A Multi-Center, Open-Label Phase 1b/2 Study of a Novel FGFR3 Inhibitor (B-701) Combined With Pembrolizumab in Subjects With Locally Advanced or Metastatic Urothelial Carcinoma Who Have Progressed Following Platinum-based Chemotherapy
Phase: PHASE1
Conditions: Locally Advanced or Metastatic Urothelial Cell Carcinoma, Urinary Bladder Disease, Urological Diseases
Sponsor: Rainier Therapeutics

CONFIDENTIAL MATERIAL 
 
This protocol is the property of Rainier Therapeutics Inc. and is a confidential communication. Acceptance implies an 
agreement not to disclose information contained herein that is not otherwise publicly available, except for use by an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for the purpose of obtaining approval/favorable 
opinion to conduct the study. The IRB/IEC is requested and expected to maintain confidentiality. This document may not be 
used or published in whole or in part without the consent of Rainier Therapeutics Inc. 
CLINICAL RESEARCH PROTOCOL 
Study Title: 
A Multi-Center, Open-Label Phase 1b/2 Study of a 
Novel FGFR3 Inhibitor (B-701) Combined with 
Pembrolizumab in Subjects with Locally Advanced or 
Metastatic Urothelial Carcinoma who have Progressed 
Following Platinum-based Chemotherapy 
 
 
 
Protocol Number: 
B-701-U22 (FIERCE-22) 
Investigational Product: 
Vofatamab (B-701) (anti-FGFR3 fully human monoclonal 
antibody) 
IND Number: 
123185 
Eudra CT Number: 
2017-001292-23 
 
 
Amendment 5 (USA) 
01 July 2019 
Amendment 4.2  
Amendment 4.1 
Amendment 4 
Amendment 3.1 
Amendment 3 
20 June 2019 
07 June 2018 
16 May 2018 
14 March 2018 
05 January 2018 
Amendment 2 
11 July 2017 
Amendment 1 
16 December 2016 
Original Date of Issue: 
03 October 2016 
 
 
Indication: 
Locally Advanced or Metastatic Urothelial Cell 
Carcinoma 
Sponsor: 
Rainier Therapeutics, Inc. 
1040 Davis Street, Ste. 202 
San Leandro, CA 94577 
 
 

Protocol Number: B-701-U22  
CONFIDENTIAL  
Amendment 5  
Rainier Therapeutics, Inc. 
 
 
 
Medical Monitor: 
Steve Abella, MD 
Chief Medical Officer 
Rainier Therapeutics 
Phone: +1-650-529-4788 
 
 
Development Phase: 
Phase 1b/2 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................3 
LIST OF TABLES .....................................................................................................................6 
LIST OF FIGURES ...................................................................................................................6 
LIST OF APPENDICES ............................................................................................................6 
PROTOCOL SYNOPSIS ..........................................................................................................7 
GLOSSARY OF TERMS ........................................................................................................25 
1 
INTRODUCTION .................................................................................................28 
1.1 
Background on Urothelial Cell Carcinoma ......................................................28 
1.1.1 
FGFR3 in Bladder Cancer ...................................................................28 
1.2 
Background on Vofatamab ..............................................................................29 
1.2.1 
Non-clinical Data with Vofatamab ......................................................29 
1.2.2 
Clinical Data with Vofatamab .............................................................30 
1.3 
Background on Pembrolizumab .......................................................................34 
1.4 
Rationale for Combining Vofatamab and Pembrolizumab ..............................35 
2 
OBJECTIVES AND ENDPOINTS .......................................................................38 
2.1 
Objectives ........................................................................................................38 
2.1.1 
Phase 1b ...............................................................................................38 
2.1.2 
Phase 2 and Phase 2 Expansion ...........................................................38 
2.2 
Endpoints .........................................................................................................39 
2.2.1 
Phase 1b ...............................................................................................39 
2.2.2 
Phase 2 (Cohorts 1, 2, 3, and 4) ...........................................................39 
3 
STUDY DESIGN...................................................................................................41 
3.1 
Summary of Study Design ...............................................................................41 
3.2 
Discussion and Rationale for Study Design.....................................................45 
3.2.1 
Selection of Dose and Dosing Schedule ..............................................45 
3.2.2 
Safety Monitoring Rules and the Safety Steering Committee .............46 
3.2.3 
Selection of Study Population ..............................................................46 
3.2.4 
Blinding................................................................................................47 
3.2.5 
Duration of Subject Participation.........................................................47 
3.2.6 
Definition of End of Study ...................................................................47 
4 
STUDY POPULATION AND WITHDRAWAL .................................................48 
4.1 
Inclusion Criteria .............................................................................................48 
4.2 
Exclusion Criteria ............................................................................................49 
4.3 
Removal of Subjects for Therapy or Assessment ............................................51 
4.3.1 
Subject Discontinuation from the Study or Treatment ........................51 
4.3.2 
Study Discontinuation ..........................................................................52 
5 
TREATMENT OF SUBJECTS .............................................................................53 

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5.1 
Treatment Regimens ........................................................................................53 
5.1.1 
Guidelines for Continued Dosing ........................................................53 
5.1.2 
Dose Modification ...............................................................................54 
5.1.3 
Post-Study Access to Study Drug ........................................................56 
5.2 
Preparation, Administration, and Storage of Study Drug ................................56 
5.2.1 
Vofatamab ............................................................................................56 
5.2.2 
Pembrolizumab ....................................................................................58 
5.3 
Study Drug Accounting ...................................................................................58 
5.3.1 
Receipt of Drug Supplies .....................................................................58 
5.3.2 
Return or Destruction of Study Drug ...................................................58 
5.4 
Concomitant and Prohibited Therapies ............................................................59 
5.4.1 
Concomitant Therapy...........................................................................59 
5.4.2 
Prohibited Therapy...............................................................................59 
5.5 
Treatment Compliance .....................................................................................59 
6 
STUDY PROCEDURES (PHASE 1B AND 2 INCLUDING EXPANSION 
COHORT) ..............................................................................................................60 
6.1 
Assessments by Study Visit .............................................................................60 
6.1.1 
Screening..............................................................................................60 
6.1.2 
Cycle 0 .................................................................................................61 
6.1.3 
Day 1 of Cycle 1 (± 3 days) .................................................................62 
6.1.4 
Day 1 of Cycles 2+ (± 7 days) until Disease Progression....................64 
6.1.5 
End of Treatment .................................................................................66 
6.1.6 
End of Study ........................................................................................66 
7 
STUDY ASSESSMENTS .....................................................................................67 
7.1 
Screening/Baseline Assessments .....................................................................67 
7.1.1 
Informed Consent.................................................................................67 
7.1.2 
Collection of Biomarker Tumor Biopsy Samples ................................67 
7.1.3 
Archival/Diagnostic Tissue Collection ................................................68 
7.1.4 
Subject Eligibility ................................................................................68 
7.1.5 
Medical History and Demographics ....................................................68 
7.2 
Safety Assessments ..........................................................................................68 
7.2.1 
Adverse Events ....................................................................................68 
7.2.2 
Physical Examination, Height, and Weight .........................................77 
7.2.3 
Vital Signs ............................................................................................77 
7.2.4 
Laboratory Assessments ......................................................................78 
7.2.5 
Electrocardiogram Assessments ..........................................................78 
7.3 
Response/Efficacy Assessments ......................................................................79 
7.3.1 
Tumor and Response Assessments ......................................................79 

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7.3.2 
Survival ................................................................................................79 
7.3.3 
Patient-Reported Outcome/European Organization for Research 
and Treatment Quality of Life Questionnaire ......................................80 
7.4 
Pharmacokinetic Assessments .........................................................................80 
7.5 
Anti-therapeutic Antibody Assessments ..........................................................80 
7.6 
Biomarker Assessments ...................................................................................80 
7.7 
Appropriateness of Measurements ...................................................................81 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE.........................82 
8.1 
Site Training and Monitoring Procedures ........................................................82 
8.2 
Data Management Procedures .........................................................................83 
8.3 
Access to Source Data .....................................................................................83 
8.4 
Accuracy and Reliability of Data .....................................................................83 
8.5 
Quality Assurance Procedures .........................................................................83 
8.6 
Data Handling and Record Keeping ................................................................84 
8.6.1 
Data Handling ......................................................................................84 
8.6.2 
Records Retention ................................................................................84 
9 
STATISTICAL METHODS ..................................................................................85 
9.1 
Sample Size Consideration ..............................................................................85 
9.2 
Interim Analysis ...............................................................................................85 
9.3 
Analysis Populations ........................................................................................86 
9.4 
Planned Analyses .............................................................................................86 
9.4.1 
Safety Monitoring Rule........................................................................86 
9.4.2 
Primary Biomarker Analysis................................................................87 
9.4.3 
Subject Disposition ..............................................................................87 
9.4.4 
Demographic and Baseline Characteristics .........................................87 
9.4.5 
Medical History and Physical Examination .........................................87 
9.4.6 
Study Drug Administration ..................................................................87 
9.4.7 
Safety Analyses ....................................................................................87 
9.5 
Efficacy Analysis .............................................................................................89 
9.5.1 
Primary Efficacy Endpoint ..................................................................89 
9.5.2 
Secondary Efficacy Endpoints .............................................................89 
9.6 
Exploratory Endpoints .....................................................................................90 
9.6.1 
Pharmacokinetic Analyses ...................................................................90 
9.6.2 
Immunogenicity Analyses ...................................................................90 
10 
ETHICAL AND REGULATORY CONSIDERATIONS .....................................91 
10.1 
Informed Consent.............................................................................................91 
10.2 
Confidentiality of Personal Subject Information .............................................91 
10.3 
Biospecimens ...................................................................................................92 

