominator for the calculation of the response rate for phase
II trials (in some protocols it will be appropriate to include all
treated patients). It is generally preferred that 95% two-sided
conﬁdence limits are given for the calculated response rate.
Trial conclusions should be based on the response rate for
all eligible (or all treated) patients and should not be based
on a selected ‘evaluable’ subset.
4.9.2.
Phase III trials
Response evaluation in phase III trials may be an indicator
of the relative anti-tumour activity of the treatments eval-
uated and is almost always a secondary endpoint. Ob-
served differences in response rate may not predict the
clinically relevant therapeutic beneﬁt for the population
studied. If objective response is selected as a primary end-
point for a phase III study (only in circumstances where a
direct relationship between objective tumour response and
a clinically relevant therapeutic beneﬁt can be unambigu-
ously demonstrated for the population studied), the same
criteria as those applying to phase II trials should be used
and all patients entered should have at least one measur-
able lesion.
In those many cases where response is a secondary end-
point and not all trial patients have measurable disease, the
method for reporting overall best response rates must be
pre-speciﬁed in the protocol. In practice, response rate may
be reported using either an ‘intent to treat’ analysis (all ran-
domised patients in the denominator) or an analysis where
only the subset of patients with measurable disease at
baseline are included. The protocol should clearly specify
how response results will be reported, including any subset
analyses that are planned.
The original version of RECIST suggested that in phase III
trials one could write protocols using a ‘relaxed’ interpreta-
tion of the RECIST guidelines (for example, reducing the num-
ber of lesions measured) but this should no longer be done
since these revised guidelines have been amended in such a
way that it is clear how these criteria should be applied for
all trials in which anatomical assessment of tumour response
or progression are endpoints.
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Appendix I. Summary of major changes RECIST 1.0 to RECIST 1.1
RECIST 1.0
RECIST 1.1
Rationale
Reference in special issue
(if applicable)
Minimum size measurable
lesions
CT: 10 mm spiral
CT 10 mm; delete reference to
spiral scan
Most scans used have 5 mm or less slice
thickness Clearer to give instruction based on
slice interval if it is greater than 5 mm
20 mm non-spiral
Clinical: 20 mm
Clinical: 10 mm (must be
measurable with calipers)
Caliper measurement will make this reliable
Lymph node: not mentioned
CT:
Since nodes are normal structure need to deﬁne
pathological enlargement. Short axis is most
sensitive
Schwartz et al.15
P15 mm short axis for target
P10–<15 mm for non-target
<10 mm is non-pathological
Special considerations on
lesion measurability
–
Notes included on bone
lesions, cystic lesions
Clarify frequently asked questions
Overall tumour burden
10 lesions (5 per organ)
5 lesions (2 per organ)
Data warehouse analysis shows no loss of
information if lesion number reduced from 10 to
5. A maximum of 2 lesions per organ yields
sufﬁcient representation per disease site
Bogaerts et al.10
Response criteria target
disease
CR lymph node not mentioned
CR lymph nodes must be
<10 mm short axis
In keeping with normal size of nodes
Schwartz et al.15
PD 20% increase over smallest sum on
study or new lesions
PD 20% increase over smallest
sum on study (including
baseline if that is smallest) and
at least 5 mm increase or new
lesions
Clariﬁcation that if baseline measurement is
smaller than any on study measurement, it is
reference against which PD is assessed
5 mm absolute increase to guard against over
calling PD when total sum is very small and 20%
increase is within measurement error
Response criteria non-target
disease
‘unequivocal progression’ considered as PD
More detailed description of
‘unequivocal progression’ to
indicate that it should not
normally trump target disease
status. It must be
representative of overall
disease status change, not a
single lesion increase
Confusion with RECIST 1.0 where some were
considering PD if ‘increase’ in any non-target
lesion, even when target disease is stable or
responding
New lesions
–
New section on New lesions
To provide guidance on when a lesion is
considered new (and thus PD)
Overall response
Table integrated target and non-target
lesions
Two tables: one integrating
target and non-target and the
other of non-target only
To account for the fact that RECIST criteria are
now being used in trials where PFS is the
endpoint and not all patients have measurable
(target) disease at baseline
Dancey et al.21
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RECIST 1.0
RECIST 1.1
Rationale
Reference in special issue
(if applicable)
Special notes:
Frequently asked questions on these topics
How to assess and measure
lymph nodes
CR in face of residual tissue
Discussion of ‘equivocal’
progression
Conﬁrmatory measure
For CR and PR: criteria
must be met again 4
weeks after initial
documentation
Retain this requirement ONLY
for
non-randomised trials with
primary endpoint of response
Data warehouse shows that response rates
rise when conﬁrmation is eliminated, but
the only circumstance where this is
important is in trials where there is no
concurrent comparative control and where
this measure is the primary endpoint
Bogaerts et al.10
Progression-free survival
General comments only
More speciﬁc comments on
use of PFS (or proportion
progression-free) as
phase II endpoint
Increasing use of PFS in phase III trials
requires guidance on assessment of PD in
patients with non-measurable disease
Dancey et al.21
Greater detail on PFS
assessment in phase III trials
Reporting of response
results
9 categories suggested for
reporting phase II results
Divided into phase II and phase
III
Simpliﬁes reporting and clariﬁes how to
report phase II and III data consistently
9 categories collapsed into 5
In phase III, guidance given
about reporting response
Response in phase III
trials
More relaxed guidelines
possible if protocol speciﬁed
This section removed and
referenced in section
above: no need to have
different criteria for phase II
and III
Simpliﬁcation of response assessment by
reducing number of lesions and eliminating
need for conﬁrmation in randomised
studies where response is not the primary
endpoint makes separate ‘rules’
unnecessary
Imaging appendix
Appendix I
Appendix II: updated with
detailed guidance on
use of MRI, PET/CT
Evolving use of newer modalities addressed.
Enhanced guidance in response to frequent
questions and from radiology review
experience
Other practical guidance
included
New appendices
Appendix I: comparison of
RECIST 1.0 and 1.1
Appendix III: frequently asked
questions
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Conﬂict of interest statement
None declared.
Acknowledgements
The RECIST Working Group would like to thank the following
organisations which made data bases available to us in order
to perform the analyses which informed decisions about
changes to this version of the criteria: Amgen; AstraZeneca;
Breast Cancer International Research Group (BCIRG); Bristol-
Myers
Squibb; European
Organisation for
Research and
Treatment of Cancer (EORTC) Breast Cancer Group and Gas-
trointestinal
Group;
Erasmus
University
Medical
Center,
Rotterdam, The Netherlands; Genentech; Pﬁzer; RadPharm;
Roche; SanoﬁAventis.
We would also like to thank the following individuals from
academic, government, and pharmaceutical organisations for
providing helpful comments on an earlierdraft of these revised
guidelines: Ohad Amit, Phil Murphy, Teri Crofts and Janet Be-
gun, GlaxoSmithKline, USA; Laurence H. Baker, Southwest
Oncology Group, USA; Karla Ballman, Mayo Clinic, USA;
Charles Baum, Darrel Cohen, and Mary Ashford Collier, Pﬁzer,
USA; Gary J. Becker, American Board of Radiology, Tucson,
USA; Jean-Yves Blay, University Claude Pertrand, Lyon France;
Renzo Canetta, Bristol-Myers Squibb, USA; David Chang, Am-
gen Inc., USA; Sandra Chica, Perceptive Informations Inc. (PAR-
EXEL),
USA;
Martin
Edelman,
University
of
Maryland
Greenbaum Cancer Centre, USA; Gwendolyn Fyfe, Genentech,
USA; Bruce Giantonio, Eastern Cooperative Oncology Group,
USA; Gary Gordon, Abbott Pharmaceuticals, USA; Ronald Gott-
lieb, Roswell Park Cancer Institute, USA; Simon Kao, University
of Iowa College of Medicine, USA; Wasaburo Koizumi, Kitasato
University, Japan; Alessandro Riva, Novartis Pharmaceuticals,
USA; Wayne Rackhoff, Ortho Biotech Oncology Research and
Development, USA; Nagahiro Saijo, President Japanese Society
of Medical Oncology, Japan; Mitchell Schnall American College
of Radiology Imaging Network, USA; Yoshik Shimamura, PAR-
EXEL International Inc., Japan; Rajeshwari Sridhara, Centre
for Drug Evaluation and Research, Food and Drug Administra-
tion, USA; Andrew Stone, Alan Barge, AstraZeneca, United
Kingdom; Orhan Suleiman, Centre for Drug Evaluation and Re-
search, Food and Drug Administration, USA; Daniel C. Sullivan,
Duke University Medical Centre, USA; Masakazu Toi, Kyoto
University, Japan; Cindy Welsh, Centre for Drug Evaluation
and Research, Food and Drug Administration, USA.
Finally, the RECIST Working Group would like to thank indi-
vidualswho were not permanent members of the group (which
are all acknowledged as co-authors) but who attended working
group meetings from time to time and made contributions to
the total process over the past 7 years: Richard Pazdur, Food
and Drug Administration, USA; Francesco Pignatti, European
Medicines Agency, London, UK.
Appendix II.
Speciﬁcations for standard
anatomical radiological imaging
These protocols for image acquisition of computed tomogra-
phy (CT) and magnetic resonance imaging (MRI) are recom-
mendations intended for patients on clinical trials where
RECIST assessment will be performed. Standardisation of
imaging requirements and image acquisition parameters is
ideal to allow for optimal comparability of subjects within a
study and results between studies. These recommendations
are designed to balance optimised image acquisition proto-
cols with techniques that should be feasible to perform glob-
ally at imaging facilities in all types of radiology practices.
These guidelines are not applicable to functional imaging
techniques or volumetric assessment of tumour size.
Scanner quality control is highly recommended and should
follow
standard
manufacturer
and
facility
maintenance
schedules using commercial phantoms. It is likely that for RE-
CIST unidimensional measurements this will be adequate to
produce reproducible measurements. Imaging quality control
for CT includes an analysis of image noise and uniformity and
CT number as well as spatial resolution. The frequency of
quality control analysis is also variable and should focus on
clinically relevant scanning parameters. Dose analysis is al-
ways important and the use of imaging should follow the
ALARA principle, ‘As Low As Reasonably Achievable’, which
refers to making every reasonable effort to maintain radiation
exposures as far below the dose limits as possible.
Speciﬁc.notes
Chest X-ray measurement of lesions surrounded by pulmon-
ary
parenchyma
is
feasible,
but
not
preferable
as
the
measurement represents a summation of densities. Further-
more, there is poor identiﬁcation of new lesions within the
chest on X-ray as compared with CT. Therefore, measure-
ments of pulmonary parenchymal lesions as well as medias-
tinal disease are optimally performed with CT of the chest.
MRI of the chest should only be performed in extenuating cir-
cumstances. Even if IV contrast cannot be administered (for
example, in the situation of allergy to contrast), a non-con-
trast CT of the chest is still preferred over MRI or chest X-ray.
CT scans: CT scans of the chest, abdomen, and pelvis should
be contiguous throughout all the anatomic region of interest.
As a general rule, the minimum size of a measurable lesion at
baseline should be no less than double the slice thickness and
also have a minimum size of 10 mm (see below for minimum
size when scanners have a slice thickness more than 5 mm).
While the precise physics of lesion size and partial volume
averaging is complex, lesions smaller than 10 mm may be dif-
ﬁcult to accurately and reproducibly measure. While this rule
is applicable to baseline scans, as lesions potentially decrease
in size at follow-up CT studies, they should still be measured.
Lesions which are reported as ‘too small to measure’ should
be assigned a default measurement of 5 mm if they are still
visible.
The most critical CT image acquisition parameters for opti-
mal tumour evaluation using RECIST are anatomic coverage,
contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most
solid tumours is the chest, abdomen and pelvis. Cover-
age should encompass all areas of known predilection
for metastases in the disease under evaluation and
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should additionally investigate areas that may be
involved based on signs and symptoms of individual
patients. Because a lesion later identiﬁed in a body part
not scanned at baseline would be considered as a new
lesion representing disease progression, careful consid-
eration should begiven to the extent of imaging coverage
at baseline and at subsequent follow-up time points.
This will enable better consistency not only of tumour
measurements but also identiﬁcation of new disease.
b. IV contrast administration: Optimal visualisation and
measurement of metastases in solid tumours requires
consistent administration (dose and rate) of IV contrast
as well as timing of scanning. Typically, most abdomi-
nal imaging is performed during the portal venous
phase and (optimally) about the same time frame after
injection on each examination (see Fig. 1 for impact of
different phase of IV contrast on lesion measurement).
Most solid tumours may be scanned with a single
phase after administration of contrast. While triphasic
CT scans are sometimes performed on other types of
vascular tumours to improve lesion conspicuity, for
consistency and uniformity, we would recommend tri-
phasic
CT
for
hepatocellular
and
neuroendocrine
tumours for which this scanning protocol is generally
standard of care, and the improved temporal resolution
of the triphasic scan will enhance the radiologists’ abil-
ity to consistently and reproducibly measure these
lesions. The precise dose and rate of IV contrast is
dependent upon the CT scanning equipment, CT acqui-
sition protocol, the type of contrast used, the available
venous
access
and
the
medical
condition
of
the
patient. Therefore, the method of administration of
intravenous contrast agents is variable. Rather than
try to institute rigid rules regarding methods for
administering contrast agents and the volume injected,
it is appropriate to suggest that an adequate volume of
a suitable contrast agent should be given so that the
metastases are demonstrated to best effect and a con-
sistent method is used on subsequent examinations for
any given patient (ideally, this would be speciﬁed in
the protocol or for an institution). It is very important
that the same technique be used at baseline and on fol-
low-up examinations for a given patient. This will
greatly enhance the reproducibility of the tumour mea-
surements. If prior to enrolment it is known a patient is
not able to undergo CT scans with IV contrast due to
allergy
or
renal
insufﬁciency,
the
decision
as
to
whether a non-contrast CT or MRI (with or without IV
contrast) should be used to evaluate the subject at
baseline and follow-up should be guided by the tumour
type under investigation and the anatomic location of
the disease. For patients who develop contraindica-
tions to contrast after baseline contrast CT is done,
the decision as to whether non-contrast CT or MRI
(enhanced or non-enhanced) should be performed
should also be based on the tumour type, anatomic
location of the disease and should be optimised to
allow for comparison to the prior studies if possible.
Each case should be discussed with the radiologist to
determine if substitution of these other approaches is
possible and, if not, the patient should be considered
not evaluable from that point forward. Care must be
taken in measurement of target lesions on a different
modality and interpretation of non-target disease or
new lesions, since the same lesion may appear to have
a different size using a new modality (see Fig. 2 for a
comparison of CT and MRI of the same lesion). Oral
contrast is recommended to help visualise and differ-
entiate structures in the abdomen.
c. Slice thickness and reconstruction interval: RECIST measure-
ments may be performed at most clinically obtained
slice thicknesses. It is recommended that CT scans be
performed at 5 mm contiguous slice thickness or less
and indeed this guideline presumes a minimum 5 mm
thickness in recommendations for measurable lesion
deﬁnition. Indeed, variations in slice thickness can have
an impact on lesion measurement and on detection of
new lesions. However, consideration should also be
given for minimising radiation exposure. With these
parameters, a minimum 10 mm lesion is considered
measurable at baseline. Occasionally, institutions may
perform medically acceptable scans at slice thicknesses
greater than 5 mm. If this occurs, the minimum size of
measurable lesions at baseline should be twice the slice
Fig. 1 – Difference in measurement/visualisation with different phases of IV contrast administration. Hypervascular
metastases imaged in the arterial phase (left) and the portal venous phase (right). Note that the number of lesions visible
differs greatly between the two phases of contrast administration as does any potential lesion measurement. Consistent CT
scan acquisition, including phase of contrast administration, is important for optimal and reproducible tumour
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thickness of the baseline scans. Most contemporary CT
scanners are multidetector which have many imaging
options for these acquisition parameters.23 The equip-
ment vendor and scanning manual should be reviewed
if there are any speciﬁc system questions.
d. Alternative contrast agents: There are a number of other,
new contrast agents, some organ speciﬁc.24 They may
be used as part of patient care for instance, in liver
lesion assessment, or lymph node characterisation25,
but should not as yet be used in clinical trials.
FDG-PET has gained acceptance as a valuable tool for
detecting, staging and restaging several malignancies. Criteria
for incorporating (or substituting) FDG-PET into anatomical
assessment of tumour response in phase II trials are not yet
available, though much research is ongoing. Nevertheless,
FDG-PET is being used in many drug development trials both
as a tool to assess therapeutic efﬁcacy and also in assessment
of progression. If FDG-PET scans are included in a protocol, by
consensus, an FDG uptake period of 60 min prior to imaging
has been decided as the most appropriate for imaging of pa-
tients with malignancy.26 Whole-body acquisition is impor-
tant since this allows for sampling of all areas of interest
and can assess if new lesions have appeared thus determining
the possibility of interval progression of disease. Images from
the base of the skull to the level of the mid-thigh should be ob-
tained 60 min post injection. PET camera speciﬁcations are
variable and manufacturer speciﬁc, so every attempt should
be made to use the same scanner, or the same model scanner,
for serial scans on the same patient. Whole-body acquisitions
can be performed in either 2- or 3-dimensional mode with
attenuation correction, but the method chosen should be con-
sistent across all patients and serial scans in the clinical trial.
PET/CT scans: Combined modality scanning such as with
PET–CT is increasingly used in clinical care, and is a modal-
ity/technology that is in rapid evolution; therefore, the recom-
mendations in this paper may change rather quickly with
time. At present, low dose or attenuation correction CT por-
tions of a combined PET–CT are of limited use in anatomically
based efﬁcacy assessments and it is therefore suggested that
they should not be substituted for dedicated diagnostic con-
trast enhanced CT scans for anatomically based RECIST mea-
surements. However, if a site can document that the CT
performed as part of a PET–CT is of identical diagnostic qual-
ity to a diagnostic CT (with IV and oral contrast) then the CT
portion of the PET–CT can be used for RECIST measurements.
Note, however, that the PET portion of the CT introduces addi-
tional data which may bias an investigator if it is not routinely
or serially performed.