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10.4 
Ethical Conduct of the Study ...........................................................................92 
10.5 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) .......92 
10.6 
Regulatory Requirements.................................................................................92 
10.7 
Investigators and Administrative Structure .....................................................93 
10.8 
Protocol Amendments and Study Termination ................................................93 
10.9 
Clinical Study Report .......................................................................................94 
10.10 
Disclosure of Source Data and Documents .....................................................94 
10.11 
Publication Policy ............................................................................................94 
11 
REFERENCES ......................................................................................................95 
12 
SIGNATURE PAGE .............................................................................................98 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments for Phase 1b and Phase 2 ........................................20 
Table 2 
Dosing for Dose De-escalation ........................................................................42 
Table 3 
Study Drug Dosing Guidelines ........................................................................53 
Table 4 
Management of Infusion-Related Symptoms (e.g., fever, chills/rigors, 
nausea, vomiting, pruritus, headache, rhinitis, rash, hypotension, 
hypersensitivity, anaphylaxis, dyspnea, wheezing, bronchospasm, 
tachycardia, reduced oxygen saturation, or respiratory distress) .....................57 
Table 5 
Adverse Event Severity Grading Scale ............................................................71 
Table 6            Three- Look Group Sequential Sample Size, Boundary and Alpha Allocation 
Table 7 
Time Point Response: Subjects with Target Disease (With or Without 
Non-Target Lesions) ......................................................................................107 
Table 8 
Time Point Response: Subjects with Non-Target Disease Only ...................108 
Table 9 
Best Overall Response when Confirmation of CR and PR Required ............109 
 
LIST OF FIGURES 
Figure 1: 
Progression-Free Survival in Subjects with UCC (Study MFG4991g) ...........32 
Figure 2:  
Study Design ....................................................................................................44 
 
LIST OF APPENDICES 
Appendix 1 
Eastern Cooperative Oncology Group Performance Status Scale .................100 
Appendix 2 
Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)...101 
Appendix 3 
Anaphylaxis Precautions and Procedures ......................................................111 
Appendix 4 
Information Regarding Effectiveness of Contraceptive Methods .................112 

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PROTOCOL SYNOPSIS 
 
Title of Study: 
A Multi-Center, Open-Label Phase 1b/2 Study of a Novel FGFR3 
Inhibitor (B-701) Combined with Pembrolizumab in Subjects with 
Locally Advanced or Metastatic Urothelial Carcinoma who have 
Progressed Following Platinum-based Chemotherapy 
Protocol Number: 
B-701-U22 (FIERCE-22) 
Location: 
Global 
Study Centers: 
Approximately 50-75 sites will participate in this study. 
Study Period:  
The study period will include a 4-week screening period, a 2 
week treatment period of vofatamab monotherapy, followed by 
a treatment period of vofatamab plus pembrolizumab to 
complete 2 years of  combination vofatamab and 
pembrolizumab therapy (21-days per cycle for combination 
treatment), End of Treatment visit, and telephone follow-up to 
monitor survival.  
Phase of Development: 
1b/2  
Study Rationale: 
To date, several FDA-approved second-line therapies for the treatment of bladder cancer are 
available, including immune checkpoint inhibitors such as atezolizumab, avelumab, 
durvalumab, nivolumab, and pembrolizumab. While immune checkpoint inhibitors (CPIs) are 
highly effective in a small subset of patients, the majority of patients have disease which 
progresses while receiving CPI therapy. A significant unmet medical need exists for patients 
with relapsed or refractory urothelial cell carcinoma (UCC) who have failed first or second line 
therapy. 
The inhibition of programmed cell death protein (PD-1) pathway by CPIs relies on a host 
immune response against tumor cells for efficacy. Consequently, emerging clinical and 
nonclinical data suggest that tumors with a non-inflamed phenotype are less likely to respond 
to immune CPI therapy. Research has found that mutations in fibroblast growth factor receptor 
3 (FGFR3) and FGFR3 expression are associated with the non-inflamed bladder cancer 
phenotype (Sweis 2015). Furthermore, luminal type I bladder cancers, which have the highest 
expression of FGFR3 when compared across bladder cancer subtypes, have been reported to 
have the poorest response rate to CPI treatment (Rosenberg 2016). 
Vofatamab is a novel fully human monoclonal antibody specific for FGFR3 that is being 
developed to target FGFR3-positive tumors. Non-clinical studies have also shown that 
vofatamab suppresses FGFR3 mediated cell proliferation and exerts strong anti-tumor activity 
in mouse xenograft models of bladder cancer. Clinical data demonstrate that the majority of 
patients with UCC express FGFR3 on the tumor cell surface (Cancer Genome Atlas Research 
Network 2014; Carneiro 2015). 

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This study is evaluating the safety, tolerability and efficacy of combining vofatamab with 
pembrolizumab. It is designed to assess whether vofatamab enhances the efficacy of 
pembrolizumab and whether response to the combination is enhanced in any particular sub-
class of disease. In addition, it will explore the impact of the combination on the tumor cell 
microenvironment. 
Study Objectives: 
Phase 1b 
Primary Objective: 
• To establish the initial safety and determine a recommended Phase 2 dose (RP2D) of 
vofatamab in combination with pembrolizumab 
Phase 2 and Phase 2 Expansion 
Primary Objectives: 
• To evaluate the safety and tolerability of vofatamab plus pembrolizumab in subjects with 
UCC 
• To evaluate the efficacy of vofatamab in combination with pembrolizumab in the treatment 
of subjects with UCC as measured by objective response rate (ORR) by Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)  
Secondary Objectives (Cohorts 1, 2 and 3): 
• To evaluate the efficacy of vofatamab in combination with pembrolizumab in the treatment 
of subjects with UCC as measured by duration of objective response (DOR), progression 
free survival (PFS), and disease control rate (DCR) by RECIST 1.1, and overall survival 
(OS) 
• To describe the impact of FGFR3 status at enrollment [wildtype (WT), mutation and/or 
fusion (Mut/Fus)] on the safety and efficacy after one cycle of B-701 alone, followed by B-
701 in combination with pembrolizumab in subjects with advanced UCC 
• To evaluate the change in patient reported outcome (PRO) using quality of life 
measurements over time by the European Organization for Research and Treatment 
Quality of Life Questionnaire (EORTC QLQ-C30) 
• To evaluate the change in expression of markers associated with tumor subtype, immune 
cell infiltrate, and immune response when vofatamab is administered alone during the 14-
day lead-in period.(Cohorts 1 and 2). 
• To evaluate the change in expression of markers associated with luminal tumor subtype, 
immune cell infiltrate, and immune response after start of the combination treatment using 
a later timepoint for the 2nd biopsy only for Cohort 3 (at the end Cycle 1, Week 5) 
 

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1. Exploratory Objectives (Cohorts 1, 2 and 3): 
• To evaluate the pharmacokinetics (PK) of vofatamab in subjects with UCC 
• To assess the immunogenicity of vofatamab in subjects with UCC 
• To determine if other molecular markers predict treatment response 
• To evaluate the efficacy of vofatamab in combination with pembrolizumab in the treatment 
of  subjects with UCC as measured by ORR, DOR, PFS, and DCR per iRECIST 
Secondary Objectives (Cohort 4): 
• To evaluate the efficacy of vofatamab in combination with pembrolizumab in the treatment 
of unselected subjects with UCC as measured by duration of objective response (DOR), 
progression free survival (PFS), and disease control rate (DCR) by RECIST 1.1, and 
overall survival (OS)  
• To evaluate the change in patient reported outcome (PRO) using quality of life 
measurements over time by the European Organization for Research and Treatment 
Quality of Life Questionnaire (EORTC QLQ-C30) 
2. Exploratory objective (Cohort 4): 
• To evaluate the efficacy of vofatamab in combination with pembrolizumab in the treatment 
of  unselected subjects with UCC as measured by ORR, DOR, PFS, and DCR per iRECIST 
Study Design and Methodology: 
This is a Phase 1b/2, multi-center, open-label study to determine the safety, tolerability, and 
efficacy of vofatamab plus pembrolizumab in the treatment of subjects with locally advanced 
or metastatic UCC, who have progressed following platinum-based chemotherapy, and who 
have not received prior immune checkpoint inhibitor or FGFR inhibitor-targeted therapy. The 
study consists of 3 parts:  
1. A Phase 1b which planned to enroll up to 18 patients in a 6+6 design. 8 subjects, 7 WT 
and 1 Mut/Fus were enrolled (study completed). 
2. A Phase 2 enrolling 60 subjects in 3 seperate cohorts: 20 WT (Cohort 1), 20 Mut/Fus 
(Cohort 2), and 20 with luminal biology sub-type (Cohort 3).  
3. A Phase 2 expansion enrolling 30 unselected subjects (independent of their FGFR3 
genetic status) (Cohort 4) 
Prior to study enrollment, the availability of an archival tumor sample must be requested from 
participants and availability must be confirmed during screening. A blood sample may be 
substituted to determine FGFR3 genetic status archival tumor is not available. If an archival 
biopsy is not available, during the screening window a pre-treatment diagnostic biopsy within 
56 days of first study treatment may be obtained to satisfy this requirement, if submitted for 
additonal required studies. A second biopsy will be taken during treatment for cohorts 1, 2 and 
3 or if an expansion phase patient opts in. Study biopsies may not be obtained from lung, bone, 
or brain.  

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For the Phase 2 expansion (Cohort 4), the paired biopsies are optional, but if they are taken, the 
second biospy will be taken at the end of cycle 1, Week 5. Subjects will be required to sign a 
separate consent form and must confirm their decision to opt-in.  
Study Schema 
 
 
FGFR3 = fibroblast growth factor receptor 3; Mut/Fus = mutant/fusion; Q3W = once every 3 weeks; WT = wild 
type. 
*As of April 03 2018, Phase 1b of the study is complete. 
**As of Dec 31 2018, 28 subjects (20 WT and 8 Mut/Fus) have already been enrolled in Phase 2. A total of 32 
subjects will be added, 12 Mut/Fus (Cohort 2) and 20 with luminal biology (Cohort 3)  
 
In Phase 2, Cohort 1 and Cohort 2 of the study, subjects will be assigned to a cohort by baseline FGFR3 genetic 
status of 1) WT or 2) Mut/Fus; in Phase 2, Cohort 3, at selected sites, the patient’s bladder cancer sub-type will be 
luminal enriched as determined by IHC testing for GATA3 and post enrollment by the Decipher Bladder test or 
acceptable comparable test on samples that were obtained at or after the time when the subject was found to have 
muscle invasive / metastatic disease.  
 
Phase 1b 
Enrolled subjects in Phase 1b will have a biomarker tumor biopsy taken prior to Cycle 0 (lead-
in cycle) 
• Within 7 days prior if an archival sample is available for screening  

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• If an archival sample is not available, a biopsy should be obtained within the 28-days 
screening window. If the sample is adequate, it may be substituted for the initial (pre-
treatment) Cycle 0 biomarker biopsy.  
After this first biomarker tumor biopsy, subjects will be treated in Cycle 0 with an intravenous 
(IV) infusion of vofatamab alone. The second biomarker tumor biopsy should be obtained 
within 3 days of Cycle 1 Day 1 infusion of vofatamab plus pembrolizumab. If the biopsy 
occurs on Cycle 1 Day 1, it should be obtained prior to the start of the infusion of vofatamab 
and pembrolizumab.  
The first cohort of 6 subjects will be treated with vofatamab 25 mg/kg IV monotherapy as a 
2-week cycle (Cycle 0) and vofatamab 25mg/kg IV in combination with pembrolizumab as a 
3-week cycle (Cycle 1). Subjects will be followed for at least a 35-day dose-limiting toxicity 
(DLT) window from first dose of  vofatamab (14 days of vofatamab monotherapy and 21 days 
of combination therapy). If ≤ 1 subject experiences a DLT (a Grade 3 or higher AE attributed 
to vofatamab and/or pembrolizumab), then 25 mg/kg will be declared the RP2D. If 2 or more 
subjects experience a DLT, then the dose of vofatamab will be de-escalated as outlined in the 
table below. 
Dosing for Dose De-escalation 
 
Dose Level 0 
Dose Level -1 
Dose Level -2 
Vofatamab 
25 mg/kg IV q 3 
weeks (n=6) 
20 mg/kg IV q 3 
weeks (n=6) 
15 mg/kg IV q 3 
weeks (n=6) 
 
On Cycle 1 Day 1, Phase 1b subjects will receive treatment of vofatamab (25 mg/kg [or the 
RP2D if different than 25 mg/kg]) plus pembrolizumab (200 mg) once every 3 weeks (Q3W) 
until disease progression, death, decision to discontinue treatment, investigator discretion, or 
study termination. Subjects who do not experience a study defined DLT, but do not complete 
the 35-day observation window may be replaced. As of April 03 2018, Phase 1b of the study is 
complete. 
Phase 2 and Phase 2 expansion:  
Phase 2 opened on April 04, 2018 following review of the aggregate adverse event (AE) and 
serious adverse event (SAE) by the vofatamab program Safety Steering Committee (SSC) after 
the 35-day DLT observation period in the Phase 1b subjects. The dose of vofatamab selected 
was dose level 0 (25 mg/kg given every 3 weeks) for the RP2D as no subjects met the study 
DLT definition of a Grade 3 or higher AE attributed to vofatamab and/or pembrolizumab. 
After the 1st planned interim analysis which was conducted in April of 2019, the decision to 
open the expansion phase was made based on initial efficacy and safety (reported ASCO 2019) 
to unselected subjects based on the ORR seen in both cohorts. Additionally, the exclusion 
criteria for existing anticoagulation use was removed following a review of the existing safety 
data by the data safety steering committee that was accepted on review by the FDA. 
For Phase 2, subjects will be assigned to one of three cohorts by either baseline FGFR3 genetic 
status of WT (Cohort 1) or Mut/Fus (Cohort 2), or by bladder cancer molecular subtype 
(Cohort 3). For Cohort 2, Mut/Fus status must be confirmed prior to initiation of treatment. 

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Any subject whose biopsy or circulating tumor specimen results in indeterminate or failed 
result will be considered WT in the analysis  
 As of December 31, 2018, Cohort 1 has been fully enrolled and is closed. 
Cohort 3 will be enrolled at selected sites enrolling patients enriched with tumors showing 
luminal biology as determined by IHC (GATA 3 positive with the absence of KRT14) and post 
enrollment by the Decipher Bladder test or acceptable comparable test on samples that were 
obtained at or after the time when the subject was found to have muscle invasive / metastatic 
disease. Cohort 3 will be used to study the molecular changes in the tumor after the first dose 
of combination treatment of vofatamab and pembrolizumab. 
All subjects in Phase 2 (Cohorts 1, 2 and 3) will have a biomarker tumor biopsy taken within 
14 days prior to Cycle 0 (lead-in cycle). If the subject has undergone a diagnostic tumor biopsy 
procedure within 56 days of enrolling in the study, and the biopsy has adequate material, this 
sample may be used in place of the first biomarker biopsy. A second biopsy will be taken 
during treatment.  
Subjects will be treated in Cycle 0 with an IV infusion of vofatamab alone (without 
pembrolizumab). 
For Phase 2, Cohort 1 and Cohort 2, a second tumor biopsy will be obtained 14 days after 
Cycle 0 Day 1 of vofatamab. The second tumor biopsy should always occur within 3 days 
before Cycle 1 Day 1 infusion and prior to the first dose of vofatamab plus pembrolizumab. 
For patients enrolled in Cohort 3, the second tumor biopsy will occur at the end of cycle 1 of 
the combination (Week 5), within 3 days before Cycle 2, Day 1 and prior to the administration 
of the second combination dose of vofatamab and pembrolizumab. Disease re-staging will 
occur following Cycle 1 for biomarker correlation for all subjects whom underwent paired 
biopsies but will not be utilized for RECIST evaluation. Subjects whom do not get paired 
biopsies would not be required to get a scan at the end of Cycle 1. Paired Biopsies will be 
optional for any patient enrolled in Phase 2 expansion, Cohort 4. If biopsies are performed, the 
second biospy will be taken at end of cycle 1, Week 5.  
On Cycle 1 Day 1, subjects will receive combined treatment of vofatamab (25 mg/kg) plus 
pembrolizumab (200 mg). Subjects will continue to receive vofatamab plus pembrolizumab 
Q3W until disease progression, death, decision to discontinue treatment, investigator 
discretion, or study termination or the completion of 2 years of vofatamab and pembrolizumab 
therapy.  
Subjects may continue vofatamab and/or pembrolizumab treatment beyond radiological 
disease progression following discussion with the medical monitor and based on clinical 
judgement of the investigator that the subject is experiencing clinical benefit. It is highly 
encouraged that prior to discontinuation of any subject whom is receiving clinical benefit that a 
consultation occur with the study PI or medical monitor.  
Subjects who discontinue vofatamab may continue on study and receive pembrolizumab alone 
until disease progression, death, withdrawal of patient consent, investigator discretion, or study 
termination, or the completion of 2 years of pembrolizumab therapy.  