Ultrasound examinations should not be used in clinical trials
to measure tumour regression or progression of lesions be-
cause the examination is necessarily subjective and operator
dependent. The reasons for this are several: Entire examina-
tions cannot be reproduced for independent review at a later
date, and it must be assumed, whether or not it is the case,
that the hard-copy ﬁlms available represent a true and accu-
rate reﬂection of events. Furthermore, if, for example, the
only measurable lesion is in the para-aortic region of the
abdomen and if gas in the bowel overlies the lesion, the lesion
will not be detected because the ultrasound beam cannot
penetrate the gas. Accordingly, the disease staging (or restag-
ing for treatment evaluation) for this patient will not be
accurate.
While evaluation of lesions by physical examination is also
of limited reproducibility, it is permitted when lesions are
superﬁcial, at least 10 mm size, and can be assessed using
calipers. In general, it is preferred if patients on clinical trials
have at least one lesion that is measurable by CT. Other skin
or palpable lesions may be measured on physical examina-
tion and be considered target lesions.
Use of MRI remains a complex issue. MRI has excellent
contrast, spatial and temporal resolution; however, there
are many image acquisition variables involved in MRI, which
greatly impact image quality, lesion conspicuity and mea-
surement. Furthermore, the availability of MRI is variable
globally. As with CT, if an MRI is performed, the technical
speciﬁcations of the scanning sequences used should be
optimised for the evaluation of the type and site of disease.
Furthermore, as with CT, the modality used at follow-up
should be the same as was used at baseline and the lesions
should be measured/assessed on the same pulse sequence.
Generally, axial imaging of the abdomen and pelvis with T1
and T2 weighted imaging along with gadolinium enhanced
imaging should be performed. The ﬁeld of view, matrix,
number of excitations, phase encode steps, use of fat sup-
pression and fast sequences should be optimised for the spe-
Fig. 2 – CT versus MRI of same lesions showing apparent ‘progression’ due only to differing method of measurement.
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ciﬁc body part being imaged as well as the scanner utilised. It
is beyond the scope of this document or appendix to pre-
scribe speciﬁc MRI pulse sequence parameters for all scan-
ners, body parts and diseases. Ideally, the same type of
scanner should be used and the image acquisition protocol
should be followed as closely as possible to prior scans. Body
scans should be performed with breath-hold scanning tech-
niques if possible.
Selection of target lesions: In general, the largest lesions rep-
resentative of involved organs (up to a maximum of two per
organ and ﬁve total) are selected to follow as target lesions.
However, in some cases, the largest lesions may not be easily
measured and are not suitable for follow-up because of their
conﬁguration. In these cases, identiﬁcation of the largest most
reproducible lesions is advised. Fig. 3 provides an illustrative
example where the largest lesion is not the most reproducible
and another lesion is better to select and follow:
Measurement of lesions
The longest diameter of selected lesions should be measured
in the plane in which the images were acquired. For body CT,
this is the axial plane. In the event isotropic reconstructions
are performed, measurements can be made on these recon-
structed images; however, it should be cautioned that not
all radiology sites are capable of producing isotropic recon-
structions. This could lead to the undesirable situation of
measurements in the axial plane at one assessment point
and in a different plane at a subsequent assessment. There
are some tumours, for instance paraspinal lesions, which
are better measured in the coronal or sagittal plane. It would
be acceptable to measure these lesions in these planes if the
reconstructions in those planes were isotropic or the images
were acquired with MRI in those planes. Using the same plane
of evaluation, the maximal diameter of each target lesion
should always be measured at subsequent follow-up time
points even if this results in measuring the lesion at a differ-
ent slice level or in a different orientation or vector compared
with the baseline study. Software tools that calculate the
maximal diameter for a perimeter of a tumour may be em-
ployed and may even reduce variability.
The only exception to the longest diameter rule is lymph
node measurement. Because malignant nodes are identiﬁed
by the length of their short axis, this is the guide used to
determine not only whether they are pathological but is also
the dimension measured for adding into the sum of target le-
sions. Fig. 4 illustrates this point: the large arrow identiﬁes a
malignant node: the shorter perpendicular axis is P15 mm
and will be recorded. Close by (small arrow) there is a normal
node: note here the long axis is greater than 10 mm but the
short axis is well below 10 mm. This node should be consid-
ered non-pathological.
If a lesion disappears and reappears at a subsequent time
point it should continue to be measured. However, the pa-
tient’s response at the point in time when the lesion reap-
pears will depend upon the status of his/her other lesions.
For example, if the patient’s tumour had reached a CR status
and the lesion reappeared, then the patient would be consid-
ered PD at the time of reappearance. In contrast, if the tumour
status was a PR or SD and one lesion which had disappeared
then reappears, its maximal diameter should be added to the
sum of the remaining lesions for a calculated response: in
other words, the reappearance of an apparently ‘disappeared’
single lesion amongst many which remain is not in itself en-
Fig. 3 – Largest lesion may not be most reproducible: most reproducible should be selected as target. In this example, the
primary gastric lesion (circled at baseline and at follow-up in the top two images) may be able to be measured with thin
section volumetric CT with the same degree of gastric distention at baseline and follow-up. However, this is potentially
challenging to reproduce in a multicentre trial and if attempted should be done with careful imaging input and analysis. The
most reproducible lesion is a lymph node (circled at baseline and at follow-up in the bottom two images).
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ough to qualify for PD: that requires the sum of all lesions to
meet the PD criteria. The rationale for such a categorisation is
based upon the realisation that most lesions do not actually
‘disappear’ but are not visualised because they are beyond
the resolving power of the imaging modality employed.
The identiﬁcation of the precise boundary deﬁnition of a
lesion may be difﬁcult especially when the lesion is embed-
ded in an organ with a similar contrast such as the liver, pan-
creas, kidney, adrenal or spleen. Additionally, peritumoural
oedema may surround a lesion and may be difﬁcult to distin-
guish on certain modalities between this oedema and actual
tumour. In fact, pathologically, the presence of tumour cells
within the oedema region is variable. Therefore, it is most
critical that the measurements be obtained in a reproducible
manner from baseline and all subsequent follow-up time-
points. This is also a strong reason to consistently utilise
the same imaging modality.
When lesions ‘fragment’, the individual lesion diameters
should be added together to calculate the target lesion
sum. Similarly, as lesions coalesce, a plane between them
may be maintained that would aid in obtaining maximal
diameter measurements of each individual lesion. If the le-
sions have truly coalesced such that they are no longer sep-
arable, the vector of the longest diameter in this instance
should be the maximal longest diameter for the ‘merged
lesion’.
Progression of non-target lesions
To achieve ‘unequivocal progression’ there must be an overall
level of substantial worsening in non-target disease that is of
a magnitude that, even in the presence of SD or PR in target
disease, the treating physician would feel it important to
change therapy. Examples of unequivocal progression are
shown in Figs. 5 and 6.
Fig. 5 – Example of unequivocal progression in non-target lesions in liver.
Fig. 6 – Example of unequivocal progression in non-target lesion (nodes).
Fig. 4 – Lymph node assessment: large arrow illustrates a
pathological node with the short axis shown as a solid line
which should be measured and followed. Small arrow illus-
trates a non-pathological node which has a short axis
<10 mm.
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Appendix III. Frequently asked questions
Question
Answer
What should be done if several unique lesions at
baseline become conﬂuent at a follow-up
evaluation?
Measure the longest diameter of the conﬂuent mass and record to add into the sum of
the longest diameters
How large does a new lesion have to be to count
as progression? Does any small subcentimetre
lesion qualify, or should the lesion be at least
measurable?
New lesions do not need to meet ‘measurability criteria’ to be considered valid. If it is
clear on previous images (with the same technique) that a lesion was absent then its
deﬁnitive appearance implies progression. If there is any doubt (because of the
techniques or conditions) then it is suggested that treatment continue until next
scheduled assessment when, generally, all should be clear. Either it gets bigger and the
date of progression is the date of the ﬁrst suspicion, or it disappears and one may then
consider it an artefact with the support of the radiologists
How should one lesion be measured if on
subsequent exams it is split into two?
Measure the longest diameter of each lesion and add this into the sum
Does the deﬁnition of progression depend on
the status of all target lesions or only one?
As per the RECIST 1.1 guideline, progression requires a 20% increase in the sum of
diameters of all target lesions AND a minimum absolute increase of 5 mm in the sum
Are RECIST criteria accepted by regulatory
agencies?
Many cooperative groups and members of pharma were involved in preparing RECIST
1.0 and have adopted them. The FDA was consulted in their development and supports
their use, though they don’t require it. The European and Canadian regulatory
authorities also participated and the RECIST criteria are now integrated in the European
note for guidance for the development of anticancer agents. Many pharmaceutical
companies are also using them. RECIST 1.1 was similarly widely distributed before
publication
What is the criterion for a measurable lesion if
the CT slice thickness is >5 mm?
RECIST 1.1 recommends that CT scans have a maximum slice thickness of 5 mm and the
minimum size for a measurable lesion is twice that: 10 mm (even if slice thickness is
<5 mm). If scanners with slice thickness >5 mm are used, the minimum lesion size must
have a longest diameter twice the actual slice thickness
What should we record when target lesions
become so small they are below the 10 mm
‘measurable’ size?
Target lesion measurability is deﬁned at baseline. Thereafter, actual measurements,
even if <10 mm, should be recorded. If lesions become very small, some radiologists
indicate they are ‘too small to measure’. This guideline advises that when this occurs, if
the lesion is actually still present, a default measurement of 5 mm should be applied. If
in fact the radiologist believes the lesion has gone, a default measurement of 0 mm
should be recorded
If a patient has several lesions which have
decreased in size to meet PR criteria and one
has actually disappeared, does that patient have
PD if the ‘disappeared’ lesion reappears?
Unless the sum meets the PD criteria, the reappearance of a lesion in the setting of PR (or
SD) is not PD. The lesion should simply be added into the sum.
If the patients had had a CR, clearly reappearance of an absent lesion would qualify for
PD
When measuring the longest diameter of target
lesions in response to treatment, is the same
axis that was used initially used subsequently,
even if there is a shape change to the lesion that
may have produced a new longest diameter?
The longest diameter of the lesion should always be measured even if the actual axis is
different from the one used to measure the lesion initially (or at different time point
during follow-up)
The only exception to this is lymph nodes: as per RECIST 1.1 the short axis should
always be followed and as in the case of target lesions, the vector of the short axis may
change on follow-up
Target lesions have been selected at baseline
and followed but then one of these target
lesions then becomes non-evaluable (i.e.
different technique used)
What may be done in such cases is one of the following:
What is the effect this has on the other target
lesions and the overall response?
(a) If the patient is still being treated, call the centre to be sure that future evaluations are
done with the baseline technique so at least SOME courses are fully evaluable
(b) If that is not possible, check if there IS a baseline exam by the same technique which
was used to follow patients...in which case if you retrieve the baseline measures from
that technique you retrieve the lesion evaluability
(c) If neither (a) nor (b) is possible then it is a judgement call about whether you delete
the lesion from all forms or consider the impact of the lesion overall is so important that
its being non-evaluable makes the overall response interpretation inevaluable without
it. Such a decision should be discussed in a review panel
It is NOT recommended that the lesion be included in baseline sums and then excluded
from follow-up sums since this biases in favour of a response
(continued on next page)
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R E F E R E N C E S
1. Paesmans M, Sculier JP, Libert P, et al. Response to
chemotherapy has predictive value for further survival of
patients with advanced non-small cell lung cancer: 10 years
experience of the European Lung Cancer Working Party. Eur J
Cancer 1997;33:2326–32.
2. Buyse M, Thirion P, Carlson RW, et al. Relation between tumor
response to ﬁrst-line chemotherapy and survival in advanced
colorectal cancer: a meta-analysis. Meta-analysis group in
Cancer. Lancet 2000;356:373–8.
3. Gofﬁn J, Baral S, Tu D, et al. Objective responses in patients
with malignant melanoma or renal cell cancer in early
clinical studies do not predict regulatory approval. Clin Cancer
Res 2005;15:5928–34.
4. El-Maraghi RH, Eisenhauer EA. Review of phase II trial designs
used in studies of molecular targeted agents: outcomes and
predictors of success in phase III. J Clin Oncol 2008;10:1346–54.
5. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting
results of cancer treatment. Cancer 1981;47:207–14.
6. Tonkin K, Tritchler D, Tannock I. Criteria of tumor response
used in clinical trials of chemotherapy. J Clin Oncol
1985;3:870–5.
7. Baar J, Tannock I. Analyzing the same data in two ways: a
demonstration model to illustrate the reporting and
misreporting of clinical trials. J Clin Oncol 1989;7:969–78.
8. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines
to evaluate the response to treatment in solid tumors (RECIST
Guidelines). J Natl Cancer Inst 2000;92:205–16.
9. Therasse P, Eisenhauer EA, Verweij J. RECIST revisited: a
review of validation studies on tumour assessment. Eur J
Cancer 2006;42:1031–9.
10. Bogaerts J, Ford R, Sargent D, et al. Individual patient
data analysis to assess modiﬁcations to the RECIST criteria.
Eur J Cancer 2009;45:248–60.
11. Moskowitz CS, Jia X, Schwartz LH, Go¨nen M. A simulation
study to evaluate the impact of the number of lesions
measured on response assessment. Eur J Cancer
2009;45:300–10.
12. Sargent D, Rubinstein L, Schwartz L, et al. Validation of novel
imaging methodologies for use as cancer clinical trials
end-points. Eur J Cancer 2009;45:290–9.
Appendix III – continued
Question
Answer
What if a single non-target lesion cannot be reviewed, for
whatever reason; does this negate the overall assessment?
Sometimes the major contribution of a single non-target lesion may be in
the setting of CR having otherwise been achieved: failure to examine one
non-target in that setting will leave you unable to claim CR. It is also
possible that the non-target lesion has undergone such substantial
progression that it would override the target disease and render patient
PD. However, this is very unlikely, especially if the rest of the measurable
disease is stable or responding
A patient has a 32% decrease in sum cycle 2, a 28% decrease cycle
4 and a 33% decrease cycle 6. Does conﬁrmation of PR have to
take place in sequential scans or is a case like this conﬁrmed PR?
It is not infrequent that tumour shrinkage hovers around the 30% mark.
In this case, most would consider PR to have been conﬁrmed looking at
this overall case. Had there been two or three non-PR observations
between the two time point PR responses, the most conservative
approach would be to consider this case SD
In the setting of a breast cancer neoadjuvant study, would
mammography not be used to assess lesions? Is CT preferred in
this setting?
Neither CT nor mammography are optimal in this setting. MRI is the
preferred modality to follow breast lesions in a neoadjuvant setting
A patient has a lesion measurable by clinical exam and by CT
scan. Which should be followed?
CT scan. Always follow by imaging if that option exists since it can be
reviewed and veriﬁed
A lesion which was solid at baseline has become necrotic in the
centre. How should this be measured?
The longest diameter of the entire lesion should be followed. Eventually,
necrotic lesions which are responding to treatment decrease in size. In
reporting the results of trials, you may wish to report on this
phenomenon if it is seen frequently since some agents (e.g. angiogenesis
inhibitors) may produce this effect
If I am going to use MRI to follow disease, what is minimum size
for measurability?
MRI may be substituted for contrast enhanced CT for some sites, but not
lung. The minimum size for measurability is the same as for CT (10 mm)
as long as the scans are performed with slice thickness of 5 mm and no
gap. In the event the MRI is performed with thicker slices, the size of a
measurable lesion at baseline should be two times the slice thickness. In
the event there are inter-slice gaps, this also needs to be considered in
determining the size of measurable lesions at baseline
Can PET–CT be used with RECIST?
At present, the low dose or attenuation correction CT portion of a
combined PET–CT is not always of optimal diagnostic CT quality for use
with RECIST measurements. However, if your site has documented that
the CT performed as part of a PET–CT is of the same diagnostic quality as
a diagnostic CT (with IV and oral contrast) then the PET–CT can be used
for RECIST measurements. Note, however, that the PET portion of the CT
introduces additional data which may bias an investigator if it is not
routinely or serially performed
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13. Macdonald DR, Cascino TL, Schold Jr SC, Cairncross JG.
Response criteria for phase II studies of supratentorial
malignant glioma. J Clin Oncol 1990;8:1277–80.
14. Cheson BD, Pﬁstner B, Juweid ME, et al. Revised response
criteria for malignant lymphoma. J Clin Oncol 2007;10:579–86.
15. Schwartz LH, Bogaerts J, Ford R, et al. Evaluation of lymph
nodes with RECIST 1.1. Eur J Cancer 2009;45:261–7.
16. Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to
evaluate the response to treatment in solid tumors (ovarian
cancer). J Natl Cancer Inst 2004;96:487–8.
17. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response
guidelines for phase II clinical trials in androgen-independent
prostate cancer: recommendations from the Prostate-Speciﬁc
Antigen Working Group. J Clin Oncol 1999;17:3461–7.
18. Scher H, Halabi S, Tannock I, et al. Design and end points of
clinical trials for patients with progressive prostate cancer
and castrate levels of testosterone: recommendations of the
Prostate Cancer Clinical Trials Working Group. J Clin Oncol
2008;26:1148–59.
19. Vergote I, Rustin GJ, Eisenhauer EA, et al. Re: new guidelines
to evaluate the response to treatment in solid tumors [ovarian
cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst
2000;92:1534–5.
20. Van Glabbeke M, Verweij J, Judson I, Nielsen OS. EORTC Soft
Tissue and Bone Sarcoma Group: Progression-free rate as the
principal end-point for phase II trials in soft-tissue sarcomas.
Eur J Cancer 2002;38:543–9.
21. Dancey JE, Dodd LE, Ford R, et al. Recommendations for the
assessment of progression in randomised cancer treatment
trials. Eur J Cancer 2009;45:281–9.
22. Ford R, Schwartz L, Dancey J, et al. Lessons learned
from independent central review. Eur J Cancer 2009;45:
268–74.
23. Catalano C, Francone M, Ascarelli A, Mangia M, Iacucci I,
Passariello R. Optimizing radiation dose and image quality.
Eur Radiol 2007;17(Suppl 6):F26–32.
24. Low RN. Abdominal MRI advances in the detection of liver
tumours and characterization. Lancet Oncol 2007;8(6):525–35.
25. Barrett T, Choyke PL, Kobayashi H. Imaging of the lymphatic
system: new horizons. Contrast Media Mol Imaging
2006;1(6):230–45.
26. Shankar LK, Hoffman JM, Bacharach S, et al. National
Cancer Institute. Consensus recommendations for the use
of 18F-FDG PET as an indicator of therapeutic response
in patients in National Cancer Institute Trials.
J Nucl Med 2006;47(6):1059–66.
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APPENDIX 7:  
NEW YORK HEART ASSOCIATION CLASSIFICATION 
Table 15: 
New York Heart Association Classification 
Class I 
Subjects with no limitation of activities; they suffer no symptoms from ordinary activities. 
Class II 
Subjects with slight, mild limitation of activity; they are comfortable with rest or with mild 
exertion. 
Class III 
Subjects with marked limitation of activity; they are comfortable only at rest. 
Class IV 
Subjects who should be at complete rest, confined to bed or chair; any physical activity brings on 
discomfort and symptoms occur at rest. 
 
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APPENDIX 8:  
ALGORITHMS FOR EARLY DETECTION AND TREATMENT 
OF IMMUNE RELATED ADVERSE EVENTS (IRAES) 
The guidelines provided below have been adapted from the European Society for Medical 
Oncology (ESMO) clinical practice guidelines for management of toxicities from 
immunotherapy (Haanen 2018).  Please refer to the full publication for management of irAEs not 
specifically discussed below (Appendix 9).  These may be supplemented by discussions with the 
sponsor’s medical monitor as well as institutional guidelines on management of these toxicities. 
Diarrhea and Colitis  
Grade 
FPT155 Dosing  
Management Escalation 
Pathway 
Assessment and 
Investigations 
Grade 1 
Diarrhea: <4 stools/ day 
over baseline 
Colitis: asymptomatic 
No delay or 
missed dose 
Symptomatic management: 
Oral fluids, loperamide, avoid 
high fiber/lactose diet 
Persists >14 days or worsens, 
treat as Grade 2 
Close monitoring for worsening 
symptoms 
Patient education to 
immediately report worsening 
symptoms 
Grade 2 
Diarrhea: 4-6 stools per 
day over baseline; 
Outpatient management 
if appropriate 
Colitis: abdominal pain, 
blood in stool 
Delay or miss 
dose  
Reinitiate upon 
recovery to 
≤Grade 1 
Symptomatic management: 
Oral fluids, loperamide, avoid 
high fiber/lactose diet 
Persists > 3 days or worsens 
0.5-1.0 mg/kg 
(methyl)prednisolone or oral 
equivalent 
Persists >3 days or worsens, 
treat as Grade 3/4 
Clinical safety labs (eg, CBC, 
chemistry, CRP) 
Stool microscopy for 
leukocytes/ova/parasites, 
culture, viral polymerase chain 
reaction (PCR), clostridium 
difficile toxin, cryptosporidia 
Grade 3/4 
Diarrhea (G3): ≥7 stools 
per day over baseline; 
incontinence; requires 
hospitalization 
Colitis (G3): severe 
abdominal pain, fever, 
ileus, peritoneal signs; 
medical intervention 
indicated 
G4: Life-threatening, 
perforation 
Permanently 
discontinue 
FPT155 
1.0-2.0 mg/kg (methyl) 
prednisolone IV or IV 
equivalent 
Persists > 3 days, infliximab 
5 mg/kg (if no 
contraindication) 
Assess as above 
Urgent gastrointestinal (GI) 
consult and abdominal CT 
and/or sigmoido/colonoscopy  
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Hepatitis  
Grade 
FPT155 Dosing  
Management Escalation 
Pathway 
Assessment and 
Investigations 
Grade 1 
AST or ALT > ULN-3.0 
x ULN and/or T. bili 
> ULN-1.5 x ULN 
No delay or 
missed dose 
N/A 
Close monitoring for worsening 
symptoms or laboratory 
parameters 
Grade 2 
AST or ALT > 3.0 -≤ 5 x 
ULN and/or T. bili > 
1.5- ≤ 3 x ULN 
Delay or miss 
dose  
Reinitiate upon 
recovery to 
≤Grade 1 
Monitor liver function tests 
(LFTs) every 3 days 
Review concomitant 
medications (e.g. statins, 
antibiotics) alcohol use 
Perform liver screen: Hepatitis 
A/B/C serology, Hepatitis E 
PCR, anti- smooth muscle 
antibody (SMA)/anti-nuclear 
antibody (ANA)/liver kidney 
microsome (LKM)/soluble liver 
antigen (SLA) /lipoprotein 
(LP)/ Anti-liver cytosol 1 
autoantibody (LCI), iron 
studies 
Consider Liver imaging 
Grade 3/4 
AST or ALT >5 x ULN 
or T.bili >3 x ULN 
Permanently 
discontinue 
FPT155 
Monitor LFTs every 1-2 days 
1.0-2.0 mg/kg (methyl) 
prednisolone IV or IV 
equivalent (2 mg/kg/day IV 
methylprednisolone for 
Grade 4 AEs) 
Assess as above 
Refer to Hepatologist  
Liver imaging 
Consider liver biopsy for Grade 
4 AEs 
 
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Renal Adverse Events 
Grade 
FPT155 Dosing  
Management Escalation 
Pathway 
Assessment and 
Investigations 
Grade 1 
Creatinine >1-1.5 x 
baseline or  
> ULN-1.5 x ULN 
No delay or 
missed dose 
Monitor serum creatinine 
weekly 
Review hydration status, 
medications, urinalysis/culture 
if urinary tract infection 
symptoms Dipstick urine and 
send for protein assessment.  If 
obstruction suspected: renal 
ultrasound +/- doppler to 
exclude obstruction/clot 
If worsens treat as below 
Grade 2-3 
G2: creatinine > 1.5-3 x 
baseline or > 1.5-3 x 
ULN 
G3: creatinine > 3 x 
baseline or > 3-6 x ULN 
Delay or miss 
dose  
Reinitiate upon 
recovery to 
≤Grade 1 
Monitor serum creatinine every 
2-3 days 
0.5-1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent 
Persists >7 days or worsens, 
treat as Grade 4 
Assess as above 
If proteinuria: perform 24 h 
urine collection or urine 
protein to creatinine ratio 
(UPCR) 
Refer to nephrologist 
Grade 4 
Creatinine > 6x ULN 
Permanently 
discontinue 
FPT155 
Monitor serum creatinine daily  
1.0-2.0 mg/kg methyl 
prednisolone IV or IV 
equivalent  
Assess as above 
Refer to nephrologist 
Consider renal biopsy 
 
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Pneumonitis 
Grade 
FPT155 Dosing  
Management Escalation 
Pathway 
Assessment and 
Investigations 
Grade 1 
Radiographic changes 
only  
Ground glass change, 
non-specific interstitial 
pneumonia 
Consider delay 
or miss dose 
Monitor symptoms every 
2-3 days 
Re-image ≤ every 3 weeks  
Consider pulmonary and 
Infectious disease referral 
Clinical safety labs (eg, 
CBC, chemistry, CRP) 
Consider sputum sample 
and screening for viral 
opportunistic or specific 
bacterial infections 
Grade 2 
Mild/moderate new 
symptoms 
Dyspnea, cough, chest 
pain 
Delay or miss 
dose  
Reinitiate upon 
recovery to 
≤Grade 1 
Monitor symptoms daily 
Re-image ≤weekly  
1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent 
Consider pneumocystis 
prophylaxis 
Assess as above  
Pulmonary and Infectious 
disease referral 
Consider bronchoscopy, 
lung biopsy 
Grade 3/4 
Severe new symptoms 
New/worsening hypoxia 
Life threatening 
Difficulty in breathing, 
Acute Respiratory 
Distress Syndrome 
(ARDS) 
Permanently 
discontinue 
FPT155 
2.0-4.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
Persists >2 days, add infliximab 
5 mg/kg (if no contraindication) 
or additional immunosuppression 
(e.g., mycophenolate mofetil 
[MMF], cyclophosphamide, 
intravenous immunoglobulin G 
[IVIG]) 
Hospitalize and assess as 
above 
Pulmonary and Infectious 
disease referral 
Consider bronchoscopy, 
lung biopsy 
 
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Skin Adverse Events 
CTCAE Grade 
FPT155 Dosing  
Management Escalation 
Pathway 
Assessment and 
Investigations 
Grade 1/2 
G1: Skin rash with or 
without symptoms; 
<10% body surface area 
(BSA) 
G2: rash covers 10-30% 
BSA 
No delay or 
missed dose 
Avoid skin irritants and sun 
exposure 
Symptomatic therapy (e.g. 
antihistamines, topical steroids 
and emollients) 
Persists >1-2 weeks, consider 
0.5-1.0 mg/kg/ day 
methylprednisolone IV or oral 
equivalent 
Physical exam, exclude 
other causes (eg viral 
infections, concomitant 
medication) 
Grade 3/4 
G3: rash covers >30% 
BSA or G2 with 
substantial symptoms 
G4: skin sloughing 
>30% BSA with 
associated symptoms or 
life-threatening 
consequences 
Delay or miss 
dose or 
discontinue 
FPT155 
permanently 
Reinitiate upon 
recovery to 
≤Grade 1  
Symptomatic therapy (e.g. 
antihistamines, topical steroids 
and emollients) 
1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
Refer to dermatologist 
Consider skin biopsy 
 
 
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Endocrinopathy 
Patients with unexplained symptoms such as fatigue, myalgias, mental status changes, or 
constipation should be investigated for the presence of thyroid, pituitary or adrenal 
endocrinopathies.  An endocrinologist should be consulted if an endocrinopathy is suspected.  
Thyroid-stimulating hormone (TSH) and free thyroxine (free T4) levels should be obtained to 
determine if thyroid abnormalities are present.  If a subject has thyroid dysfunction and 
concomitant symptoms (ie, fatigue), the subject should be monitored more frequently and be 
treated as per standard medical practice.  Appropriate hormone replacement therapy should be 
instituted if an endocrinopathy is documented. 
Specific guidance for management of suspected hypophysitis is provided below. 
Symptoms 
FPT155 Dosing  
Management Escalation 
Pathway 
Assessment and 
Investigations 
Vague symptoms (eg, 
mild fatigue, 
anorexia), no 
headache or 
Asymptomatic 
No delay or missed 
dose 
Perform pituitary axis assessment* 
to confirm diagnosis 
Initiate hormone 
replacement therapy as 
necessary after consultation 
with endocrinologist 
Moderate symptoms, 
ie, headache but no 
visual disturbance or 
Fatigue/mood 
alteration but 
haemodynamically 
stable, no electrolyte 
disturbance 
Delay or miss dose  
Reinitiate upon 
recovery to 
baseline 
Perform pituitary axis assessment* 
to confirm diagnosis  
Oral prednisolone 0.5-1 mg/kg/day 
(Taper over at least 1 month) 
If no improvement in 48h, treat as 
severe (see below) 
MRI (pituitary protocol), 
exclude brain metastases 
Consider formal visual field 
assessment 
Refer to endocrinologist 
Severe mass effects 
(ie, severe headache, 
any visual 
disturbance) or 
severe 
hypoadrenalism 
(ie, hypotension, 
severe electrolyte 
imbalance) 
Delay or miss dose 
or permanently 
discontinue 
FPT155 
Perform pituitary axis assessment* 
to confirm diagnosis  
Initiate IV methylprednisolone 
1 mg/kg (Taper over at least 
1 month) 
Analgesia as needed for headache 
(discuss with neurologist if 
resistant to paracetamol and 
nonsteroidal anti-inflammatory 
drugs [NSAIDs])  
MRI (pituitary protocol), 
exclude brain metastases 
Consider formal visual field 
assessment 
Refer to endocrinologist 
*Pituitary Axis assessment: 9 am serum cortisol (or random if unwell and treatment cannot be delayed), 
adrenocorticotropic hormone (ACTH), TSH/free T4, luteinizing hormone (LH), follicle-stimulating hormone (FSH), 
oestradiol if premenopausal, testosterone in men, insulin-like growth factor-1 (IGF-1), prolactin 
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APPENDIX 9:  
MANAGEMENT OF TOXICITIES FROM IMMUNOTHERAPY: 
ESMO CLINICAL PRACTICE GUIDELINES FOR DIAGNOSIS, 
TREATMENT AND FOLLOW-UP
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CLINICAL PRACTICE GUIDELINES
Management of toxicities from immunotherapy:
ESMO Clinical Practice Guidelines for diagnosis,
treatment and follow-up†
J. B. A. G. Haanen1, F. Carbonnel2, C. Robert3, K. M. Kerr4, S. Peters5, J. Larkin6 & K. Jordan7, on behalf of
the ESMO Guidelines Committee*
1Netherlands Cancer Institute, Division of Medical Oncology, Amsterdam, The Netherlands; 2Department of Gastroenterology, Kremlin Bic^etre Hospital, Assistance
Publique-Hoˆpitaux de Paris (AP-HP), Paris, France; 3Department of Medicine, Dermatology Unit, Gustave Roussy Cancer Campus, Villejuif, France; 4Department of
Pathology, Aberdeen University Medical School & Aberdeen Royal Inﬁrmary, Aberdeen, UK; 5Oncology Department, Centre Hospitalier Universitaire Vaudois
(CHUV), Lausanne, Switzerland; 6Royal Marsden Hospital NHS Foundation Trust, London, UK; 7Department of Medicine V, Hematology, Oncology and
Rheumatology, University Hospital of Heidelberg, Heidelberg, Germany
*Correspondence to: ESMO Guidelines Committee, ESMO Head Ofﬁce, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland. E-mail: clinicalguidelines@esmo.org
†Approved by the ESMO Guidelines Committee: May 2017.
General aspects of immune checkpoints
blockade
Incidence and epidemiology
Immunotherapy with monoclonal antibodies (MoAbs) targeting
cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and the
programmed death-1 receptor (PD-1) and its ligand PD-L1 has
become standard of care for an increasing number of indications
(Table 1). Therefore, an increasing number of patients will be
exposed to these drugs with a chance of developing toxicities
from these treatments. Depending on the immune checkpoint
that is targeted, the incidence of toxicity varies. Toxicities from
immune checkpoint inhibitors (ICPis) can be divided into infu-
sion reactions and immune-related adverse events (irAEs) or ad-
verse events of special interest (AEoSI). The latter will be the
subject of these Clinical Practice Guidelines. Any organ or tissue
can be involved, although some irAEs occur much more com-
monly than others. The most frequently occurring irAEs affect
skin, colon, endocrine organs, liver and lungs. Others are very in-
frequent, but may be very serious, even lethal, such as neuro-
logical disorders and myocarditis.
Ipilimumab-associated immune-related toxicities
irAEs from ipilimumab, anti-CTLA4, at a dose of 3 mg/kg, have
been documented to occur in 60%–85% of patients [1, 2], mostly
grades 1 and 2, but between 10% and 27% of patients develop
grade 3 to 4 toxicities, and 2.1% ipilimumab-related deaths have
been reported in the ﬁrst phase III trial [1]. The onset of these
toxicities varies but usually starts within the ﬁrst 8 to 12 weeks
of initiation of treatment [an example of onset of adverse events
(AEs) upon ipilimumab treatment is depicted in Figure 1], with
skin toxicities often being the ﬁrst to develop. These toxicities are
dose-dependent as no grade 3 to 4 AEs were observed at a dose of
0.3 mg/kg ipilimumab, whereas these toxicities increased to 30%
with a dose of 10 mg/kg [3]. In the adjuvant setting with ipilimu-
mab 10 mg/kg followed by a maintenance dose, the recorded
grade 3 to 4 irAE rate was 41.6%, and the grade 5 irAE rate
1.1% [4].
PD-1/PD-L1 blockade immune-related toxicities
The most frequently reported AE with anti-PD-1/PD-L1 is
fatigue. Incidence of fatigue, of which the pathogenesis is poorly
understood, across single drug studies, is 16%-37% for anti-PD-1
and 12%-24% for anti-PD-L1 [5]. Only in a minority of patients
fatigue can be attributed to hypothyroidism. High-grade toxic-
ities from anti-PD-1 (either nivolumab or pembrolizumab) are
less common than for the CTLA4 blocking agent ipilimumab.
For nivolumab, any treatment-related AE was documented
in 74%–85% of patients, with 12%–20% being grade 3 and 4
[2, 6, 7] for metastatic melanoma patients, 58% and 7%, respect-
ively, for advanced cisplatin refractory squamous non-small-cell
lung cancer (NSCLC) [8], 69% and 10%, respectively, for meta-
static cisplatin refractory non-squamous NSCLC [9] and 79% and
V
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19%, respectively, for tyrosine kinase inhibitor refractory meta-
static renal cell carcinoma [10].