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Subjects who discontinue pembrolizumab may continue on study and receive vofatamab alone 
(25 mg/kg Q3W [or RP2D if different than 25 mg/kg]) until disease progression, death, 
withdrawal of patient consent, investigator discretion, or study termination. 
 
Number of Subjects Planned: 
This study will enroll approximately 100 subjects in total. 
1. A Phase 1b which planned to enroll up to 18 patients in a 6+6 design. 8 subjects, 7 WT 
and 1 Mut/Fus were enrolled (study completed 8 subjects enrolled). 
2. A Phase 2 enrolling 60 subjects: 20 WT(Cohort 1), 20 Mut/Fus (Cohort 2), and 20 with 
tumors showing luminal biology (Cohort 3). Of these, 20 WT and 8 Mut/Fus subjects 
have already been enrolled. No further WT patients will be enrolled; a further 12 
Mut/Fus and 20 with luminal biology will be enrolled  
3. Phase 2 expansion enrolling 30 unselected patients (independent of their FGFR3 
genetic status) (Cohort 4) 
 
Inclusion Criteria: 
1. Have locally advanced (on TNM staging: T4b and any N, or any T and N2-3) or metastatic 
transitional cell carcinoma of the urothelium, including the urinary bladder, urethra, ureter, 
and/or renal pelvis. The diagnosis must be histologically or cytologically confirmed. 
For subjects in the Phase 2, Cohort 2 (Mut/Fus), tumors must have at least one of the following 
FGFR3 mutations: R248C, S249C, G370/2C, S371/3C, Y373/5C, G380/82R, F384/6L, K650/2X 
(X=E,T or M) or FGFR3-TACC3 fusion, as shown by tests performed by a CAP or CLIA certified 
laboratory on samples that were obtained at or after the time when the subject was found to have 
muscle invasive / metastatic disease or high grade papillary non-muscle invasive disease.  
In the absence of pre-existing genetic test results, subjects can submit archival tissue (obtained at 
or after the time subject was found to have muscle invasive / metastatic disease) for genetic 
testing. If no suitable tissue is available, a blood sample may be used to determine FGFR3 genetic 
status.  
Subjects in Phase 2, Cohort 3 (luminal biology) must have a tumor that appears to have luminal 
biology as determined by IHC markers (GATA3 positive with the absence of KRT14) or 
acceptable comparable test on samples that were obtained at or after the time when the subject was 
found to have muscle invasive / metastatic disease, as evaluated by local pathology interpretation.  
Subjects in the phase 2 expansion cohort (Cohort 4) will have FGFR3 genetic status determined 
but this will not be used to assign treatment. 
2. Have progression during or following platinum-containing chemotherapy in metastatic 
setting or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing 
chemotherapy 
3. Have available archival tumor or be willing to undergo diagnostic biopsy during screening  

Protocol Number: B-701-U22  
CONFIDENTIAL  
Amendment 5  
Rainier Therapeutics, Inc. 
 
July 01, 2019  
Page 14 
4. Have measurable disease according to Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST 1.1). 
5. Male and female subjects, age ≥ 18 years. 
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1. 
7. Willingness to avoid pregnancy or fathering children based on the criteria below: 
a. Women of non-childbearing potential (i.e., surgically sterile with a hysterectomy 
and/or bilateral oophorectomy OR chemically sterile OR ≥ 12 months of amenorrhea in 
the absence of chemotherapy, anti-estrogens, or ovarian suppression). Women of non-
childbearing potential need not undergo pregnancy testing. 
b. Women of childbearing potential who have a negative urine or serum pregnancy test at 
Screening and before the first dose of study drug and who agree to take appropriate 
precautions to avoid pregnancy (with approximately 99% certainty) from Screening 
through 120 days after the last dose of study drug. Permitted methods of contraception 
that are approximately 99% effective in preventing pregnancy should be communicated 
to the subject, and the subject’s understanding confirmed.  
c. Men who agree to take appropriate precautions to avoid fathering children (with at least 
99% certainty) from Screening through 120 days after the last dose of study drug. 
Permitted methods of contraception that are approximately 99% effective in preventing 
pregnancy should be communicated to the subject, and the subject’s understanding 
confirmed. 
8. Ability to understand and sign informed consent form (ICF) and comply with all study 
procedures 
9. Have adequate hematologic and end organ function defined by the following laboratory 
results obtained within 14 days prior to the first dose of study treatment: 
a. Absolute neutrophil count ≥ 1,500/µL. 
b. Platelet count ≥ 100,000/µL. 
c. Hemoglobin ≥ 9.0 g/dL without transfusion. 
d. Albumin ≥ 2.5 g/dL. 
e. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline 
phosphatase (ALP) ≤ 2.5 × upper limit of normal (ULN), with the following exception: 
ALP ≤ 5 × ULN for subjects with documented bone metastases 
i. 
Creatinine clearance ≥ 30 mL/min on the basis of the Cockroft-Gault glomerular 
filtration rate estimation: 
(140 −𝑎𝑔𝑒) × (𝑤𝑒𝑖𝑔ℎ𝑡 𝑖𝑛 𝑘𝑔) × (0.85 𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒) 
72 × (𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝑖𝑛 𝑚𝑔/𝑑𝐿)
 
Note: Creatine clearance < 30 mL/min may have confirmatory re-testing done using a 
24-hour creatinine clearance by Cockroft-Gault estimation or direct measurement 

Protocol Number: B-701-U22  
CONFIDENTIAL  
Amendment 5  
Rainier Therapeutics, Inc. 
 
July 01, 2019  
Page 15 
f. Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin 
time (PTT) must be ≤ 1.5 × ULN. 
Exclusion Criteria: 
1. Participants with a history of idiopathic pulmonary fibrosis, organizing pneumonia, 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis 
on the Screening chest CT scan.  
2. Prior therapy with an anti-programmed cell death 1 (PD-1) or anti-PD-Ligand 1 agent, 
or with an agent directed to another co-inhibitory T-cell receptor or FGFR inhibitor.  
3. Patients with autoimmune disease or medical conditions that required systemic 
corticosteroids (> 10 mg/day prednisone or its equivalent) or other immunosuppressive 
medications or any other form of systemic immunosuppressive therapy within 7 days 
prior to the first dose of study treatment. Note: Replacement therapy (e.g. physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment. 
4. Prior anti-cancer therapy (e.g. biologic or other targeted therapy, chemotherapy or 
hormonal therapy) within 14 days prior to the first dose of study treatment. 
A washout of less than 14 days may be allowed after discussion with the Medical 
Monitor, provided that the subject has recovered from any clinically relevant toxicity 
(Exception: participants with neuropathy of Grade 1 will be allowed study entry). 
5. Acute clinical AEs, except for alopecia, from any previous treatments must have 
resolved to ≤ Grade 1, or chronic defined as present for more than 6 months without 
worsening and not greater than Grade 2.  
6. Laboratory AEs from any previous treatments must have resolved to ≤ Grade 1 or to 
within 10% of baseline prior to the first dose of study treatment. 
7. Participants who are receiving or have received any other investigational drugs or 
devices within 14 days prior to the first dose of study medications. 
8. Participants with a diagnosis of immunodeficiency. 
9. Primary central nervous system (CNS) malignancy or CNS metastases (past or current).  
10. Participants with a history of allergic reactions attributed to monoclonal antibody 
therapy (or recombinant antibody-related fusion proteins). 
11. History of major bleeding (requiring a blood transfusion ≥ 2 units) not related to a 
tumor within the past 12 months. 
12. History of clinically significant coagulation or platelet disorder in the past 12 months. 
13. Participants who have not recovered adequately from the toxicity and/or complications 
from the interventions prior to starting therapy. 
14. Incomplete healing from wounds from prior surgery (wounds larger than 2 cm in 
length) within 28 days prior to the first dose of study treatment. 

Protocol Number: B-701-U22  
CONFIDENTIAL  
Amendment 5  
Rainier Therapeutics, Inc. 
 
July 01, 2019  
Page 16 
15. Participants with an active uncontrolled infection requiring systemic therapy (e.g., IV 
antibiotics or antifungal therapy).  
Note: The use of oral anti-infectious agents for prophylaxis or treatment of resolving 
infections is not considered exclusionary under this rule. 
16. Participants who have received a live vaccine within 30 days of planned start of study 
therapy. 
Note: Seasonal influenza vaccines with inactivated flu vaccines are allowed; however, 
live attenuated vaccines such as intranasal influenza vaccines (e.g., Flu-Mist®) are not 
allowed. 
 