For pembrolizumab, the Keynote-002 study, comparing pem-
brolizumab at doses of 2 and 10 mg/kg to chemotherapy in ipili-
mumab pre-treated metastatic melanoma, showed grade 1 to 2
irAEs in 57%–60% and grade 3 to 4 toxicity in 14% of patients
[11]. In the Keynote-006 study comparing pembrolizumab, given
at 10 mg/kg either every 3 or 2 weeks, to ipilimumab, treatment-
related toxicity was observed in 73%–80% of patients, with 10%–
13.5% having grade 3 or higher AEs [12]. In a similar design to
the Keynote-002, the Keynote-010 study in cisplatin refractory
NSCLC patients compared pembrolizumab (2 mg/kg) and pem-
brolizumab (10 mg/kg) with docetaxel. The reported treatment-
related AEs for the pembrolizumab-treated groups were 63% and
66% for any AE, and 13% and 16% for grade 3 to 4 toxicities, re-
spectively [13]. In the Keynote-024 study pembrolizumab given
at 200 mg ﬂat dose every 3 weeks was compared with cisplatin-
Table 1. Approved indications for ICPis
Drug
Indications
EMA/FDA approval
Ipilimumab
Metastatic melanoma
EMA þ FDA
Adjuvant therapy stage III melanoma
FDA
Nivolumab
Metastatic melanoma
EMA þ FDA
2nd line metastatic NSCLC
EMA þ FDA
2nd line metastatic RCC
EMA þ FDA
Classical Hodgkin’s diseasea
EMA þ FDA
Recurrent or metastatic SCCHNb
EMA þ FDA
Locally advanced or metastatic UCCc
EMA þ FDA
Pembrolizumab
Metastatic melanoma
EMA þ FDA
2nd line metastatic NSCLC (PD-L1  1%)
EMA þ FDA
1st line metastatic NSCLC (PD-L1  50%)
EMA þ FDA
1st line metastatic NSCLC in combination with pemetrexed þ carboplatin
FDA
Classical Hodgkin’s disease
EMAa þ FDAd
Locally advanced or metastatic UCCc
FDA
MSI-H or MMR deﬁcient metastatic malignanciese
FDA
Atezolizumab
Locally advanced or metastatic UCCc
FDA
2nd line metastatic NSCLC
FDA
Avelumab
Locally advanced or metastatic UCCc
FDA
Metastatic Merkel cell carcinoma
FDA
Durvalumab
Locally advanced or metastatic UCCc
FDA
Ipilimumab þ nivolumab
Metastatic melanoma
EMA þ FDA
aFor the treatment of patients with cHL who have relapsed or progressed after auto-HSCT and post-transplantation brentuximab vedotin. bFor the treat-
ment of patients with recurrent or metastatic SCCHN with disease progression on or after platinum-based therapy. cFor patients with locally advanced or
metastatic UCC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant
treatment with platinum-containing chemotherapy. dFor the treatment of adult and pediatric patients with cHL who are refractory or have relapsed after
3 or more lines of therapy. eFor adult and paediatric patients with unresectable or metastatic, MSI-H or dMMR that have progressed following prior treat-
ment and who have no satisfactory alternative treatment options or with MSI-H or dMMR CRC that has progressed following treatment with a ﬂuoropyri-
midine, oxaliplatin, and irinotecan.
Auto-HSCT, autologous hematopoietic stem cell transplantation; cHL, classic Hodgkin’s lymphoma; CRC, colorectal cancer; dMMR, deﬁcient MMR; EMA,
European Medicines Agency; FDA, Food and Drug Administration; ICPi, immune checkpoint inhibitor; MMR, DNA mismatch repair; MSI-H; microsatellite
instability-high; NSCLC, non-small-cell lung cancer; PD-L1, programmed death ligand 1; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of
the head and neck; UCC, urothelial carcinoma.
Rash, pruritis
0
2
4
6
8
10
12
14
Time (weeks)
Liver toxicity
Diarrhoea, colitis
Hypophysitis
Toxicity grade
Figure 1. Timing of occurence of immune-related adverse events
following ipilimumab treatment.
Reprinted from [86] with permission. V
C 2012 American Society of
Clinical Oncology. All rights reserved.
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based chemotherapy as ﬁrst-line treatment in metastatic NSCLC
patients (tumour PD-L1 expression  50%). Treatment-related
toxicity was reported in 73.4% (any AE) and 26.6% of patients
with a grade 3 or higher AE [14].
Combination of CTLA4 and PD-1/PD-L1 blockade
immune-related toxicities
Combination immunotherapy has only been approved for pa-
tients with metastatic melanoma. Treatment-related AEs were
observed in 95% of patients. In 55% of patients these AEs were of
grade 3 or higher [2]. The onset of grade 3 to 4 toxicities for either
monotherapy with nivolumab or combination immunotherapy
differs, as irAEs not only may develop earlier in combination
therapy but also may start over a prolonged period of time
(Figure 2).
General aspects of irAEs
In general, irAEs occur quite early, mostly within weeks to
3 months after initiation of immune checkpoint blockers.
However, the ﬁrst onset of irAEs has been documented as long as
1 year after discontinuation of treatment.
The role of tissue biopsy in the diagnosis of immune-therapy
related toxicity is not established. Some recommendations sug-
gest tissue biopsy in higher grade (3 and 4) toxicity [skin, gastro-
instestinal (GI), liver, kidney, lung] where there is diagnostic
doubt about the aetiology of the complication and management
would be altered by the outcome of the biopsy procedure [15]. In
general, when biopsy is carried out in such circumstances, the re-
porting pathologist must be apprised of the speciﬁc reasons for
the biopsy procedure.
Patient selection and baseline assessments
Before starting treatment, patients should be assessed in terms of
susceptibility to develop irAEs. This includes a work-up consist-
ing of patient history (and family history), general physical con-
dition, autoimmune diseases, baseline laboratory tests and
radiological exams (Supplementary Table S1, available at Annals
of Oncology online) [mostly computed tomography (CT) scans of
the chest, abdomen/pelvis and often brain magnetic resonance
imaging (MRI)]. Patients with a history of autoimmune disease,
or who are being actively treated for an autoimmune disease, are
at risk for worsening of their autoimmune disease while on im-
mune checkpoint blockade [16]. Similarly, patients that have had
irAEs on ipilimumab are at risk of developing irAEs following
anti-PD-1 treatment and vice versa [16, 17]. Results from these
retrospective series showed a higher rate of grade 3 to 4 toxicity in
patients treated with ipilimumab following anti-PD-1 (up to
35%) and patients with grade 3 to 4 toxicity on ipilimumab fol-
lowed by anti-PD-1 developed grade 3 to 4 irAEs in > 20% of
cases. The time between last dose of ﬁrst drug and initiation of
the second drug, however, may be important, considering the
long half-lives of these MoAbs.
Patients should be informed of the potential AEs of immuno-
therapy before treatment initiation. In all cases, patients should
report directly to the treating physician or team (nurse, nurse
5.6 (0.1–55.0)
Skin (n=18)
Skin (n=5)
Gastrointestinal (n=46)
Gastrointestinal (n=7)
Endocrine (n=15)
Endocrine (n=2)
Hepatic (n=60)
Hepatic (n=8)
Pulmonary (n=3)
Pulmonary (n=1)
Renal (n=6)
Renal (n=1)
0
10
Circles represent medians; bars signify ranges
Combination ipilimumab + nivolumab:
Single agent nivolumab:
20
30
40
50
60
7.4 (1.0–48.9)
26.3 (13.1–57.0)
12.1 (2.9–17.0)
28.6 (19.1–38.1)
7.4 (2.1–48.0)
14.1 (1.9–25.1)
3.7 (3.7–9.4)
6.7 (6.7–6.7)
11.3 (3.3–23.7)
Weeks
50.9 (50.9–50.9)
NIVO+IPI
NIVO
19.4 (1.3–50.9)
Figure 2. Time to onset of grade 3–4 treatment-related select AEs.
AE, adverse event; IPI, ipilimumab; NIVO, nivolumab.
Reprinted from [87] with permission.
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practitioner, physician). Once irAEs have developed, prompt
work-up is required and action should be taken to prevent fur-
ther aggravation of AEs, In many cases, especially the most severe,
immunotherapy should be discontinued and immunosuppres-
sive or immune modulating drugs including high-dose cortico-
steroids, and sometimes tumour necrosis factor alpha (TNFa)
antagonists, mycophenolate or tacrolimus, are needed to over-
come these toxicities, followed by careful tapering of immuno-
suppression.
Long-term
(> 6 weeks)
treatment
with
immunosuppressive drugs or use of inﬂiximab increases the
chance of opportunistic infections; therefore, pneumocystis
prophylaxis should be considered according to local guidelines.
Importantly, so far there is no evidence that the clinical outcome
of patients on ICPis is affected by the use of immunosuppressive
agents for the management of immune-related toxicities [7, 18].
Immune-related skin toxicity
Incidence
Skin AEs are among the most frequent AEs observed by patients
treated with MoAbs inhibiting either immune checkpoints
CTLA4 (ipilimumab in 43%–45% of the patients) or PD-1 (nivo-
lumab and pembrolizumab in 34%) [1, 3, 19, 20] and usually
develop early in the course of treatment (within the ﬁrst few
weeks after initiation).
However, serious skin AEs are rare and do not usually require
dose reductions or treatment discontinuation.
One immune-related skin AE, vitiligo, seems to be associated
with good clinical responses to anti-PD-1 MoAbs in patients
treated for melanoma [21].
The most frequent skin AEs are rash, pruritus and vitiligo,
but the latter is seen mostly in patients treated for melanoma
[20]. Rash is reported in 24% of the patients treated with
ipilimumab, in 15% of those receiving anti-PD-1 MoAbs
and in 40% with the combination of ipilimumab and nivolu-
mab. However, grade 3 or 4 rashes are rare, with an inci-
dence of < 3% with monotherapy ipilimumab or anti-PD-1
and < 5% with the combination [2, 22]. Pruritus is reported
in around 25%–35% of the cases with ipilimumab, 13%–
20% with anti-PD-1 and 33% with the combination, but
reaches a grade 3 and 4 in < 2.5% [22]. Vitiligo is reported
in about 8% of patients with melanoma treated with anti-
PD-1 MoAbs [20] or with the combination of checkpoint in-
hibitors, but is more rarely reported with ipilimumab alone.
In a small prospective study, vitiligo was found in up to
25% of patients treated with pembrolizumab [21]. It is likely
that the incidence is underreported in clinical trials, due to
the fact that patients are not routinely seen and systematic-
ally subjected to a full-body skin exam by a dermatologist.
In this study, the occurrence of vitiligo was signiﬁcantly
associated
with
the
clinical
response
to
the
drug.
Development of vitiligo is predominantly observed in melan-
oma patients treated with ICPis but not in NSCLC or renal
cancer. More rarely, other skin AEs have been reported with
checkpoint inhibitors: alopecia areata, stomatitis, xerosis cutis
and photosensitivity. Exacerbation of psoriasis has also been
anecdotally reported with these drugs, as well as psoriasiform
or lichenoid skin reactions in patients without any history of
such skin disease [19, 23].
Histopathologically, skin reactions may be categorised into
four broad groups [24]:
• Inﬂammatory skin disorders, which comprise a range of
changes reﬂecting acute, subacute or chronic inﬂammation
of various patterns, associated with variable epidermal changes,
including psoriasiform or lichenoid reactions. A lichenoid
interface chronic dermatitis is a common ﬁnding [25, 26];
• Immunobullous skin lesions akin to dermatitis herpetiformis
or bullous pemphigoid;
• Keratinocyte alteration—Grover’s disease [27]/acantholytic
dyskeratosis;
• Immune-reaction mediated by alteration of melanocytes (regres-
sion of nevi, prurigo nodularis, tumoural melanosis and vitiligo).
Diagnosis and pathology/molecular biology
When a patient treated with a checkpoint inhibitor presents with
a skin AE, the ﬁrst requirement is ruling out any other aetiology
of the skin problem, such as an infection, an effect of another
drug or a skin condition linked to another systemic disease. Next,
the severity of the skin AE needs to be evaluated by a careful and
thorough physical examination of the skin including the mucosal
areas, an appreciation of the general patient status (fever,
enlarged lymph nodes etc.), and if needed, a biological checkup
including a blood cell count, liver and kidney tests. This will help
to eliminate the possibility of a dermatological emergency such as
drug rash with eosinophilia and systemic symptoms (DRESS),
acute febrile neutrophilic dermatosis (Sweet syndrome), Stevens-
Johnson syndrome or toxic epidermal necrolysis (TEN). In such
life-threatening cases (fatal cases have already been described),
the treatment with checkpoint inhibitor(s) should be perman-
ently discontinued, the patient should be hospitalised, and symp-
tomatic treatment should be initiated immediately by a
dermatologist or at a specialised dermatology unit.
To gauge the severity of the skin AE, the Common
Terminology Criteria for Adverse Events (CTCAE) classiﬁcation
is usually used.
Concerning a maculopapular rash, the most frequent event
with checkpoint inhibitors, the fourth version of the CTCAE clas-
siﬁcation proposes:
• Grade 1: macules/papules covering < 10% the body surface
area (BSA) with or without symptoms (e.g. pruritus, burning,
tightness);
• Grade 2: macules/papules covering 10%–30% BSA with or
without symptoms (e.g. pruritus, burning, tightness); limiting
instrumental activities of daily living (ADL);
• Grade 3: macules/papules covering > 30% BSA with or with-
out associated symptoms; limiting selfcare ADL;
• Grade 4: papulopustular rash associated with life-threatening
superinfection; Stevens-Johnson syndrome, TEN and bullous
dermatitis covering > 30% of BSA and requiring intensive
care unit (ICU) admission.
The relation with impairment in instrumental or selfcare ADL
seems appropriate to evaluate the severity of the AE as well as its
impact on the patient’s life. However, the fact that when > 30%
BSA is involved, the rash is automatically graded 3, is subject to
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discussion. Indeed, when the rash is diffuse but light and not
associated with any additional symptoms, a grade 2 would seem
more appropriate than grade 3.
The ﬁfth version of the CTCAE classiﬁcation will give a more
appropriate classiﬁcation for skin AEs.
Management of rash
For grade 1 skin AEs such as rash and/or pruritus, treatment with
checkpoint inhibitors can be continued (see Figures 3 and 4).
Symptoms can be treated with topical emollients, oral antihista-
mines and/or mild strength topical corticosteroids. In the case of
grade 2 skin AEs, treatment with checkpoint inhibitors can be
continued but should be checked weekly for improvement. If not
resolved, treatment should be interrupted until the skin AE has
reverted to grade 1. Symptomatic treatment consists of topical
emollients, oral antihistamines and median-to-high strength top-
ical steroids. Grade 3 skin AEs also require immediate interrup-
tion of checkpoint inhibition, until these are back to grade 1.
Treatment includes topical emollients, oral antihistamines and
high strength topical steroids [II, B]. Systemic corticosteroids
0.5–1 mg/kg can be considered, depending on the severity of the
symptoms. In the rare event of grade 4 skin toxicity, treatment
with checkpoint inhibitors should be interrupted, and patients
should be admitted immediately and be placed under supervision
of a dermatologist. Treatment consists of intravenous (i.v.) (me-
thyl)prednisolone 1–2 mg/kg with tapering when the toxicity re-
solves to normal [II, B].
Immune-related endocrinopathies
Thyroid gland disorders
Although thyroid gland disorders have been observed quite fre-
quently in patients treated with immunotherapies such as cytokines
interleukin-2 and type I interferons, their incidence has increased
Grade 1:
skin rash, with or without
symptoms, < 10% BSA
(see Figure 4)  
Avoid skin irritants,
avoid sun exposure,
topical emollients recommended
Topical steroids (mild strength) cream
od +/- oral or topical antihistamines for itch
Proceed with treatment
Physical examination
Exclude other causes, e.g. viral illness,
infection, other drug rash
Grade 2:
rash covers 10%-30% of BSA
(see Figure 4)    
Supportive management, as above
Topical steroids (moderate strength) cream 
od or(potent) cream bd +/- oral or topical 
antihistamines for itch
Proceed with ICPi treatment
As above 
Consider dermatology referral and skin biopsy
Grade 3:
rash covers > 30% BSA (see Figure 4)
or grade 2 with substantial symptoms
Withhold ICPi
Topical treatments as above (potent)
Initiate steroids: 
if mild to moderate 0.5-1 mg/kg prednisolone
od for 3 days then wean over 1-2 weeks; 
or if severe i.v. (methyl)prednisolone
0.5 -1 mg/kg and convert to oral steroids
on response, wean over 2-4 weeks
Recommence ICPi at G1/mild G2 after discussion
with patient and consultant
As for Grade 1
Dermatology review
Consider punch biopsy and clinical photography
Grade 4:
skin sloughing > 30% BSA (see Figure 4)
with associated symptoms
(e.g. erythema, purpura, epidermal detachment) 
i.v. (methyl)prednisolone  1-2 mg/kg
Seek urgent dermatology review
Discontinue ICPi treatment
As for Grade 1
Dermatology review
Punch biopsy 
Clinical photography
Symptom Grade
Management escalation pathway
Assessment and Investigations
Figure 3. ICPi-related toxicity: management of skin rash/toxicity.
Recognised skin AEs include: (i) most common: erythema, maculopapular and pustulopapular rash; (ii) rare: toxic epidermal necrolysis,
Steven-Johnson syndrome and DRESS; (iii) vasculitis may also be present with purpuric rash.
AE, adverse event; bd, twice daily; BSA, body surface area; DRESS, drug rash with eosinophilia and systemic symptoms; ICPi, immune check-
point inhibitor; i.v., intravenous; od, once daily.
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considerably since the introduction of ICPis. Both hyper- and
hypothyroidism have been reported, although hypothyroid dis-
orders are more common than hyperthyroidism. The latter is often
transient and may precede hypothyroidism. Still, little is known
about the pathogenesis of thyroid disorders following ICPis. It is
thought to be mediated by T cells and not by B cell autoimmunity.
Recently, a cohort of 51 NSCLC patients treated with pembrolizu-
mab in the Keynote-001 study was prospectively followed by
thyroid-stimulating hormone (TSH), triiodothyronine and thyro-
xine (FT3, FT4) and anti-thyroid antibodies (Abs) measurement
[28]. The incidence of thyroid dysfunction requiring thyroid hor-
mone replacement was 21% (in 80% of these patients, anti-thyroid
Abs were detected), compared with 8% in patients that did not de-
velop thyroid dysfunction. These results suggest that the pathogen-
esis of autoimmune thyroid disease and thyroid gland dysfunction
as irAEs might have a similar pathogenesis.
Thyroid dysfunction is most common upon treatment with
anti-PD-1/PD-L1 or combination of anti-CTLA4 and agents
blocking the PD-1/PD-L1 axis. With ipilimumab (3 mg/kg), the
incidence was reported to be between 1% and 5% [1, 2], but
higher incidence (up to 10%) has been observed with the higher
doses of ipilimumab (10 mg/kg) [4].
With anti-PD-1 (either pembrolizumab or nivolumab) or anti-
PD-L1 (atezolizumab) therapy, the reported thyroid dysfunction
rate varies from 5% to 10% (irrespective of tumour type) [6, 10,
12]. With combination immunotherapy (ipilimumab 3 mg/kg
plus nivolumab 1 mg/kg), the frequency of thyroid disorders in-
creases to 20% [2]. These events are rarely higher than grade 2. In
most cases, thyroid dysfunction is found by routine blood tests
(TSH and FT4); they should be carried out before every infusion or
at least once a month (in the case of 2-weekly infusions).
Management
Even with subclinical hypothyroidism, substitution with thyroid
hormone should be considered in the case of fatigue or other
complaints that could be attributed to hypothyroidism [IV–V,
B]. In symptomatic patients, especially in the case of hyperthy-
roidism, treatment with beta-blockers should be started (pro-
pranolol or atenolol) [IV–V, B]. Rarely, carbimazole or steroids
are required. In those cases, treatment with ICPis should be inter-
rupted until recovery from symptoms. Hormone replacement
therapy (HRT) is usually long lasting (see Figure 5).
Hypophysitis
Before introduction of anti-CTLA4 therapy, hypophysitis, an in-
ﬂammation of the anterior lobe of the pituitary gland, was ex-
tremely rare. Now, incidence rates of hypophysitis have been
4.5%
4.5%
18%
9%
9%
9%
9%
1%
4.5%
4.5%
4.5%
4.5%
18%
Figure 4. Schematic of body surface area (BSA).
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Withhold ICPi if patient is unwell with symptomatic hyperthyroidism
Subclinical hyperthyroidism (low TSH, normal FT4) often precedes
overt hypothyroidism
Normal
Elevated FT4
Low FT4
Repeat
If still abnormal discuss
with endocrinologist
If no symptoms, repeat next
cycle and check 9 am cortisol
(may indicate hypopituitarism)
TSH
Elevated
Normal FT4
Low FT4
If no symptoms, repeat next cycle;
If symptoms, consider thyroxine
if TSH > 10
If no symptoms, repeat next cycle;
If symptoms, initiate thyroxine
Low
Elevated FT4
Low FT4
If no symptoms, repeat next cycle; 
If symptoms hyperthyroidism:
beta blocker, thyroid Abs and
uptake scan
Check 9 am cortisol
(may indicate hypopituitarism)
Baseline Endocrine Panel:
TSH, FT4, T3* TFTs
Baseline abnormal values do not preclude
treatment; discuss with endocrinologist if uncertain
*when indicated
Monitoring during treatment:
Anti-CTLA4 (including combination with anti-PD-1)
· TFTs every cycle 
· TFTs 4-6 weeks after cycle 4 (i.e. with restaging CT)
Late endocrine dysfunction can occur
Anti-PD-1/Anti-PD-L1
· TFTs every cycle for ﬁrst 3 months, every second
cycle thereafter (in case of 2-weekly schedule)
· Cortisol as indicated by symptoms/falling TSH
A falling TSH across two measurements with normal or lowered T4 may also suggest pituitary dysfunction and weekly
cortisol measurements should be performed (see also Figure 6)
If TSH is abnormal, refer to algorithm below. Iodine from CT scans may impact TFTs
Hypothyroidism: Low FT4 with
elevated TSH or TSH > 10 with normal FT4
Treatment: Thyroxine 0.5-1.5 μg/kg
(start low in elderly, if cardiac history)
Continue ICPi
Thyrotoxicosis (DDx thyroiditis, Grave’s disease):
Investigations: Anti-TSH Receptor Ab, anti-TPO Ab,
nuclear medicine thyroid uptake scan 
Treatment: Propranolol or atenonol for symptoms; consider
carbimazole if anti-TSH Receptor Ab positive
Painful thyroiditis – consider prednisolone 0.5 mg/kg and taper 
If unwell, withhold ICPi and consider restarting
when symptoms controlled
Figure 5. ICPi monitoring and management: thyroid function.
Ab, antibody; CT, computed tomography; CTLA4, cytotoxic T-lymphocyte associated antigen 4; DDx, differential diagnosis; FT4, free thyroxine; ICPi, immune checkpoint inhibitor; PD-1, pro-
grammed death 1; PD-L1, programmed death ligand 1; T3, triiodothyronine; T4, thyroxine; TFTs, thyroid function tests; TPO, thyroid peroxidase; TSH, thyroid-stimulating hormone.
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reported for ipilimumab 3 mg/kg, ipilimumab 10 mg/kg and the
combination of ipilimumab and nivolumab in 1%, 16% and 8%,
respectively [1, 2, 4].
Hypophysitis is very rare in patients treated with anti-PD-1
and anti-PD-L1 [29].
The aetiology of anti-CTLA4-induced hypophysitis remains
unresolved. Recently, in a murine model, low-level ectopic RNA
and protein expression of CTLA4 on thyrotropin and prolactin
secreting cells of the pituitary gland [30] was demonstrated. So
far, no explanation for this expression was found. Anti-CTLA4
treatment, however, led to mononuclear cell inﬁltration in the pi-
tuitary gland, anti-pituitary antibodies and activation of the com-
plement cascade in these animals, causing inﬂammation of the
gland, similar to what has been observed in full-blown hypophy-
sitis in patients. Whether this ectopic CTLA4 expression occurs
in human is unknown.
Patients may present with different complaints. Headache and
visual disturbances require immediate evaluation and differenti-
ation between cerebral metastasis, leptomeningeal disease, cere-
brovascular disease and hypophysitis. On brain MRI, a swollen or
enlarged pituitary gland may be visible. Frequently, simultaneous
low blood levels of TSH, adrenocorticotropic hormone and/or
follicle-stimulating
hormone/luteinizing
hormone
(FSH/LH)
point towards hypophysitis as the most likely diagnosis. Patients
can present with hypothyroidism and/or hypocortisolism and with
complaints relating to low testosterone levels.
Management
Once the diagnosis is conﬁrmed, treatment with ICPis should be
interrupted in any grade 2 or higher hypophysitis and treatment
consisting of HRT should be instigated immediately [V, B]. In
the case of headaches and other neurological problems, high-
dose steroids should be given; however, high-dose steroids appear
not to counteract the hormonal deﬁciency resulting from anti-
CTLA4 treatment. In most cases, the immune checkpoint inhib-
ition can be continued. Long-term HRT is required in most
patients (see Figure 6).
Type 1 diabetes mellitus
De novo diabetes induced by treatment with ICPis occurs at low
frequency (<1%). Diabetes mellitus (DM) appears to be more
common with PD-1 and PD-L1 blockade (or combination im-
munotherapy) than with ipilimumab [31]. The PD-1 pathway
plays a role in autoimmune DM as blockade of the PD-1/PD-L1
axis triggers the development of type 1 DM mediated by speciﬁc
CD8 T cells in murine models. However, incidence of type 1 DM
may rise as a consequence of treatment of larger patient popula-
tions with anti-PD-1 or anti-PD-L1 drugs.
It is recommended that blood glucose levels are regularly
monitored in patients treated with ICPis in order to detect the
emergence of DM. This could be either type 1 or type 2 DM. Even
patients with type 2 DM may develop ketoacidosis, an infrequent
but life-threatening event that should be treated according to
standard local guidelines [I, A]. Whether treatment with high-
dose steroids can prevent total loss of beta cells of the islands of
Langerhans is unclear. Steroids will most likely negatively inﬂu-
ence diabetes control in these patients.
C-peptide and Abs against glutamic acid decarboxylase (GAD)
and islet cell (ICA) should be measured to distinguish between
type 1 and type 2 DM.
Once the patient has been regulated with insulin substitution,
restarting treatment with ICPis may be considered.
Immune-related hepatotoxicity
Incidence
Hepatitis occurs in 5%–10% (of which 1%–2% is grade 3) of
patients during therapy with ipilimumab, nivolumab and
pembrolizumab at the approved doses as single agents and in
25%–30% (of which 15% is grade 3) of those treated with the
combination of ipilimumab 3mg/kg and nivolumab 1mg/kg [2, 12].
Diagnosis
All patients undergoing ICPi therapy should be assessed for signs
and symptoms of hepatitis with serum transaminases and biliru-
bin measured before every cycle of treatment. Hepatitis is usually
asymptomatic and detected on such routine blood monitoring. If
hepatitis develops, disease-related causes, concomitant drug ad-
ministration (including alcohol) and infectious causes, particu-
larly viral hepatitis, should be ruled out. However, initiation of
therapy, if needed, should not be delayed while awaiting sero-
logical results if there is no other apparent cause.
Liver biopsy may be considered in assisting in the differential
diagnosis of more severe hepatitic reactions [15]. Lobular hepa-
titis indistinguishable from autoimmune hepatitis is most com-
monly reported [32, 33]; most cases are panlobular but
inﬂammation may be conﬁned to zone 3. Additional sinusoidal
histiocytosis and central vein endothelitis may help identify
ipilimumab-associated inﬂammation. Rare cases show portal
tract inﬂammation and cholangitis or changes indistinguishable
from non-alcoholic steatohepatitis (NASH).
Management
In the event of moderate (grade 2) transaminase or total bilirubin
elevation, checkpoint inhibitor therapy should be withheld and
transaminases and bilirubin measured twice weekly. Persistent
grade 2 elevation lasting longer than 1–2 weeks, after having ruled
out other causes, should be treated with corticosteroids at a dose
of 1 mg/kg/day (methyl)prednisolone or equivalent. Upon im-
provement, checkpoint inhibitor therapy may be resumed after
corticosteroid tapering. If worsening or no improvement occurs
despite initiation of corticosteroids, corticosteroid dose should
be increased to 2 mg/kg/day (methyl)prednisolone or equivalent
and checkpoint inhibitor therapy permanently discontinued
[IV–V, B]. For grade 3 or 4 transaminase or total bilirubin eleva-
tion, checkpoint inhibitor therapy should be permanently dis-
continued,
and
corticosteroids
started
at
1–2 mg/kg/day
(methyl)prednisolone or equivalent. If there is no response to
corticosteroids within 2–3 days, mycophenolate mofetil should
be added at 1000 mg twice daily [IV–V, B] [34]. Consultation
with a hepatologist and consideration of liver biopsy (see above)
is recommended in steroid and mycophenolate-refractory cases
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[IV–V, B]. Third-line immunosuppressive therapy is not well
deﬁned but the successful use of anti-thymocyte globulin (ATG)
has been reported in a case of ipilimumab-induced hepatitis re-
fractory to steroids and mycophenolate. Another third-line im-
munosuppressive therapy option is tacrolimus. Inﬂiximab is not
recommended for the treatment of immune-related hepatitis (see
Figure 7).
Hepatitis usually resolves within 4–6 weeks with appropriate
treatment but in the event that it does not resolve, other contribu-
tory causes should be reconsidered and the initial diagnostic
work repeated as necessary, particularly bearing in mind the con-
comitant administration of other hepatotoxic drugs (including
herbal medications and those purchased over the counter) and
cytomegalovirus (CMV) reactivation.
Gastrointestinal toxicity
GI toxicity from cancer immunotherapy is well described for
anti-CTLA4 Abs. It is less well described for anti-PD-1 and anti-
PDL-1 Abs as well as for combined anti-CTLA4 and anti-PD-1 Abs.
Gastrointestinal toxicity of anti-CTLA4 antibodies
Incidence. Diarrhoea occurs in 27%–54% of cancer patients
treated with anti-CTLA4 Abs [35]. In most series, approximately
one-third of patients have diarrhoea, while the frequency of col-
itis ranges from 8% to 22% [35]. GI toxicity is one of the most fre-
quent and is the most severe (grade 3 or higher) of irAEs
associated with anti-CTLA4 [18]. It is usually the ﬁrst irAE
Patient education (with assistance of a nurse practitioner):
“Sick day rules”, prescription and education for use of IM steroid if required
Consider alert card or bracelet
Severe mass effect symptoms,
i.e. severe headache, any visual disturbance
or
Severe hypoadrenalism, 
i.e. hypotension, severe electrolyte disturbance
Initiate i.v. (methyl)prednisolone 1 mg/kg after
sending bloods for pituitary axis assessment* 
Analgesia as needed for headache
(discuss with neurologist if resistant to
paracetamol and NSAIDs)
Withhold ICPi
MRI pituitary protocol 
also exclude brain metastases)
Consider formal visual ﬁeld assessment
(if abnormal patient to inform driver 
licensing agency)
Aim convert to prednisolone and wean
as symptoms allow over 4 weeks to 5 mg
Do not stop steroids
Refer to or consult endocrinologist
Monitor TFTs
MRI pituitary protocol
(also exclude brain metastases),
visual ﬁeld assessment
Wean steroids based on symptoms over
2-4 weeks to 5 mg prednisolone
Do not stop steroids 
Refer to or consult endocrinologist
Monitor TFTs
Moderate symptoms, i.e. headache
but no visual disturbance
or
Fatigue/mood alteration but haemodynamically
stable, no electrolyte disturbance
Oral prednisolone 0.5-1 mg/kg od after
sending pituitary axis assessment
If no improvement in 48h, treat as severe with
i.v. (methyl)prednisolone as above
Withhold ICPi
Replace cortisol and/or thyroxine per
guide below**
MRI pituitary protocol
Refer to endocrinologist
Vague symptoms
(e.g. mild fatigue, anorexia),
no headache
or
Asymptomatic 
Await pituitary axis to conﬁrm diagnosis but warn
patients to seek urgent review if unwell
Continue ICPi with appropriate HRT**
Symptoms
Management escalation pathway
Further assessment and management 
Figure 6. ICPi-related toxicity: management of hypophysitis.
*Pituitary Axis bloods: 9 am cortisol (or random if unwell and treatment cannot be delayed), ACTH, TSH/FT4, LH, FSH, oestradiol if premeno-
pausal, testosterone in men, IGF-1, prolactin. Mineralocorticoids replacement is rarely necessary in hypopituitarism.
**Initial replacement advice for cortisol and thyroid hormones:
• If 9 am cortisol < 250 or random cortisol < 150 and vague symptoms:
- Replace with hydrocortisone 20/10/10 mg
- If TFTs normal, 1–2 weekly monitoring initially (always replace cortisol for 1 week prior to thyroxine initiation)
• If falling TSH +/- low FT4
- Consider need for thyroxine replacement (guide is 0.5-1.5 mg/kg) based on symptoms þ/ check 9 am weekly cortisol
- See Thyroid Guidelines for further information regarding interpretation of an abnormal TSH/T4
ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; FT4, free thyroxine; HRT, hormone replacement therapy; ICPi, immune
checkpoint inhibitor; IGF-1, insulin-like growth factor-1; IM, intramuscular; i.v. intravenous; LH, luteinizing hormone; MRI, magnetic resonance
imaging; NSAIDs, nonsteroidal anti-inﬂammatory drugs; od, once daily; TSH, thyroid-stimulating hormone; TFTs, thyroid function tests.
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leading to anti-CTLA4 discontinuation [18]. Colon perforation
occurred in 1%–1.5% of melanoma patients receiving ipilimu-
mab [35–37]; it may reach 6.6% of patients with renal cell carcin-
oma [36], and 1.1% of patients die of complications related to
ipilimumab-induced enterocolitis [4].
In a recent series, non-steroidal anti-inﬂammatory drug
(NSAID) use was associated with an increased risk of anti-
CTLA4-induced enterocolitis [38]. Very few data are available on
the risk of immune-related colitis in patients with Crohn’s disease
(CD) and ulcerative colitis (UC). Two out of six patients with
CD or UC had ipilimumab-induced colitis or a relapse of UC
or CD [39].
Diagnosis. Onset of GI symptoms may occur at any time during
1-10 infusions of anti-CTLA4 [36]. Enterocolitis may even occur
several months after the last dose of ipilimumab [40]. The half-
life of ipilimumab is 2 weeks; however, the biological effect may
persist long after drug clearance.
The most common symptom of anti-CTLA4-induced entero-
colitis is diarrhoea [1–4]. In a recent series, 92% of patients with
anti-CTLA4-induced enterocolitis had diarrhoea [38]. Other
presenting symptoms are abdominal pain, hematochezia, weight
loss, fever and vomiting [38]. Mouth ulcers, anal lesions (ﬁstulas,
abscesses, ﬁssures) and extra-intestinal manifestations (such as
arthralgia, endocrine disorders, skin disorders, hepatitis, neph-
ritis, pericarditis and pancreatitis) may be associated with anti-
CTLA4-induced enterocolitis [38].
The main biological abnormalities observed in patients with
anti-CTLA4-induced enterocolitis are anaemia, increased serum
C-reactive protein and low serum albumin levels [38]. Faecal level
of calprotectin has been found to be elevated in patients with
ipilimumab-induced enterocolitis in one study [38] but failed to
correlate with GI toxicity in another series [41]. Abs against the
enteric ﬂora and antineutrophil cytoplasmic Abs are found in the
serum of a minority of patients with ipilimumab-induced entero-
colitis [41].
The main differential diagnoses of anti-CTLA4 enterocolitis
are GI infections and tumour-related symptoms. Stool analyses
for bacterial enteropathogens and Clostridium difﬁcile toxin
should be carried out in every patient with signiﬁcant diarrhoea
treated with anti-CTLA4. In addition, GI metastases are not un-
common in patients with disseminated melanoma and are not
Steroid wean:
· G2: once G1, wean over 2 weeks; re-escalate if worsening; treatment may be resumed once prednisolone ≤ 10 mg
· G3/4: once improved to G2, can change to oral prednisolone and wean over 4 weeks; for G3, rechallenge only at
consultant discretion
Worsening despite steroids:
· If on oral change to i.v. (methyl)prednisolone 
· If on i.v. add MMF 500-1000 mg bd
· If worse on MMF, consider addition of tacrolimus
· A case report has described the use of anti-thymocyte globulin in steroid + MMF-refractory fulminant hepatitis [31]
Grade 1:
ALT or AST > ULN-3x ULN
If > ULN–3x ULN repeat in 1 week
Continue treatment
Grade 3:
ALT or AST 5-20x ULN
As above; daily LFTs/INR/albumin
Perform US with Doppler
Low threshold to admit if clinical concern
Cease treatment
ALT/AST < 400 and normal
bilirubin/INR/albumin: oral prednisolone 1 mg/kg
ALT/AST > 400 or raised bilirubin/INR/low
albumin: i.v. (methyl)prednisolone 2 mg/kg
Grade 4:
ALT or AST > 20x ULN
As above; hepatology consult
Consider liver biopsy
i.v. (methyl)prednisolone 2 mg/kg
Permanently discontinue treatment
Grade 2:
ALT or AST 3-5x ULN
Re-check LFTs/INR/albumin every 3 days
Review medications,
e.g. statins, antibiotics and alcohol history
Perform liver screen: Hepatitis A/B/C serology,
Hepatitis E PCR, anti-ANA/SMA/LKM/SLA/LP/LCI, 
iron studies 
Consider imaging for metastases/clot
Withhold ICPi treatment
If rising ALT/AST when re-checked
start oral prednisolone 1 mg/kg
Symptom Grade
Management escalation pathway
Assessment and Investigations
Figure 7. ICPi-related toxicity: management of hepatitis.