17. Participants with uncontrolled intercurrent illness including, but not limited to, ongoing 
or symptomatic congestive heart failure, unstable angina pectoris, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
18. Participants with a history of other malignancy which could affect compliance with the 
protocol or interpretation of results. Individuals with a history of curatively treated 
basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, and 
definitively treated prostate cancer discovered incidentally at surgery are allowed. 
Participants with other malignancies that have been treated with curative intent will 
also be allowed if the malignancy has been in remission without treatment for ≥ 2 years 
prior to Cycle 0 Day 1 (prior to first dose of study treatment). 
19. Pregnant and breast-feeding women are excluded from this study because the risks with 
vofatamab and pembrolizumab are unknown. Because there is an unknown but 
potential risk for AEs in nursing infant(s) secondary to treatment of the mother with 
vofatamab and pembrolizumab, breastfeeding should be discontinued.  
20. Presence of positive test results for Hepatitis B (Hepatitis B surface antigen [HBsAg] 
and/or total Hepatitis B core antibody [HBcAb]), Hepatitis C (Hepatitis C virus 
antibody serology testing [HCV Ab]), human immunodeficiency virus (HIV1/2 
antibody +), and /or evidence of active tuberculosis (history and/or radiology findings).  
Note: Subjects positive for Hepatitis core antibody [HBcAb] are eligible only if 
confirmatory polymerase chain reaction (PCR) is negative for evidence of Hepatitis B 
Virus DNA (within the Institution cutoff value) and for study purposes the reported 
positive antibody testing will be considered to be a false positive test result. 

Protocol Number: B-701-U22  
CONFIDENTIAL  
Amendment 5  
Rainier Therapeutics, Inc. 
 
July 01, 2019  
Page 17 
Study Drug, Dose, and Mode of Administration: 
Vofatamab will be provided as a sterile lyophilized powder in single-use vials. Vofatamab will 
be reconstituted with sterile water for injection, and the drug product will be delivered at a 
final concentration of ≥ 3 mg/mL. Additional instructions on vofatamab preparation and 
administration are provided in the Pharmacy Manual. 
The study drug dosing regimen is as follows:  
Subjects will receive one IV infusion of vofatamab (25 mg/kg) monotherapy over 
90 (± 15) minutes. Subjects will begin combination treatment with vofatamab plus 
pembrolizumab on approximately Day 15 (i.e., Cycle 1 Day 1). Subjects will receive 
pembrolizumab (200 mg) by IV infusion over 30 (-5/+10) minutes followed by vofatamab 
(25 mg/kg) by IV infusion over 90 (± 15) minutes. If Cycle 0 and Cycle 1 vofatamab infusions 
have been well tolerated, subsequent doses of- vofatamab may be administered over 
30 (± 10) minutes, followed by a 30 minute observation period-. The vofatamab infusion will 
begin approximately 30 minutes after completion of the pembrolizumab infusion. Thereafter, 
combination treatment of vofatamab plus pembrolizumab will be administered Q3W (Day 1 of 
each cycle ± 7 days) until disease progression, death, decision to discontinue treatment, 
investigator discretion, or study termination, or the completion of 2 years of vofatamab and 
pembrolizumab therapy.  
 
Control Arm, Dose, and Mode of Administration: 
Not applicable. There is no control arm in study design. 
Endpoints: 
Phase 1b:  
o 
DLTs within the 35-day observation period. 
Phase 2 (Cohorts 1, 2, 3 and 4): 
o 
Primary Endpoints: 
o 
Safety and tolerability measurements of AEs, physical examination findings, 
laboratory test results, and vital signs over time. 
o 
ORR defined as the percentage of subjects who have baseline measurable disease 
and who achieve a best response of either complete response (CR) or partial 
response (PR) (as defined by RECIST 1.1) 
o 
Secondary Endpoints: 
o 
Efficacy Endpoints: 
           Assessed by the investigator using RECIST 1.1 criteria (for progression) 
▪ DOR defined as the time from first occurrence of a documented, objective 
response until the time of relapse or death from any cause.  

Protocol Number: B-701-U22  
CONFIDENTIAL  
Amendment 5  
Rainier Therapeutics, Inc. 
 
July 01, 2019  
Page 18 
▪ DCR defined as the percentage of subjects who achieve either CR or PR or 
stable disease (SD). 
• 
DCR (90), defined as the absence of disease progression and death 90 
days from the time of first study drug administration. 
• 
DCR (180), defined as the absence of disease progression and death 
180 days from the time of first study drug administration.  
▪ PFS defined as the time from a first study treatment dose to first occurrence 
of disease progression (per RECIST 1.1) or death from any cause, whichever 
occurs first. 
▪ OS defined as the time from first study drug administration to death from any 
cause. 
o The change over time in subject reported quality of life as measured by the European 
Organization for Research and Treatment Quality of Life Questionnaire (EORTC 
QLQ-C30) 
o The change following vofatamab 14-day lead-in period (Cohort 1 and Cohort 2) and 
after combination treatment with vofatamab and pembrolizumab (Cohort 3 and in 
Cohort 4 if biopsy material is available) on the immune infiltration of tumors in 
subjects with UCC by evaluating the expression of markers associated with tumor 
sub-type, immune cell infiltrates and cytokine expression  
o The impact of FGFR3 status at enrollment (WT or Mut/Fus) on the safety and 
efficacy of vofatamab alone and in combination with pembrolizumab in subjects with 
advanced UCC.  
 
o 
Exploratory Endpoints 
o 
The PK of vofatamab  
o 
The immunogenicity of vofatamab as measured by ATA levels  
o 
The safety and efficacy of vofatamab in combination with pembrolizumab by 
bladder cancer subtype 
o 
The impact of molecular markers on treatment response 
o 
The efficacy of vofatamab in combination with pembrolizumab in the treatment of  
subjects with UCC as measured by ORR, DOR, PFS, and DCR per iRECIST 
Statistical Methods: 
Phase 1b: 
Phase 1b endpoint will be number of events of dose limiting toxicity (DLT) observed over the 
safety observation period.  
 
Phase 2 (Cohorts 1, 2, 3 and 4): 
Primary Efficacy and Safety Analysis: 
• The safety data will be summarized descriptively for AEs, laboratory test results, ECGs, 
prior and concomitant medication, and vital signs.  

Protocol Number: B-701-U22  
CONFIDENTIAL  
Amendment 5  
Rainier Therapeutics, Inc. 
 
July 01, 2019  
Page 19 
• The ORR will be calculated as the percentage of subjects who have a best overall response 
of either CR or PR  and its 95% CIs at two interim analyses and the primary analysis.  
 
Secondary Efficacy Analyses: 
• The time-to-event (OS, PFS, DOR) endpoints will be summarized with descriptive 
statistics, including median time and its 95% confidence intervals (CIs).  
• The categorical response (DCR) endpoint will be summarized with the frequency count, 
percentage, and 95% CIs. 
• PRO EORTC QLQ-C30 endpoints and time to deterioration will be summarized 
descriptively.  
• An evaluation of biomarkers, cytokines, immunogenicity, and predictive biomarker 
analysis pre and post treatment will be summarized descriptively.  
 
Exploratory Endpoint Analyses: 
• Pharmacokinetic parameters will be summarized at baseline and over time.   
• ATA levels will be summarized at baseline and over time 
• The safety and efficacy of vofatamab in combination with pembrolizumab by FGFR3 
status at enrollment will be summarized  
• The safety and efficacy of vofatamab in combination with pembrolizumab by bladder cancer 
subtype at enrollment will be summarized. 
 
Interim Analyses: 
There will be two pre-specified interim analyses during Phase 2, one has already been 
completed on the first 28 subjects (20 WT and 8 Mut/Fus). The second planned interim will 
occur when a minimum of 52 subjects have been enrolled and have data available to determine 
ORR.  
 
All tumor assessments scans used in the interim analysis will be evaluated. Analysis will then be 
conducted using RECIST 1.1 and iRECIST. 
 
The primary efficacy analysis will be performed when approximately 90 subjects (including 
expansion) in Phase 2  have been followed with sufficient duration to evaluate the primary 
efficacy endpoint, at the discretion of the sponsor. The number and proportion of responders along 
with DOR (duration of response) will be reported.  The final analysis will be when all OS endpoint 
has been met or 3 years after the last subject enrolled, at the discretion of the sponsor.  
 
Sample Size Calculations: 
 
Given the expected π=0.343 with Type I error (alpha) at 0.05 (one-sided), 90 subjects will give a 
power of approximately 87.5% to reject the null hypothesis of π≤0.211. With the expected 
π=0.343, the 95% CI half width is around 0.098 for the sample size of 90 subjects. 
 
 

Protocol Number: B-701-U22 
CONFIDENTIAL  
Amendment 5 
Rainier Therapeutics, Inc.  
July 01, 2019 
Page 20 
Table 1 
Schedule of Assessments for Phase 1b and Phase 2 
 
Screening 
Treatment Phase 
End of 
Treatment/
ET Visit a,c 
Survival, 
End of 
Study 
Telephone 
Contact a 
Cycle 0a,b,w 
Cycle 1w  
Cycles 2+ 
(until 
progression) a,b 
 
 
 
Days -28 
to -1 
14-day 
cycle 
 
21-day 
cycle (± 3 
days) 
21-day cycles 
(± 7 days) 
 
 
Written informed consent d 
X 
 
 
 
 
 
Confirm availability and request archival 
tumor tissue, blood sample, or perform 
diagnostic tumor biopsy e 
X 
 
 
 
 
 
Review inclusion/exclusion criteria 
X 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
Complete physical examination f 
X 
 
 
 
 
 
Targeted physical examination f 
 
X 
X 
X 
X 
 
Biomarker tumor biopsy g 
 
X g 
X g 
 
 
 
Height (screening only) and weight 
X 
X 
X 
X 
X 
 
Vital signs h 
X 
X h 
X h 
X h 
X 
 
ECOG performance status 
X 
X 
X 
X 
X 
 
Adverse events i,j 
 
X i 
X 
X 
X j 
 
Concomitant medications and therapies 
X 
X 
X 
X 
X 
 
Tumor assessment k,l 
X k 
 
X l 
X l 
X l 
 
Hematology m 
X 
X 
X 
X 
X 
 
Viral serology (HIV -1/2, HBsAg, HBcAb 
and HCVAb)x 
X 
 
 
 
 
 
Serum chemistry and urinalysis n 
X 
X 
X 
X 
X 
 

Protocol Number: B-701-U22 
CONFIDENTIAL  
Amendment 5 
Rainier Therapeutics, Inc.  
July 01, 2019 
Page 21 
 
Screening 
Treatment Phase 
End of 
Treatment/
ET Visit a,c 
Survival, 
End of 
Study 
Telephone 
Contact a 
Cycle 0a,b,w 
Cycle 1w  
Cycles 2+ 
(until 
progression) a,b 
 
 
 
Days -28 
to -1 
14-day 
cycle 
 
21-day 
cycle (± 3 
days) 
21-day cycles 
(± 7 days) 
 
 
Electrocardiogram o 
X 
X 
X 
X 
X 
 
Coagulation (aPTT, PT/INR, and 
fibrinogen) p 
X 
X 
X 
X 
X 
 
Urine or serum pregnancy test q 
X 
X 
X 
X 
X 
 
Pharmacokinetic measurements r 
 
X 
X 
X 
X 
 
Anti-therapeutics antibody assessment s 
 
X 
Xs 
Xs 
X 
 
Biomarker assessment t 
 
X 
X 
X 
X 
 
Survival (via visits or telephone contact) u 
 
 
 
 
 
X u 
EORTC QLQ-C30w 
X 
X  
X  
X  
X  
 
Study drug infusion v 
 
X 
X 
X 
 
 
aPTT = activated partial thromboplastin time; ECOG = Eastern Cooperative Oncology Group; ET = early termination; FGFR3 = fibroblast growth factor 
receptor 3; IHC = immunohistochemistry; INR = international normalized ratio; PT = prothrombin time; EORTC QLQ-C30 = quality of life questionnaire. 
 

Protocol Number: B-701-U22 
CONFIDENTIAL  
Amendment 5 
Rainier Therapeutics, Inc.  
July 01, 2019 
Page 22 
a 
Study visits for Cycle 2+ may occur ± 7 days from the date scheduled if required for logistical/scheduling reasons.  
b 
Local laboratory assessments (i.e., hematology, coagulation, serum chemistry, viral serology, urine/serum pregnancy testing, and urinalysis) may be 
performed within 72 hours preceding study drug administration unless otherwise specified. If an institution performs an equivalent test (e.g., urine albumin 
rather than urine protein), this may be acceptable and must be approved by the sponsor prior to subject enrollment    
c 
Perform within 30 days after the last infusion of study drug. 
d 
Informed consent form(s) must be signed by the subject before any study-specific procedures are performed. 
e 
For Phase 1b, archival tumor tissue will be tested retrospectively, but the availability of samples of suitable quality and quantity should be determined and 
requested prior to study enrollment. For Phase 2, Cohort 1 and Cohort 2, subjects will be assigned based on FGFR3 genetic status 1) wild type (WT) or 2) 
mutant and/or fusion (Mut/Fus). An archival biopsy should be submitted for confirmation of genetic status. If archival biopsy is not (readily) available, a pre-
treatment diagnostic biopsy within 56 days of first study treatment, or a blood sample may be used to determine genetic status. This biopsy may also be used 
in place of the first biomarker biopsy sample (if there is adequate material). A pre-treatment diagnostic biopsy will only be accepted while the WT cohort is 
open for enrollment. If the archival tumor tissue sample(s) and blood sample used to assess FGFR3 genetic status are non-informative, then any subject who 
has initiated treatment will be assigned to the WT cohort for the purpose of analysis. 
f 
Complete physical exam includes all systems described in the body of the protocol. The targeted physical exam should only include systems of primary 
clinical relevance (i.e., cardiovascular, respiratory, and those associated with symptoms, and any system that might be associated with tumor assessment). 
g 
All subjects enrolled in Phase 1b and Phase 2, Cohort 1, 2 and 3 will have a biomarker tumor biopsy taken within 14 days prior to Cycle 0 (lead-in cycle). If 
the subject has undergone a diagnostic tumor biopsy procedure within 56 days of enrolling in the study, and the biopsy has adequate material, this sample 
may be used in place of the first biomarker biopsy. Subsequent biopsies will only be required for subjects in Phase 2, Cohorts 1, 2 , and 3 (luminal biology). 
For Phase 1b and Phase 2, Cohort 1 and Cohort 2, a second tumor biopsy will be obtained 14 days after Cycle 0 Day 1 of vofatamab. The second tumor 
biopsy should always occur within 3 days before Cycle 1 Day 1 infusion and prior to the first dose of vofatamab plus pembrolizumab. For patients enrolled 
in Cohort 3, the second tumor biopsy will occur at the end of cycle 1, Week 5, within 3 days before Cycle 2, Day 1 and prior to the administration of the 
second combination dose of vofatamab and pembrolizumab. For the Phase 2 expansion (Cohort 4), biopsies are optional. If a second biopsy is performed, it 
will be at end of cycle 1, Week 5. Subjects will be required to sign a separate consent form and must confirm their decision to opt-in.  
h 
Blood pressure, pulse rate, and temperature. On Day 1 of Cycle 0 (if applicable) and Cycle 1, vital signs for vofatamab should be assessed pre-infusion, 
every 15 (± 5) minutes during the infusion, at the end of the infusion, and 30 (± 10) minutes, 60 (± 10) minutes, and 90 (± 10) minutes post-infusion. On 
subsequent cycles, vital signs for vofatamab should be assessed pre-infusion and as clinical indicated. For infusions with pembrolizumab, vital signs should 
be assessed per institutional guidelines, or regional label. 
i 
Subjects will be monitored for any untoward effects during study drug infusion, for 90 minutes following completion of the infusion on Day 1 of Cycle 0 (if 
applicable) and Cycle 1 and then at least 30 minutes for all subsequent cycles in the absence of infusion-related adverse events (AEs). All AEs will be 
followed until resolution, stabilization, or until it has been determined that the study treatment or participation is not the cause.  
j 
Follow-up for AEs will occur for 30 days after the subject’s last dose of study drug or until initiation of another anti-tumor therapy, whichever occurs first. 
k 
All evaluable and measurable disease must be documented at screening and re-assessed at each subsequent tumor evaluation. A documented standard-of-care 
tumor assessment performed within 28 days prior to first study treatment may be used for the screening assessment. For subjects with measurable disease, 
response will be assessed by investigator per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). Screening assessments must include: 
(1) computerized tomography (CT) scans of the chest, abdomen, and pelvis and all known or suspected sites of disease, and (2) brain scans (CT or magnetic 
resonance imaging [MRI]). At the investigator’s discretion, additional methods of assessment of measurable disease per RECIST 1.1 may be used in addition 
to those listed above (e.g., bone scan by MRI). For subsequent tumor assessments, a CT scan of the chest, abdomen, and pelvis, and all known or suspected 
sites of disease must be obtained each time. The same imaging methods used at screening should be used throughout the study for each subject. 