ALT, alanine transaminase; ANA, antinuclear antibodies; AST, aspartate transaminase; bd, twice daily; ICPi, immune checkpoint inhibitor; INR,
international normalised ratio of prothrombin time; i.v. intravenous; LCI, lung clearance index; LFTs, liver function tests; LKM, liver kidney
microsomal; MMF, mycophenolate mofetil; PCR, polymerase chain reaction; SLA/LP, soluble liver antigen/liver-pancreas antibody; SMA,
smooth muscle autoantibody; ULN, upper limit of normal; US, ultrasound.
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unknown in lung cancer; these should, therefore, be eliminated.
Anti-CTLA4-induced enterocolitis should be conﬁrmed by ﬂex-
ible sigmoidoscopy or colonoscopy with biopsies. Endoscopic
lesions of anti-CTLA4 colitis are erythema/loss of vascular pat-
tern, erosions and ulcerations. The sigmoid colon and the rec-
tum
are
involved
in
most
cases;
therefore,
a
ﬂexible
sigmoidoscopy is generally sufﬁcient to make the diagnosis of
anti-CTLA4-induced enterocolitis [38]. However, endoscopic
lesions of the colon are often extensive and may extend prox-
imal to the sigmoid colon in two thirds of cases. Patchy discon-
tinuous endoscopic lesions are observed in half of the patients
[38]. The histological picture generally differs from that
observed in inﬂammatory bowel disease (IBD). In most cases, it
is that of an acute colitis (inﬁltration with neutrophils, eosino-
phils), either diffuse or focal with patchy crypt abscesses. In
some cases, features of chronic IBD such as granulomas, basal
plasmocytosis and crypt abnormalities (atrophy, distortion,
branching, budding) have been reported [38].
Upper GI symptoms (dysphagia and epigastric pain) and
endoscopic
lesions
(oesophageal
ulcerations,
gastritis,
duodenitis) have been reported [35, 38]. About half of the pa-
tients with anti-CTLA4-induced enterocolitis have chronic, mild,
patchy inﬂammation of the stomach and the duodenum (crypt
distortion, focal and heterogeneous villus shortening, increased
eosinophils and mononuclear inﬂammatory cells in the lamina
propria) [38].
Staging and risk assessment. Assessment of severity relies upon
the National Cancer Institute’s CTCAE, version 4. Severe diar-
rhoea refers to grade 3 or 4 diarrhoea but also to patients with
grade 1 or 2 diarrhoea with dehydration, fever, tachycardia or
haematochezia. Flexible sigmoidoscopy or colonoscopy is recom-
mended in patients with severe diarrhoea or persistent grade 2
diarrhoea.
Management. Two randomised trials have failed to show any
beneﬁt from oral administration of budesonide, in an attempt to
prevent occurrence of ipilimumab-induced enterocolitis [41, 42].
Patients with diarrhoea on anti-CTLA4 therapy should undergo a
workup including complete blood count, serum electrolyte
Figure 8. ICPi-related toxicity: management of diarrhoea and colitis.
bd, twice daily; CHF, congestive heart failure; CRP, C-reactive protein; CT, computed tomography; FBC, full blood count; ICPi, immune check-
point inhibitor; i.v. intravenous; LFTs, liver function tests; MMF, mycophenolate mofetil; Mx, management; NYHA, New York Heart Association;
od, once daily; PCR, polymerase chain reaction; PJP, Pneumocystis jiroveci pneumonia; TB, tuberculosis; TFTs, thyroid function tests; TPN, total
parenteral nutrition; UEC, urea, electrolytes, creatinine; VitD, vitamin D.
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proﬁle, stool analyses for enteropathogens and Clostridium difﬁ-
cile toxin (see Figure 8).
Patients with non-severe diarrhoea should be treated with anti-
diarrhoeals, ﬂuid and electrolyte supplementation, if needed
[IV–V, B] [35]. Anti-CTLA4 therapy can be continued. Patients
with persistent grade 2 diarrhoea or severe diarrhoea (grade 3/4
diarrhoea, or grade 1/2 diarrhoea with alarm symptoms, as de-
tailed above) should discontinue anti-CTLA4 therapy and receive
systemic corticosteroids (1–2 mg/kg per day, i.v.) [IV–V, B].
Patients who have a response to i.v. corticosteroids within 3–5
days should be switched to the oral form and tapered over 8–
12 weeks [35]. Patients who do not respond to corticosteroids
within 3–5 days should be switched to inﬂiximab, unless it is con-
traindicated [IV–V, B] (see Figure 8). Overall, one-third to two-
thirds of patients either do not respond to high-dose i.v. steroids,
or have a relapse requiring an increase in the corticosteroid dos-
age during the course of steroid tapering. These patients require
inﬂiximab and usually have an excellent response. A single dose
of inﬂiximab (5mg/kg) is generally sufﬁcient [18, 35, 36, 38].
Some patients may need a second dose of inﬂiximab 2 weeks after
the ﬁrst administration.
Vedolizumab is a MoAb directed towards the integrin a4b7. It
inhibits the intestinal homing of T lymphocytes. Vedolizumab is
a gut-speciﬁc immunosuppressive agent that is approved for UC
and CD. A recent case series of seven patients with mild to mod-
erate,
steroid-dependent
or
steroid-refractory
ipilimumab-
induced enterocolitis has shown that six out of seven patients
treated with vedolizumab went into remission; no AEs were
reported with vedolizumab. This preliminary study suggests that
vedolizumab is an alternative to inﬂiximab [43]. Further studies
are needed to conﬁrm the efﬁcacy and safety of vedolizumab in
patients with ipilimumab-induced enterocolitis.
Recently, a colitis, possibly due to CMV reactivation, has been
reported in a patient with medically refractory anti-CTLA4 colitis
[44]. Further studies are needed to determine whether CMV plays
a signiﬁcant role in this setting.
Some patients develop a colonic perforation, with or without
intra-abdominal abscess, either initially or during the course of
medical treatment. They should have emergency colectomy. We
recommend subtotal colectomy with ileostomy and sigmoidos-
tomy because colonic lesions are generally extensive and segmental
colonic resection is generally followed by a severe inﬂammation of
the remaining colon in the postoperative phase [38].
Prediction of ipilimumab-related colitis. No routine biomarker
has been found to predict ipilimumab-related colitis. Baseline
microbiota composition may predict ipilimumab-induced colitis.
More speciﬁcally, at baseline, an increased presence of bacteria be-
longing to the Bacteroidetes phylum species was found in patients
who remained free of colitis after ipilimumab treatment [45]. A re-
cent study has shown that distinct baseline gut microbiota com-
position is associated with colitis. Most of the baseline colitis-
associated phylotypes were related to Firmicutes (e.g. relatives of
Faecalibacterium prausnitzii and Gemmiger formicilis), whereas no-
colitis related phylotypes were assigned to Bacteroidetes [46].
Follow-up and long-term implications. Several studies have found
associations between ipilimumab-induced enterocolitis and tumour
regression or overall survival (OS) [36, 47]. However, in a dose
escalation study, higher serum levels and prolonged administration
of anti-CTLA4 Abs resulted in a trend toward a greater incidence of
grade 3/4 autoimmune toxicity, but did not seem to increase anti-
cancer response rates [48].
Neither corticosteroids nor inﬂiximab appear to affect re-
sponse and OS of patients treated with ipilimumab [18, 47].
A study has shown that some patients have endoscopic or
histological inﬂammation of the colon (including chronic in-
ﬂammation) several months after the onset of enterocolitis [38].
In this study, three out of nine patients had chronic colitis on
biopsies [38]. More studies are needed to determine whether the
changes in these patients may evolve into chronic IBD.
In a recent study, four out of six patients who had an additional
infusion of ipilimumab after going into enterocolitis remission
relapsed [38]. Among them, three patients required a new steroid
course, including one patient who had a severe steroid-refractory re-
lapse requiring inﬂiximab infusion. Reintroduction of anti-CTLA4
in patients, who had previously experienced enterocolitis, poses a
high risk of relapse and should be discussed on an individual basis.
In a recent randomised trial that compared nivolumab followed
by ipilimumab, or the reverse sequence, in patients with advanced
melanoma, a severe AE with the ﬁrst agent did not predict toxicity
with the second one [49]. This was conﬁrmed by a recent study,
which showed that, among 47 patients who had an anti-CTLA4-
induced colitis, only one relapsed under anti-PD-1 [49].
Gastrointestinal toxicity of anti-PD-1 antibodies
Very few data are available about GI irAEs associated with anti-PD-
1 MoAbs. Diarrhoea and colitis are more frequent with anti-CTLA4
agents than with either nivolumab or pembrolizumab, with grade 3
to 4 AEs occurring in 1%–2% of cases [2, 50]. A case series of
19 patients with GI toxicity after anti-PD-1 Ab administration has
been published [51]. The median time from drug initiation to symp-
tom onset was 3months. The most common symptom was diar-
rhoea,
followed
by
nausea/vomiting
and
abdominal
pain.
Endoscopic ﬁndings consisted in normal mucosa or inﬂammation
ranging from mild erythema to severe inﬂammation (mucosal fri-
ability or ulceration). Histological ﬁndings included lamina propria
expansion, villus blunting, intra-epithelial neutrophils and increased
crypt/gland apoptosis. Intra-epithelial lymphocytes were rarely
prominent. A recent pathology study based upon eight cases has
described two patterns: active colitis with neutrophilic crypt micro-
abscesses and atrophy as well as crypt epithelial cell apoptosis
(n¼ 5) or lymphocytic colitis characterised by increased intraepi-
thelial lymphocytes (n¼ 3) [51]. A preliminary report conﬁrmed
and extended this description. It depicted four different patterns of
GI irAEs induced by anti-PD-1 Abs: acute colitis similar to that
induced by anti-CTLA4 Abs, microscopic colitis, upper GI involve-
ment and pseudo-obstruction [52]. In this study, 87.5% of patients
responded to corticosteroids.
Gastrointestinal toxicity of combined anti-CTLA4
and anti-PD-1 antibodies
Diarrhoea and colitis, including severe forms, occur earlier
(Figure 2) and are more frequent with combined anti-CTLA4
and anti-PD-1 agents than with either ipilimumab [2, 53, 54] or
anti-PD-1 [2]. Other GI toxicities may also occur, including
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pancreatitis and small bowel enteritis, which may be visible on
CT scan. These rare toxicities require discontinuation of ICPi
treatment and initiation of immunosuppression treatment.
There is a need for a more detailed description of GI irAEs associ-
ated with combined anti-CTLA4 anti-PD-1 Abs.
Immune-related pneumonitis
Pneumonitis associated with checkpoint blockade is a toxicity of
variable onset and clinical, radiological and pathological appear-
ances, which has been observed with anti-PD-1/PD-L1 MoAbs
and, more rarely, with anti-CTLA4 MoAbs. It is more common
when anti-PD-1/PD-L1 MoAbs are combined with anti-CTLA4
MoAbs. Several cases of distinct life-threatening respiratory
events have been reported under anti-CTLA4 monotherapy.
Acute interstitial pneumonitis/diffuse alveolar damage syndrome
(DADS) is the most acute, life threatening event [55], but
organising inﬂammatory pneumonia, as well as a sarcoidosis-like
pulmonary granulomatosis have been described and may result
in difﬁculties in differential diagnosis with progression of disease
[56–58]. Rarely, pneumonitis worsens despite immunosuppres-
sion, and may be fatal due to infection or progressive disease.
Using treatment with anti-PD-1/PD-L1 MoAbs, respiratory
events like cough and dyspnoea have been documented in up to
20%–40% of patients, with grade 3 to 4 cough in 2%–9% and
grade 3 to 4 dyspnoea in 1%–2% of patients, respectively [59–
61]. Documentation of pneumonitis occurs in 2%–4% of pa-
tients, with 1%–2% grade  3 events, frequency of fatal pneu-
monitis in 0.2% and discontinuation due to pneumonitis in
0.2%–4% [6, 7, 62–65]. In the absence of any direct comparison,
to date there is no compelling evidence that this incidence might
signiﬁcantly differ between anti-PD-1 and anti-PD-L1 com-
pounds [63].
Data documenting pulmonary immune-related toxicities have
been progressively reported from retrospective series, from large
published prospective trials and subsequent expanded access pro-
grams, especially in the treatment of melanoma, NSCLC and
renal carcinoma. To date, however, immune-induced pneumon-
itis remains relatively poorly described.
Whereas pulmonary AEs are most often related to disease pro-
gression, particularly in the context of lung cancer or lung meta-
stases, any new respiratory symptom should prompt a dedicated
evaluation to formally exclude lung toxicity. All patients present-
ing with pulmonary symptoms, such as an upper respiratory in-
fection, new cough, shortness of breath or hypoxia should be
assessed by CT. Any respiratory symptom or sign must be care-
fully monitored, since fatal and life-threatening cases of pneu-
monitis have been reported.
Incidence
The incidence of pneumonitis is higher—possibly 1.5–2 times
more frequent, in patients receiving anti-PD-1 therapy compared
with ipilimumab monotherapy, as reported across several melan-
oma trials [12].
The combination of anti-PD-1/PD-L1 MoAbs with CTLA4 in-
hibition signiﬁcantly increases the risk of pneumonitis, with up to
3 times more all-grade and grade  3 events compared with mono-
therapy reported in a 3-arm randomised melanoma trial [2].
Incidence of pneumonitis was recently reported in a multi-
centre large retrospective analysis of patients receiving anti-PD-
1/PD-L1 monotherapy or in combination with anti-CTLA4, as
diagnosed by the treating investigator after exclusion of a tumou-
ral or infectious aetiology [66]. Of 915 patients who received
anti-PD-1/PD-L1 MoAbs, pneumonitis developed in 4.6%. Time
to onset of pneumonitis ranged from 9 days to 19.2 months, with
a median time to onset of 2.8 months, and tended to occur earlier
in
patients
receiving
combination
therapy
(2.7
versus
4.6 months). The incidence of pneumonitis was higher with com-
bination immunotherapy versus monotherapy (10% versus 3%).
Incidence was similar in patients with melanoma and NSCLC
(5% versus 4%) overall, in monotherapy (3.6 versus 3.3%) and
combination therapy (9.6% versus 7%). Of these, 72% were grade
1 to 2, and 86% improved or resolved with drug withholding and
immunosuppression. Pneumonitis occurred irrespective of the
line of therapy in which immunotherapy was received.
Although it may be observed at any time, pneumonitis tends to
occur later than other irAEs, commonly some months after treat-
ment was initiated. The rate of grade 3 to 4 pneumonitis is similar
across tumour types and irrespective of dosage; however, there
have been more treatment-related deaths due to pneumonitis in
patients with NSCLC [13, 67]. Of note, detection, diagnosis and
management of such symptoms have largely improved over time,
and related mortality has been signiﬁcantly reduced, making
pooled analysis difﬁcult to be interpreted in this context.
Importantly, radiological features of pneumonitis are not
pathognomonic, and can include ground glass opacities, a
cryptogenic organising pneumonia-like appearance and intersti-
tial pneumonia pattern [55, 66, 68], as well as characteristics of
hypersensitivity pneumonitis.
In general, lung biopsy is not required for subsequent patient
management. However, if there is radiological or clinical doubt
as to the aetiology of pulmonary inﬁltrates, then biopsy may pro-
vide an answer. It may assist in discriminating acute infection, or
lepidic or lymphangitic spread of NSCLC, from a variety of in-
ﬂammatory changes described above. If not apparent clinically,
identiﬁcation of DADS may be useful in terms of treatment and
prognostication. Other patterns of lung reaction attributed to
immunotherapy are not speciﬁc and reﬂect a range of chronic in-
ﬂammatory, presumably immune-related processes, giving rise
to changes such as non-speciﬁc interstitial pneumonitis, sarcoid-
like [69] or hypersensitivity pneumonitis-like changes and
organising pneumonia pattern of changes. All of these may be
seen in other drug toxicities or in non-drug-related scenarios.
While transbronchial lung biopsy may secure a diagnosis of infec-
tion or malignancy, and perhaps granulomatous disease or
organising pneumonia, a surgical lung biopsy using video-
assisted thoracoscopic surgery is more likely to secure a speciﬁc
diagnosis. The decision to proceed with biopsy, and choice of
technique, will depend on the location and distribution of disease
on imaging, the availability of a thoracic surgical intervention
team and any speciﬁc risks to the patient. If a biopsy is taken, it is
vital that the reporting pathologist is informed about the back-
ground to, and reason for, the diagnostic procedure.
Alternatively, depending on the radiological pattern on CT
scan, a bronchoscopy with bronchoalveolar lavage will support
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the identiﬁcation of infections, including potential opportunistic
or atypical agents, and is recommended in any symptomatic
pneumonia.
Management
In the case of documented or high suspicion of immune-related
pneumonitis, immunosuppressive treatment should be started
immediately. Ideally, an infection should be ruled out by bron-
choscopy, especially in the case of grade  2 pneumonitis, in
order to be able to safely introduce the immunosuppressive treat-
ment. If the infectious status cannot be reliably assessed, most
algorithms advocate the administration of oral or i.v. broad spec-
trum antibiotics in parallel to the immunosuppressive treatment
in grade  3 pneumonitis (see Figure 9).
In grade 1 to 2 pneumonitis, treatment consists of oral steroids
with prednisone 1 mg/kg daily or equivalent [IV–V, B]. Patients
should be clinically assessed every 2–3 days initially and, ideally,
also radiologically in grade 2 pneumonitis. Steroids should be
tapered over 4–6weeks after recovery and reintroduction of the
checkpoint inhibitor should be delayed until the daily dose of ster-
oids equals 10 mg of oral prednisone per day or less.