Protocol Number: B-701-U22 
CONFIDENTIAL  
Amendment 5 
Rainier Therapeutics, Inc.  
July 01, 2019 
Page 23 
l 
For Phase 2, Cohort 1, Cohort 2, and Cohort 3, perform tumor assessments at end of Cycle 1, and every 9 weeks (± 7 days) thereafter (i.e., every third cycle 
beginning after Cycle 1) until disease progression or lack of tolerability. Disease re-staging will occur following Cycle 1 for biomarker correlation but will 
not be utilized for RECIST evaluation. Subjects in Cohort 4 who did not have the second biopsy will not need to have the scan following Cycle 1. Additional 
tumor assessments may be conducted as clinically indicated during the study. Results must be reviewed prior to study drug infusion at next cycle and 
continuation in the study will be based on the tumor assessment results. A tumor assessment scan should be performed if the subject is discontinuing the 
study early. At the End of Treatment/ET visit, subjects will be asked to provide any optional metastatic tumor tissue sample collected during the study or at 
autopsy.  
m 
Includes complete blood count (red blood cell [RBC] count, hemoglobin, hematocrit, white blood cell [WBC] count), platelet count, and percent and 
absolute differential counts. For the Screening visit, testing should be done within 14 days of Day 1 of Cycle 0. If an institution performs an equivalent test 
to those listed above, for study purposes, this may be acceptable as long as it is noted with institutional normal(s) and approved by the sponsor prior to 
subject enrollment. 
n 
Serum chemistry includes sodium, potassium, chloride, bicarbonate, non-fasting glucose, blood urea nitrogen (or urea concentration), creatinine, calcium, 
phosphate, magnesium, total and direct bilirubin, total protein, albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate 
dehydrogenase, and uric acid. Urinalysis includes macroscopic analysis (specific gravity, pH, protein, glucose, ketones, blood, bilirubin, leukocyte esterase, 
urobilinogen, and nitrite) and microscopic urinalysis (RBCs, WBCs, epithelial cells, casts, crystals, bacteria, and yeast). For the Screening visit, testing 
should be done within 14 days of Day 1 of Cycle 0. If an institution performs an equivalent test to those listed above, for study purposes, this may be 
acceptable as long as it is noted with institutional normal(s) and approved by the sponsor prior to subject enrollment. 
o 
Subjects should be resting for ≥ 10 minutes prior to electrocardiogram (ECG) collection. One ECG reading should be obtained at each of the following time 
points: Screening, Cycle 0 Day 1 pre-treatment, Cycle 1 Day 1 pre-treatment, Cycle 2 Day 1 pre-treatment, and at the End of Treatment/ET visit. 
p 
Coagulation assessments (activated partial thromboplastin time [aPTT] or partial thromboplastin time (PTT) and prothrombin time [PT]/international 
normalization ratio [INR] and fibrinogen). For the Screening visit, testing should be done within 14 days of Day 1 of Cycle 0. 
q 
For women of childbearing potential, a serum or urine pregnancy test must be performed during Screening (within 14 days prior to first vofatamab 
administration), prior to administration of study drug on Day 1 of each cycle, and the End of Treatment/ET visit.  
r 
Blood samples for PK will be obtained prior to the administration of vofatamab and within 30 (± 15) minutes after the completion of the administration of 
vofatamab on Day 1 of Cycle 0. Blood samples will be obtained prior to the administration of pembrolizumab and within 30 (± 15) minutes after the 
completion of the administration of vofatamab on Day 1 of Cycles 1 and 4, and once at the End of Treatment/ET visit. 
s 
Blood samples for ATA assessments will be obtained prior to infusion of vofatamab on Day 1 of Cycles 0, 1 and 4, and at the End of Treatment/ET Visit.  
t 
Blood, serum, and plasma samples for biomarkers will be obtained prior to infusion of vofatamab on Day 1 of Cycles 0, 1, 3, and 5, and at the End of 
Treatment/ET Visit. Blood for circulating tumor DNA will be collected at the time of progression. 
u 
Upon discontinuation of study treatment (vofatamab and pembrolizumab), subjects will be followed for survival every 3 months via telephone until death or 
full withdrawal of consent. The End of Study visit assessment should be performed by telephone call. 

Protocol Number: B-701-U22 
CONFIDENTIAL  
Amendment 5 
Rainier Therapeutics, Inc.  
July 01, 2019 
Page 24 
v 
For Cycle 0, the initial infusion of vofatamab should be administered over 90 (± 15) minutes to well-hydrated subjects, followed by a 90-minute observation 
period post-infusion. On Day 1 of Cycle 1 and beyond, subjects will receive an infusion of pembrolizumab (200 mg) over 30 (-5/+10) minutes followed by 
an infusion of vofatamab (25 mg/kg). If prior vofatamab infusions have been well-tolerated, subsequent doses of vofatamab may be administered over 
30 (± 10) minutes, followed by a 30-minute observation period post-infusion. Vofatamab infusion will begin approximately 30 minutes after completion of 
the pembrolizumab infusion. Combination treatment will be administered once every 21-days. Doses for Cycle 2 and beyond may be given ± 7 days from the 
date scheduled if required for logistical/scheduling reasons. Doses may also be delayed up to 21 days for recovery from reversible toxicity. (Note: Subjects 
who discontinue vofatamab may continue on study and receive pembrolizumab alone [200 mg Q3W] until disease progression, death, withdrawal of patient 
consent, or study termination. Subjects who discontinue pembrolizumab may continue on study and receive vofatamab alone (25 mg/kg Q3W) until disease 
progression, death, withdrawal of patient consent, or study termination.) 
w 
The EORTC QLQ-C30 instrument is administered at Screening and at Cycles 0, 1 and 2 (prior to administration of study drug), then every 2 cycles and 30 
days after discontinuation. 
x 
Presence of positive test results for Hepatitis B (Hepatitis B surface antigen [HBsAg] and/or total Hepatitis B core antibody [HBc Ab]), Hepatitis C 
(Hepatitis C virus antibody [HCV Ab] serology testing), human immunodeficiency virus (HIV1/2 antibody +), and /or evidence of active tuberculosis 
(history and/or radiology findings). Note: Subjects positive for anti-Hepatitis B core antibody (HBc Ab) are eligible only if confirmatory polymerase chain 
reaction (PCR) is negative for evidence of Hepatitis B Virus DNA (within the Institution cutoff value) and for study purposes the reported positive antibody 
testing will be considered to be a false positive test result.  

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GLOSSARY OF TERMS  
Abbreviation/Acronym 
Definition 
95% CI 
95% confidence interval 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATA 
anti-therapeutic antibody 
ATC 
anatomical therapeutic chemical 
AUC 
area under the concentration curve 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CL 
Clearance 
CNS 
central nervous system 
CPI 
checkpoint inhibitor 
CR 
complete response 
CRF 
case report form 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
cytochrome 3A4  
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of objective response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EE 
efficacy evaluable 
ELISA 
enzyme-linked immunosorbent assay 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
ET 
early termination 
FDA 
Food and Drug Administration 
FGFR3 
fibroblast growth factor receptor 3 
GCP 
Good Clinical Practice 
HBcAb 
hepatitis B core antibody  
HBsAg 
hepatitis B surface antigen 

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Abbreviation/Acronym 
Definition 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HEENT 
head, eye, ear, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin  
IgG1 
immunoglobulin G1 
IHC 
Immunohistochemistry 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mut/Fus 
mutant fusion 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI  
National Cancer Institute 
NGS 
Next generation sequencing 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed death protein 1 
PD-L1 
programmed death ligand 1 
PK 
Pharmacokinetic 
PFS 
progression-free survival 
PR 
partial response 
PRO 
patient reported outcome 
PS 
performance status 
PT 
prothrombin time or preferred term 
QLQ 
quality of life questionnaire 
QW 
Weekly 
Q3W 
once every 3 weeks 

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Abbreviation/Acronym 
Definition 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors Version 
1.1 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SD 
stable disease 
SDV 
source data verification 
SOC 
System Organ Class 
SSC 
Safety Steering Committee 
TCC 
transitional cell carcinoma 
TCR 
T-cell receptors 
UCB 
urothelial cell carcinoma of the bladder 
UCC 
urothelial cell carcinoma 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WHO 
World Health Organization 
WT 
wild-type 