In grade 3 to 4 moderate to severe cases, the patient should be
hospitalised and treatment should consist of high-dose i.v.
Withhold ICPi
Start Ab if suspicion of infection
(fever, CRP, neutrophil counts)
If no evidence of infection or no improvement with Ab
after 48h add in prednisolone 1 mg/kg/day orally 
Consider Pneumocystis prophylaxis depending
on the clinical context
High resolution CT +/- bronchoscopy and
BAL pending appearances
Discontinue ICPi
Admit patient, baseline tests as above
(methyl)prednisolone i.v. 2-4 mg/kg/day
High resolution CT and respiratory review
+/- bronchoscopy and BAL pending appearances
Cover with empiric Ab
Discuss escalation and ventilation
Grade 1: 
Radiographic changes only
Ground glass change, 
non-speciﬁc interstitial pneumonia
Baseline indications:
Chest X-ray
Bloods (FBC/UEC/LFTs/TFTs/Ca/ESR/CRP) 
Consider sputum sample and screening for viral,
opportunistic or speciﬁc bacterial
(Mycoplasma, Legionella) infections depending
on the clinical context
Consider delay of treatment
Monitor symptoms every 2-3 days 
If worsens: treat as grade 2 or 3-4
Grade 2:
Mild/moderate new symptoms
Dyspnoea, cough, chest pain
Outpatient Monitoring:
Monitor symptoms daily
Baseline indications, as above plus: 
Repeat chest X-ray weekly and baseline bloods
Lung function tests including TCLO 
If no improvement after 48h of oral
prednisolone, manage as per Grade 3
Symptom Grade
Management escalation pathway
Assessment and Investigations
Grade 3 or 4:
Severe new symptoms
New/worsening hypoxia
Life threatening 
Difﬁculty in breathing, ARDS
Add inﬂiximab 5 mg/kg or MMF if concurrent 
hepatic toxicity
Continue with i.v. steroids- wean as clinically indicated
History:
Pulmonary hypertension/respiratory
disease/connective tissue disease 
Inﬂuenza/Mycobacterium tuberculosis exposure
Smoking history
Travel history
Allergy history including exposure to
home/occupational aeroallergens
Differential Diagnosis:
Pneumonia (including atypical,
pneumocystis, tuberculosis)
Lymphangitis
Usual interstitial pneumonias 
Pulmonary oedema
Pulmonary emboli
Sarcoidosis
Once improved to baseline:
Grade 2: wean oral steroids over at least 6 weeks,
titrate to symptoms
Grade 3/4: wean steroids over at least 8 weeks
Steroid considerations:
Calcium & Vitamin D supplementation as
per local guidelines
Pneumocystis prophylaxis - cotrimoxazole 480 mg
bd M/W/F or inhaled pentamidine if cotrim allergy
If not improving or
worsening after 48h
Figure 9. ICPi-related toxicity: management of pneumonitis.
Ab, antibody; ARDS, acute respiratory distress syndrome; BAL, bronchoalveolar lavage; bd M/W/F, twice daily Monday/Wednesday/Friday; Ca,
calcium; CRP, C-reactive protein; CT, computed tomography; ESR, erythrocyte sedimentation rate; FBC, full blood count; ICPi, immune check-
point inhibitor; i.v., intravenous; LFT, liver function tests; MMF, mycophenolate mofetil; TCLO, transfer factor for carbon monoxide; TFT, thyroid
function tests; UEC, urea, electrolytes, creatinine.
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corticosteroids [(methyl)prednisolone 2–4mg/kg/day or equivalent],
and immunotherapy treatment permanently discontinued [IV–
V, B]. Where the patient’s condition does not improve or there is
no imaging improvement after 2 days, additional immunosup-
pressive strategies should be implemented [55, 70, 71]. The add-
ition
of
inﬂiximab,
mycophenolate
mofetil
(MMF)
or
cyclophosphamide are possible options. Tapering of steroids
should be very slow and careful, over 6 weeks or more; relapses of
pneumonitis during steroid tapering have been reported, adding
considerations about recurrence in patients who rechallenge im-
munotherapy [66].
Rare-immune related toxicities
Neurological toxicity
The incidence of neuro-related AEs is reported as 1%. However, a
recent analysis of 59 trials, involving 9208 patients reported a
higher incidence: 3.8% in patients receiving anti-CTLA4, 6.1% in
patients receiving anti-PD-1 agents and 12% in patients receiving
anti-CTLA4 in combination with anti-PD-1 drugs. The time to
onset varied from 6 to 13 weeks. A range of neurological events
have been described, including polyneuropathy, facial nerve
palsy, demyelination, myasthenia gravis, Guillain Barre´ syn-
drome, posterior reversible leukoencephalopathy, transverse
myelitis, enteric neuropathy, encephalitis and aseptic meningitis.
It is important to rule out progression of the underlying cancer,
seizure activity, infection and metabolic derangement as causes
of neurological impairment. Depending on the clinical presenta-
tion and imaging of the central nervous system, nerve conduction
studies and lumbar puncture may assist in diagnosis. Early con-
sultation with a neurologist is advised.
For all but mild (grade 1) neurological symptoms, checkpoint
inhibitor therapy should be withheld until the nature of the AE is
deﬁned [V, B]. In the case of moderate symptoms prednisolone
0.5–1 mg/kg should be considered. High-dose steroid therapy
with oral prednisolone (1–2 mg/kg) or i.v. equivalent should be
used in the event of signiﬁcant neurological toxicity [V, B].
Additionally, plasmapheresis or i.v. immunoglobulin (Ig) may be
required in the treatment of myasthenia and Guillain Barre´ syn-
drome [V, B] (see Figures 10–12).
Cardiac toxicity
The incidence of cardiac AEs is <1%, but a wide range of toxic-
ities including myocarditis, pericarditis, arrhythmias, cardiomy-
opathy and impaired ventricular function have been reported
after treatment with ipilimumab, pembrolizumab and nivolumab
[72–75]. However, the incidence of cardiac toxicity is higher with
the combination of ipilimumab and nivolumab (0.27%) com-
pared with nivolumab alone (0.06%). Early consultation with a
cardiologist is recommended [V, B]. High-dose corticosteroids
have been used successfully to treat cardiac side-effects and
should be instituted rapidly if checkpoint inhibitor induced car-
diac AEs are suspected. Escalation to other immunosuppressive
drugs, such as inﬂiximab, MMF and ATG, may be necessary if
symptoms do not promptly respond to steroids [V, B].
Rheumatological toxicity
Mild or moderate myalgias and arthralgias occur in 2%–12% of
patients and are more common with anti-PD-1 agents [76].
Vasculitis, polymyositis, myositis and temporal arteritis have also
been described [73]. For mild or moderate symptoms, analgesia
with paracetamol and/or NSAIDs is recommended [V, B]. In
addition, moderate symptoms may respond to prednisolone at a
dose of 10–20 mg/day or equivalent. Severe symptoms should
prompt consultation with a rheumatologist and consideration of
the use of high-dose corticosteroids and TNFa-blocking agents
[V, B] (see Figure 13).
Renal toxicity
Renal dysfunction is rare with ipilimumab and with anti-PD-1
therapies, occurring in <1% of treated patients [77]. The inci-
dence is much higher with combination of ipilimumab plus nivo-
lumab, reaching 4.9%, with 1.7% of grade 3 to 4 toxicity.
Similarly, sequential therapy with ipilimumab followed by nivo-
lumab is associated with a high incidence of 5.1%, of which 2.2%
of cases developed grade 3 to 4 nephritis [78]. Serum sodium, po-
tassium, creatinine and urea should be measured before every in-
fusion of checkpoint inhibitor and derangement of renal
function managed initially by stopping nephrotoxic drugs
(including over the counter medications), ruling out infection,
urinary
tract
obstruction
and
correcting
hypovolaemia.
Checkpoint inhibitor therapy should be withheld in the event of
signiﬁcant renal dysfunction and consideration given to the use
of systemic corticosteroid therapy [0.5–2 mg (methyl)predniso-
lone or equivalent] [V, B]. In the event of severe renal dysfunc-
tion, a nephrologist should be consulted. Renal biopsy may be
used to clarify a difﬁcult differential diagnosis [V, B]. In one series
of patients who were biopsied after developing acute kidney in-
jury while on ICPis an acute tubulo-interstitial nephritis with
lymphocytic inﬁltration was the most frequent ﬁnding [79].
Recently, a severe case of antineutrophil cytoplasmic antibody-
associated rapid progressive glomerulonephritis was described in
a patient with thymic epithelial carcinoma on pembrolizumab
treatment [80]. In keeping with pathology described in other
organs, granulomatous changes were seen in about a quarter
of patients and one had thrombotic microangiopathy (see
Figure 14).
Ocular toxicities
irAEs of the eye are rare and occur in <1% of patients treated
with ICPis [81]. These AEs can be divided into ocular inﬂamma-
tion, such as peripheral ulcerative keratitis, uveitis and Vogt–
Koyanagi–Harada syndrome, orbital inﬂammation, including
thyroid-associated orbitopathy and idiopathic orbital inﬂamma-
tion (sceritis, myositis, neuritis, dacryadenitis) and retinal and
choroidal disease (choroidal neovascularisation and melanoma-
associated retinopathy). Treatment of these rare toxicities de-
pends on their severity, with topical corticosteroids in the case of
episcleritis and anterior uveitis, and systemic corticosteroids in
the case of severe ocular inﬂammation and orbital inﬂammation.
Intravitreal anti-vascular endothelial growth factor (VEGF) is
indicated for choroidal neovascularisation.
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Haematological toxicities
Immune-related haematological AEs have rarely been described in
patients treated with ICPi and do seem to occur. So far, lethal
aplastic anaemia, autoimmune haemolytic anaemia and immune
thrombocytopenic purpura have been described [82–84]. The op-
timal treatment of these often severe AEs is unknown. Initiation of
high-dose corticosteroids and other immunosuppressive drugs
should be carried out in close collaboration with a haematologist.
Allograft rejection
The limited literature suggests that ipilimumab as a single agent
may be administered without necessarily causing rejection of car-
diac, renal and liver allografts. However, several recent case re-
ports have documented the risk of acute allograft rejection after
anti-PD-1 therapy [85]. As such, this very signiﬁcant risk must be
considered in discussing systemic therapy options in patients that
might potentially beneﬁt from anti-PD-1 therapy but who have
allografted organs.
Methodology
These Clinical Practice Guidelines were developed in accordance
with the ESMO standard operating procedures for Clinical Practice
Guidelines
development
www.esmo.org/Guidelines/ESMO-
Guidelines-Methodology. The relevant literature has been selected
by the expert authors. A summary of recommendations is shown in
Table 2. Levels of evidence and grades of recommendation have
been applied using the system shown in Table 3. Statements with-
out grading were considered justiﬁed standard clinical practice by
the experts and the ESMO Faculty. This manuscript has been sub-
jected to an anonymous peer review process.
If worsening symptoms
manage as per severe
Withhold ICPi 
Initial observation reasonable or
initiate prednisolone 0.5-1 mg/kg
(if progressing, e.g. from mild) and/or
pregabalin or duloxetine for pain
Resume ICPi once returns to grade 1
Withhold ICPi and admit patient
Initiate (methyl)prednisolone 2 mg/kg i.v.
Involve neurologist in care 
Daily neurological review +/- daily vital capacity 
See Figure 11 for speciﬁc disorder treatments
Mild: no interference with function,
symptoms not concerning to patient 
Any mild cranial nerve problem should be
managed as ‘moderate’
Comprehensive neurological examination
Diabetic screen, B12/folate, HIV, TSH, consider
vasculitic & autoimmune screen, review alcohol
history & other medications 
Consider need for MRI/MRA
brain or spine (exclude CVA, structural cause)
Low threshold to withhold ICPi and monitor
symptoms for another week versus continue
ICPi; close monitoring for any progression
Moderate: some interference with
ADL, symptoms concerning to patient
As above
Consider NCS/EMG for lower motor neurone
motor and/or sensory change
Consider pulmonary function/sniff/diaphragmatic
function tests
Consider neurological consult
See Figure 11 for special indications
for speciﬁc disorders
MRI brain/spine advised
NCS/EMG
Lumbar puncture
Pulmonary function assessment
See Figure 11 for special indications
for speciﬁc disorders
Symptom Grade
Management escalation pathway
Assessment and Investigations
Severe: limits self-care and aids warranted,
life threatening, e.g. respiratory problems
Advice on steroid wean:
Conversion from i.v. to oral steroids at clinician discretion
once improvement noted
Suggested oral prednisolone taper for 4-8 weeks
Consider PJP prophylaxis/Vitamin D if > 4-week duration
Multidisciplinary team involvement:
Physiotherapy, occupational therapy and speech therapy as appropriate,
ophthalmology review for ocular/cranial nerve issues
Orthotic devices, e.g. for foot drop, should be considered
Figure 10. ICPi-related toxicity: management of suspected peripheral neurological toxicity.
ADL, activities of daily living; CVA, cerebrovascular accident; HIV, human immunodeﬁciency virus; ICPi, immune checkpoint inhibitor; i.v. intra-
venous; MRA, magnetic resonance angiogram; MRI, magnetic resonance imaging; NCS/EMG, nerve conduction studies/electromyography;
PJP, Pneumocystis jiroveci pneumonia; TSH, thyroid-stimulating hormone.
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Check for ocular muscle and
proximal muscle fatigability
AChR and anti-MuSK antibodies
Bedside tests, e.g. Tensilon test or ice pack
test with neurological input
Repetitive nerve stimulation and single ﬁbre EMG
Guillain-Barré syndrome: 
Progressive symmetrical muscle weakness with absent
or reduced tendon reﬂexes – involves extremities,
facial, respiratory and bulbar and oculomotor
muscles; dysregulation of autonomic nerves 
Use of steroids not recommended in idiopathic GBS;
however, trial of (methyl)prednisolone 1-2 mg/kg reasonable
Neurological consult
If no improvement or worsening, plasmapheresis
or IVIG indicated
Consider location of care where ventilatory support
available (required in 15%-30% idiopathic cases)
Nerve conduction studies (acute polyneuropathy)
Lumbar puncture (elevated protein with
normal WBC count)
Pulmonary function tests with vital capacity and
maximum inspiratory/expiratory pressures 
Antibody testing for GBS variants, e.g. GQ1b in
Miller Fisher variant
Myasthenia Gravis:
Fluctuating muscle weakness (proximal limb,
trunk, ocular, e.g. ptosis/diplopia or bulbar)
with fatigability, respiratory muscles
may also be involved
Steroids indicated (oral or i.v. depending on symptoms)
Pyridostigmine initial dose 30 mg tds
Neurological consult
If no improvement or worsening, plasmapheresis
or IVIG may be considered
Additional immunosuppressants azathioprine,
cyclosporine, mycophenolate
Avoid certain medications, e.g. ciproﬂoxacin,
beta-blockers, that may precipitate cholinergic crisis
Suspected syndrome
Suggested Investigations
Management approach
Other syndromes reported:
Motor and sensory peripheral neuropathy, multifocal radicular neuropathy/plexopathy, autonomic neuropathy, phrenic nerve palsy, cranial nerve palsies
(e.g. facial nerve, optic nerve, hypoglossal nerve)
Steroids suggested as initial management where indicated with neurology specialist input and close attention to potential for respiratory or visual compromise
Figure 11. ICPi-related toxicity: management of suspected peripheral neurological toxicity.
AChR, acetylcholine receptor; EMG, electromyography; GBS, Guillain-Barre´ syndrome; ICPi, immune checkpoint inhibitor; i.v., intravenous; IVIG, intravenous immunoglobulin; MuSK, muscle
speciﬁc kinase; tds, three times a day; WBC, white blood cell.
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Lumbar puncture- M/C/S (normal Gram stain, WBCs
usually < 250/mm3 with lymphocyte predominance,
elevated protein but < 150 mg/dL, usually
normal glucose but can be elevated), PCR for
HSV & consider viral culture, cytology
CNS imaging 
Consider viral serology
Aseptic meningitis:
Exclusion of infective causes paramount
Headache, photophobia, neck stiffness with fever or
may be afebrile, vomiting; normal cognition/cerebral
function (distinguishes from encephalitis)
Exclude bacterial and ideally
viral infections prior to high-dose steroids
Oral prednisolone 0.5-1 mg/kg or i.v.
(methyl)prednisolone 1-2 mg/kg if very unwell
Consider concurrent empiric antiviral
(i.v. acyclovir) and antibacterial therapy
Lumbar puncture- M/C/S (normal Gram stain,
WBCs < 500/μL, normal glucose), PCR for HSV, cytology
CNS imaging to exclude brain metastases
and leptomeningeal disease
Encephalitis:
Exclusion of infective and metabolic causes paramount
Confusion or altered behaviour, headaches, alteration
in Glasgow Coma Scale, motor or sensory deﬁcits,
speech abnormality, may or may not be febrile
As above for aseptic meningitis 
Suggest concurrent i.v. acyclovir
until PCR result obtained
Suspected syndrome
Suggested Investigations
Management approach
Other syndromes reported:
Neurosarcoidosis, Posterior Reversible Leucoencephalopathy Syndrome (PRES), Vogt-Harada-Koyanagi syndrome, Neurosarcoidosis, demyelination, vasculitic encephalopathy, generalised seizures
MRI brain and spine
Lumbar puncture – may be normal but lymphocytosis,
elevated protein may be noted, oligoclonal bands
not usually present, cytology
Serum B12/HIV/syphilis/ANA/anti-Ro
and anti-La Abs, TSH, anti-aquaporin-4 IgG
Transverse myelitis:
Acute or subacute neurological signs/symptoms
of motor/sensory/autonomic origin;
most have sensory level; often bilateral symptoms
(Methyl)prednisolone 2 mg/kg (or consider 1 g/day)
Neurology consultation
Plasmapheresis may be required if
non-steroid responsive
Figure 12. ICPi-related toxicity: management of suspected central neurological toxicity.
Abs, antibodies; ANA, antinuclear antibody; CNS, central nervous system; HIV, human immunodeﬁciency virus; HSV, Herpes simplex virus; ICPi, immune checkpoint inhibitor; IgG, immuno-
globulin G; i.v., intravenous; M/C/S, microscopy, culture and susceptibility; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; TSH, thyroid-stimulating hormone; WBCs, white
blood cells.
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Escalate analgesia and use diclofenac or
naproxen or etoricoxib
If inadequately controlled, initiate prednisolone
10-20 mg or consider intra-articular steroid
injections for large joints
Consider withholding ICPi and resuming upon symptom
control, prednisolone < 10 mg; if worsens
treat as per Grade 3
Grade 1:
Mild pain with inﬂammation,
erythema or joint swelling
Complete rheumatological history regarding DDx
above and examination of all joints and skin
Consider plain X ray/imaging to exclude
metastases if appropriate
Autoimmune blood panel (as above)
Arthralgia: Pain in the joints without associated swelling; may be found in conjunction with myalgia (muscle pain), a common AE 
DDx to consider:
· Arthritis (see Figure 14 for further tests and management)
· Polymyalgia rheumatica (see arthritis as may present with small joint synovitis)
· Myositis (characterised by tenderness to palpation of muscle)
Due to the paucity of literature on management of this AE, this algorithm serves as a general guide only; seek rheumatology advice if severe symptoms not responding to steroids
Initiate analgesia with paracetamol and ibuprofen
Continue ICPi
Grade 2:
Moderate pain associated with
the above, limits instrumental ADL
Complete history and examination as above;
autoimmune blood panel
US +/- MRI imaging of affected joints
Consider early referral to a rheumatologist
Grade 3:
Severe pain; irreversible joint
damage; disabling; limits self-care ADL
As for Grade 2
Seek rheumatologist advice and review
Withhold ICPi
Initiate prednisolone 0.5-1 mg/kg
If failure of improvement after 4 weeks or worsening
in meantime – refer patient to rheumatologist 
(consider anti-TNFα therapy)
Symptom Grade
Management escalation pathway
Assessment and Investigations
Figure 13. ICPi-related toxicity: management of arthralgia.
ADL, activities of daily living; AE, adverse event; DDx, differential diagnosis; ICPi, immune checkpoint inhibitor; MRI, magnetic resonance imaging; TNFa, tumour necrosis factor alpha; US,
ultrasound.
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Withhold ICPi; hydration and review creatinine
in 48h-72h; if not improving, discuss
with nephrologist and need for biopsy and
if attributed to irAE, initiate steroids
(oral prednisolone 0.5-1 mg/kg)
Repeat creatinine/K+ every 48h
If returns to G1/baseline – recommence ICPi
(if on steroids, only once < 10 mg prednisolone)
If not attributed to irAE - may continue ICPi
Grade 1:
creatinine 1.5 x baseline
or > ULN-1.5x ULN
Review hydration status, medications, urine
test/culture if urinary tract infection symptoms
Dipstick urine and send for protein assessment
UPCR
If obstruction suspected: renal ultrasound
+/- doppler to exclude obstruction/clot
Continue ICPi
Repeat creatinine weekly
If worsens, manage as per criteria below
Grade 2:
creatinine > 1.5-3x
baseline or > 1.5-3x ULN
As above
Renal ultrasound +/- doppler to exclude obstruction/clot
If proteinuria: for 24 h collection or UPCR
If blood: phase contrast microscopy and GN screen*
if nephrologist recommends
Advise patient to notify if oliguric
Grade 3:
creatinine > 3x
baseline or > 3-6x ULN
As above for Grade 3
Withhold ICPi; admit patient for monitoring and ﬂuid
balance; repeat creatinine every 24h; early discussion
with nephrologist and need for biopsy; if worsening,
initiate i.v. (methyl)prednisolone 1-2 mg/kg
Grade 4:
creatinine > 6x ULN
As above for Grade 4
As per G3; patient should be managed in hospital
where renal replacement therapy is available 
Symptom Grade
Management escalation pathway
Assessment and Investigations
Figure 14. ICPi-related toxicity: management of nephretis.
Renal injury occurs in around 1%–4% of patients treated with ICPi, usually in a pattern of acute tubulo-interstitial nephritis with a lymphocytic inﬁltrate [79]. Attention needs to be paid to
the patient’s baseline creatinine, not just abnormal results per biochemistry ULN. Confounding diagnoses include dehydration, recent i.v. contrast, urinary tract infection, medications, hypo-
tension, or hypertension. Early consideration for renal biopsy is helpful which may negate the need for steroids and determine whether renal deterioration is related to ICPis or other path-
ology. Oliguria should prompt inpatient admission for careful ﬂuid balance and plan for access to renal replacement therapy. Steroid wean: begin to wean once creatinine G1; G2 severity
episode—wean steroids over 2–4 weeks; G3/4 episode—wean over  4 weeks. If on steroids for > 4 weeks—PJP prophylaxis, calcium/vitamin D supplementation, gastric protection and
check afternoon glucose for hyperglycaemia. *GN screen: ANA, complement C3, C4, ANCA, anti-GBM, hepatitis B and C, HIV, immunoglobulins and protein electrophoresis.
ANA, antinuclear antibody; ANCA, anti-neutrophil cytoplasmic antibody; GBM; glomerular basement membrane; GN, glomerulonephritis; HIV, human immunodeﬁciency virus; ICPi, immune
checkpoint inhibitor; irAE, immune-related adverse event; i.v., intravenous; K, potassium; PJP, Pneumocystis jiroveci pneumonia; ULN, upper limit of normal; UPCR, urine protein to creatinine
ratio.
Clinical Practice Guidelines
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Table 2. Summary of recommendations for immune-related toxicities
Immune-related skin toxicity
• For grade 1–2 skin AEs, continue (at least 1 week) with ICPis. Start topical emollients, antihistamines in the case of pruritus and/or topical (mild strength)
corticosteroid creams. Reinitiate ICPi when  grade 1.
• For grade 3 skin AEs, interrupt ICPi and start immediate treatment with topical emollients, antihistamines and high strength corticosteroid creams [II, B].
• For grade 4 skin AEs, discontinue ICPi (permanently), consider admitting patient and always consult dermatologist immediately. Start i.v. corticosteroids
[1–2 mg/kg (methyl)prednisone] and taper based on response of AE [II, B].
Immune-related endocrinopathies
• In symptomatic hyperthyroism patients, usually grade 1 or 2, interrupt ICPi, start beta-blocker therapy (propranolol or atenolol/metoprolol). Restart ICPi
when asymptomatic [IV–V, B].
• In the case of hypothyroidism, rarely > grade 2, start HRT depending on the severity (50–100 lg/day). Increase the dose until TSH is normal. In the case of
inﬂammation of the thyroid gland, start prednisone orally 1 mg/kg. Taper based on recovery of clinical symptoms. Consider interruption of ICPi treatment
when symptomatic [IV–V, B].
• In the case of hypophysitis (rarely > grade 2), when headache, diplopia or other neurological symptoms are present, start (methyl)prednisone 1 mg/kg or-
ally and taper over 2–4 weeks. Start HRT depending on the affected hormonal axis (levothyroxine, hydrocortisol, testosterone) [V, B].
• In patients with type I DM grade 3 to 4 [ketoacidotic (sub)coma], admit to hospital immediately and start treatment of newly onset type I DM [I, A]. Role
of corticosteroids in preventing complete loss of insulin producing cells is unknown and not recommended.
Immune-related hepatotoxicity
• For grade 2 hepatitis, withhold ICPi and monitor AST/ALT levels closely (1–2 times/week). When no improvement over 1 week, start (methyl)prednisone
(0.5–1 mg/kg). Taper over several weeks under close monitoring of AST/ALT and bilirubin [IV–V, B].
• For grade 3 hepatitis, discontinue ICPi and immediately start with (methyl)prednisone 1–2 mg/kg. When no improvement in 2–3 days, add MMF
(1000 mg 3 daily). Taper immunosuppression over 4–6 weeks under close monitoring of AST/ALT and bilirubin [IV–V, B].
• For grade 4 hepatitis, permanently discontinue ICPi, admit patient to the hospital and initiate (methyl)prednisone 2 mg/kg i.v. Add MMF if no improve-
ment is observed within 2–3 days. Consult hepatologist if no improvement under double immunosuppression. Other immunosuppressive drugs to con-
sider are ATG and tacrolimus. Consult or refer patient to an experienced centre. Taper over 6 weeks under close monitoring of liver tests [IV–V, B].
Gastrointestinal hepatotoxicity
• In patients with non-severe diarrhoea (grade 1), ICPi can be continued. Treatment with antidiarrhoeal medication (e.g. loperamide) should be prescribed
[IV–V, B].
• In grade 2 diarrhoea, ICPi should be interrupted and the patient should start with corticosteroids depending on the severity and other symptoms (either
budesonide or oral corticosteroids 1 mg/kg). In the case of no improvement within 3–5 days, colonoscopy should be carried out and, in the case of colitis,
inﬂiximab 5 mg/kg should be administered [IV–V, B].
• In patients with severe diarrhoea (grade 3 to 4), permanently discontinue ICPi. Admit patient to the hospital and initiate (methyl)prednisone 2 mg/kg i.v.
Add MMF if improvement is observed within 2–3 days. Consult a hepatologist if no improvement under double immunosuppression. Other immunosup-
pressive drugs to consider are ATG and tacrolimus. Consult or refer patient to an experienced centre. Taper over 6 weeks under close monitoring of liver
tests [IV–V, B].
Immune-related pneumonitis
• In grade 1 and 2 pneumonitis, interrupt ICPi therapy, try to rule out infection and start with prednisone 1–2 mg/kg orally. Taper over 4–6 weeks [IV–V, B].
• In grade 3 and 4 pneumonitis, discontinue ICPi permanently, admit the patient to the hospital, even ICU if necessary and immediately start high-dose
(methyl)prednisone 2–4 mg/kg i.v. Add inﬂiximab, MMF or cyclophosphamide in the case of deterioration under steroids. Taper over a period of 4–
6 weeks [IV–V, B].
Neurological toxicity
• In the case of mild neurological AEs, withhold ICPi and perform work-up (MRI scan, lumbar puncture) to deﬁne nature of neurotoxicity. In the case of de-
terioration or severe neurological symptoms, admit the patient and start (methyl)prednisone 1–2 mg/kg orally or i.v. In the case of Guillain-Barre´ or myas-
thenia-like symptoms, consider adding plasmapheresis or i.v. Ig [V, B].
Cardiac toxicity
• When a myocarditis is suspected, admit the patient and immediately start high-dose (methyl)prednisone (1–2 mg/kg). In the case of deterioration, con-
sider adding another immunosuppressive drug (MMF or tacrolimus) [V, B].
Rheumatological toxicity
• For mild arthralgia, start NSAIDs, and in the case of no improvement, consider low dose steroids (10–20 mg prednisone). In the case of severe polyarthritis,
refer patient to or consult a rheumatologist and start prednisone 1 mg/kg. Sometimes inﬂiximab or another anti-TNFa drug is required for improvement
of arthritis [V, B].
Renal toxicity
• In case of nephritis, rule out other causes of renal failure ﬁrst. Interrupt or permanently discontinue ICPi depending on the severity of the renal insufﬁ-
ciency. Stop other nephrotoxic drugs. Start (methyl)prednisone 1–2 mg/kg. Consider renal biopsy to conﬁrm diagnosis [V, B].
AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; ATG, anti-thymocyte globulin; DM, diabetes mellitus; HRT, hormone replace-
ment therapy; ICPi, immune checkpoint inhibitor; ICU, intensive care unit; Ig, immunoglobulin; i.v. intravenous; MMF, mycophenolate mofetil; MRI, mag-
netic resonance imaging; NSAIDs, nonsteroidal anti-inﬂammatory drugs; TNFa, tumour necrosis factor alpha; TSH, thyroid-stimulating hormone.
Annals of Oncology
Clinical Practice Guidelines
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Acknowledgements
We thank Prof. M. Gore and Dr L. Spain from the Royal
Marsden Hospital, London, UK, for their help with developing
the up-to-date AE management algorithms.
Disclosure
FC has reported being a board member of Merck Sharpe &
Dohme and Bristol-Myers Squibb and honoraria from Bristol-
Myers Squibb; CR has reported consultancy for Roche, Bristol-
Myers Squibb, Amgen, Merck Sharpe & Dohme, Novartis and
Merck; KK has reported lecture honoraria and/or consultancy
from
AstraZeneca,
Bristol-Myers
Squibb,
Boehringer
Ingelheim, Eli Lilly, Merck KGaA, Merck Sharpe & Dohme,
Novartis, Pﬁzer, Roche and Roche Diagnostics; JL has reported
honoraria and research grants from Bristol-Myers Squibb,
Merck
Sharpe
&
Dohme,
Novartis,
Pﬁzer,
Eisai,
GlaxoSmithKline, Kymab, Roche/Genentech, Secarna, Fabre
and EUSA Pharma; JH, SP and KJ has reported honoraria
from Amgen, Merck, MSD, Helsinn, Tesaro and Hexaland and
being a member of the advisory board of
Merck, MSD,
Helsinn and Tesaro.
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Insufﬁcient evidence for efﬁcacy or beneﬁt does not outweigh the
risk or the disadvantages (adverse events, costs, ...). optional
D
Moderate evidence against efﬁcacy or for adverse outcome,
generally not recommended
E
Strong evidence against efﬁcacy or for adverse outcome, never
recommended
aBy permission of the Infectious Diseases Society of America [88].
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Annals of Oncology
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iv142 | Haanen et al.
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APPENDIX 10:  
CYTOKINE RELEASE SYNDROME GRADING AND 
TREATMENT GUIDELINES 
The following guidelines have been adapted from (Lee 2014).  Please refer to the full publication 
for further details.  These may be supplemented by discussions with the Sponsor’s medical 
monitor as well as institutional guidelines on management of CRS.  
Table 16: 
Cytokine Release Syndrome Grading and Treatment Guidelines 
Grade/Toxicity 
Treatment 
Grade 1  
Symptoms are not life threatening and require 
symptomatic treatment only, eg, fever, nausea, fatigue, 
headache, myalgias, malaise 
Vigilant supportive care 
Assess for infection  
Treat fever and neutropenia if present, monitor fluid 
balance, antipyretics, analgesics as needed 
Grade 2 
Symptoms require and respond to moderate 
intervention 
Oxygen requirement <40% or 
Hypotension responsive to fluids or low dose of one 
vasopressor or Grade 2 organ toxicity3 
Extensive comorbidities or older age: 
Vigilant supportive care 
Tocilizumab1 +/- corticosteroids2 
No Extensive comorbidities or older age: 
Vigilant supportive care (Monitor cardiac and other 
organ function closely) 
Grade 3  
Symptoms require and respond to aggressive 
intervention 
Oxygen requirement ≥40% or 
Hypotension requiring high dose4 or multiple 
vasopressors or 
Grade 3 organ toxicity or grade 4 transaminitis 
Vigilant supportive care 
Tocilizumab +/- corticosteroids 
Grade 4  
Life-threatening symptoms 
Requirement for ventilator support or 
Grade 4 organ toxicity (excluding transaminitis) 
Vigilant supportive care 
Tocilizumab +/- corticosteroids 
Grade 5  
Death 
NA 
1 
Tocilizumab 4 mg/kg over 1 hour.  Repeat dose if no improvement in 24-48 hours 
2 
Methylprednisolone 2 mg/kg/day IV; dexamethasone 0.5 mg/kg (10 mg/dose) IV every 6 hours  
3 
As determined by CTCAE Ver 4.03 
4 
Refer to Table 17 
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Table 17:  
High Dose Vasopressors (all doses are required for ≥ 3 hours) 
Pressor 
Dose 
Norepinephrine monotherapy 
≥20 µg/min 
Dopamine monotherapy 
≥10 µg/kg/min 
Phenylephrine monotherapy 
≥200 µg/min 
Epinephrine monotherapy 
≥10 µg/min 
If on Vasopressin 
Vasopressin + norepinephrine equivalent of ≥10 µg/min* 
If on combination vasopressors (not vasopressin) 
Norepinephrine equivalent of ≥20 µg/min* 
*VASSST Trial vasopressor equivalent equation: norepinephrine equivalent dose = [norepinephrine 
(µg/min)]+[dopamine (µg/kg/min)÷2+[epinephrine (µg/min) + [phenylephrine (µg/min) ÷10] 
 
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APPENDIX 11:  
ADDITIONAL COHORTS FOR PHASE 1B EXPANSION 
Clinical safety results from Study 155-001 were reviewed at a meeting with participating 
investigators and the Sponsor on July 22, 2020 (GMT -7). No DLTs have been observed in dose 
escalation through the FPT155 560mg dose level. Following review of cumulative safety results, 
including those from 10 patients enrolled at the FPT155 280mg dose level and 7 patients at the 
FPT155 560mg dose level, there was unanimous endorsement of expansion of enrollment at a 
recommended dose of FPT155 560mg Q3W. Based on review of the available safety, 
pharmacokinetic and pharmacodynamic results and in accordance with Section 4.1.3 of the 
protocol, the following Phase 1b cohorts will open for enrollment: 
Phase 1b Cohort 
Inclusion Criteria 
1 
Patients with advanced renal cell carcinoma as specified per Section 5.2 of the protocol. 
2 
Patients with advanced melanoma as specified per Section 5.2 of the protocol. 
3 
Patients with previously-treated unresectable or metastatic solid tumors with deficient 
mismatch repair (dMMR) or high microsatellite instability (MSI-H) and an absence of 
suitable standard treatment options. 
4 
Patients with previously-treated unresectable or metastatic non-small cell lung cancer and 
an absence of suitable standard treatment options.  
5 
Patients with previously-treated solid tumors with a response to prior PD-1 or PDL-1 
directed treatment as defined by an objective response (partial or complete response) or a 
minimum of three months on prior PD-1 or PDL-1 directed therapy.  
 
For these cohorts, patient enrollment continues to be subject to the inclusion and exclusion 
criteria as specified per protocol Sections 5.1 and 5.3. 
 
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