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1 
INTRODUCTION 
1.1 
Background on Urothelial Cell Carcinoma 
Urothelial cell carcinoma (UCC; also known as transitional cell carcinoma [TCC]) occurs in 
the urinary system (i.e., kidneys, urinary bladder, and accessory organs) and is the most 
common type of bladder cancer, accounting for 90% of all bladder tumors (Eble 2004). It is 
the fifth most common cancer in the United States (US) (Costantini 2011) and fourth most 
common cancer in Europe (Jemal 2011); with an estimated 74,690 new cases and 
15,580 deaths occurring in the US in 2014 (Cancer.org), and an estimated 136,000 new cases 
and 49,000 deaths occurring in Europe in 2009 (Bellmunt 2009). 
Clinical and pathological studies have identified two variants of urothelial cell carcinoma of 
the bladder (UCB) which arise via distinct mechanisms, a low-grade papillary variant and an 
invasive tumor variant (Wu 2005, Vallot 2011). The low-grade papillary variant accounts for 
80% of all UCBs and arises from urothelial hyperplasia. The five-year survival for this tumor 
type, when treated with surgery and intravesical immunotherapy, is greater than 90% 
(Cancer.org). The invasive tumor variant represents 20% of UCBs and has a poor prognosis. 
Cisplatin-based chemotherapy with either a dose dense MVAC (Sternberg 2001) or 
gemcitabine cisplatin (von der Maase 2000) remains the standard treatment for invasive 
UCC. Despite initial response rates on the order of 50 to 70%, this cancer typically 
progresses rapidly with a median survival of around 13 to 15 months (von der Maase 2000; 
Siefker-Radtke 2002).  
1.1.1 
FGFR3 in Bladder Cancer 
Recent studies have shown that UCC tumors often have genetic alterations in fibroblast 
growth factor receptor 3 (FGFR3) or amplification/overexpression of FGFR3 
(Cancer Genome Atlas Research Network 2013, Tomlinson 2007a, Gust 2013). FGFR3 
belongs to a family of structurally-related tyrosine kinase receptors encoded by four different 
genes (FGFR1-4). These receptors regulate various biological processes, including 
proliferation, differentiation, migration and apoptosis. Inappropriate FGFR3 signaling is 
implicated in the pathogenesis of the majority of muscle invasive UCC tumors with a notable 
percentage (approximately 20%) caused by activating FGFR3 mutations or gene fusions, and 
a significant percentage (50% or greater) expressing the receptor (Gomez-Roman 2005, 
Tomlinson 2007a, Gust 2013, Rainier unpublished data). Preclinical data from several lines 
of investigation, including short hairpin ribonucleic acid knockdown (Tomlinson 2007b, 
Qing 2009), antibody targeting (Martinez-Torrecuadrada 2005, Qing 2009), and small 
molecule inhibition (Lamont 2011) of FGFR3 in bladder cancer cell lines, also demonstrate 
that FGFR3 is essential for UCC cell growth in vitro and in vivo.  
Additional studies have shown that FGFR3 mutations and expression are associated with the 
non-inflamed bladder cancer phenotype (Sweis 2015; Rosenberg 2016). Blockade of the 
FGFR3 pathway could enhance immune cell infiltrate into tumors that express FGFR3 or in 
which the FGFR3 pathway is activated. Luminal sub-type I bladder cancers are predicted to 
be highest in FGFR3 expression, have the highest prevalence of FGFR3 mutations 
(Choi 2014, Robertson 2017), and have the poorest response rate to CPI treatment 

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(Rosenberg 2016). There is pre-clinical data suggesting that treatment of luminal cell lines 
with FGFR inhibition may enhance response including immune markers (McConkey/Hahn 
unpublished data), making these tumors more susceptible to immunotherapy and providing 
the rationale for sequential treatment with FGFR3 and programmed death ligand 1 (PD-L1) 
inhibition. A single case report by Nassar et al. reported a complete response in an FGFR3-
TACC3 fusion patient who received B-701 followed by a checkpoint inhibitor (Nassar 2018). 
1.2 
Background on Vofatamab 
Vofatamab is a phage-derived, affinity-matured, human monoclonal antibody specific for 
FGFR3. It is based on a human immunoglobulin G1 (IgG1) framework containing heavy 
chain VHIII and light chain VκI subgroup sequences.  
Vofatamab can be used to target FGFR3-positive tumors via three possible modes of action: 
(1) the blocking of ligand binding, receptor dimerization and activation, and downstream 
receptor signaling, (2) eliciting effector function such as antibody-dependent cell-mediated 
cytotoxicity (ADCC), and/or (3) antagonizing ligand-independent activating mutations 
(Qing 2009). 
1.2.1 
Non-clinical Data with Vofatamab 
In in vivo studies, vofatamab demonstrated binding to FGFR3 from multiple species, 
including mouse, rat, cynomolgus monkey, and human. Vofatamab also inhibited ligand 
binding to FGFR3, prevented receptor−receptor association, blocked receptor dimerization, 
and blocked downstream signaling from both wild-type (WT) and common mutant variants 
of FGFR3, as well as FGFR3-TACC3 fusions linked with bladder cancer.--- Vofatamab 
suppressed FGFR3mediated cell proliferation and exerted strong antitumor activity in mouse 
xenograft models of both bladder carcinoma and t(4;14)positive multiple myeloma. Anti-
tumor activity was due to direct inhibition of FGFR3 signaling and/or engagement of ADCC.  
Vofatamab was well-tolerated and resulted in no severe toxicities when administered 
intravenously weekly for 8 weeks (total of nine doses) in either rats or cynomolgus monkeys 
and weekly for 26 weeks in juvenile monkeys, at doses up to the maximum feasible dose of 
50 mg/kg. Vofatamab-related effects in the repeat-dose toxicity study in rats were limited to 
microscopic findings of minimal to slight focal tubular hypospermatogenesis/atrophy in male 
rats at the recovery necropsy. These observations were limited in distribution and severity, 
and therefore considered unlikely to result in a detectable impact on fertility. Vofatamab-
related effects that were observed in the 8-week cynomolgus monkey study included 
increased spleen weight and minimal/moderate splenic lymphoid hyperplasia at terminal 
necropsy. These effects were reversible and not considered adverse. Similarly, administration 
of vofatamab weekly for 26 weeks was well-tolerated in juvenile monkeys. Changes 
considered related to vofatamab treatment were limited to moderate increases in white blood 
cell counts at the 50 mg/kg dose (i.e., increases in lymphocytes, monocytes, basophils and 
large unstained cells). These changes were no longer present during the recovery period and 
in the absence of other correlating changes were not considered toxicologically significant. 

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Pharmacokinetic (PK) studies of vofatamab in mice, Sprague-Dawley rats, and cynomolgus 
monkeys demonstrated both non-linear and linear PK characteristics, suggesting that the total 
clearance (CL) of vofatamab consists of contributions of a specific (target-mediated) CL 
component and a non-specific CL component, with the specific CL component having a 
greater contribution at lower doses. In repeat-dose toxicology studies in rats and cynomolgus 
monkeys, drug exposure increased proportionally with weekly (qw) intravenous (IV) doses 
of 5, 15, and 50 mg/kg, suggesting limited contribution of saturable target-mediated CL to 
the overall CL at these dose levels. Overall, the PK assessment indicates that vofatamab 
behaves like a typical IgG1, with some contribution of target-mediated clearance indicated 
by higher total CL estimates at the lower doses. 
Additional non-clinical study information is provided in the Investigator’s Brochure. 
1.2.2 
Clinical Data with Vofatamab 
Vofatamab (i.e. B-701 or MFGR1877S) has been administered to 149 subjects in 4 
Genentech and Rainier-sponsored clinical trials. 
• Study MFG4809g (N = 14): a Phase 1 trial in patients with relapsed/refractory 
t(4;14)-positive multiple myeloma (NCT01122875). This study is completed. 
• Study MFG4991g (N = 26): a Phase 1 trial in patients with advanced solid tumors 
(NCT01363024). This study is completed. 
• Study B-701-U21 (N = 72) is an ongoing Phase 1b/2b trial in patients with locally 
advanced or metastatic UCC who have relapsed after or are refractory to standard 
therapy. Total enrollment as of the data cut off of 25 April 2019 is 71 subjects. The 
Phase 1b (Cohort 1) is complete N = 20 (19 treated). The Phase 2 cohort 2 (N=22, 
21 treated) and cohort 3 (N=21), as well as Phase 2b (Monotherapy expansion 
phase, N=9) have completed enrollment and patients remain on treatment or re in 
study follow-up.This study is ongoing. 
• Study B-701-U22 (adaptive design planned to enroll up to 74 subjects) is an 
ongoing Phase 1b/2 trial in subjects with locally advanced or metastatic UCC who 
have progressed following platinum-based chemotherapy. Enrollment as of the data 
cut off of 25 April 2019: Phase 1b complete n = 8; Phase 2 n = 28. Cohort WT is 
fully enrolled (as of 14 August 2018) and Cohort Mut/Fus is currently enrolling. 
This study is ongoing. 
 
In addition, 1 subject was treated with vofatamab in an investigator-sponsored trial (IST). 
Causality of AEs assessed by the investigator as possibly related and probably related are 
categorized as “related”, and unlikely related and not related AEs are categorized as “not 
related”. Evaluable patients were those who received at least one dose of vofatamab. 

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Summaries of the respective studies are provided below, and additional study information is 
provided in the Investigator’s Brochure. 
1.2.2.1 
Study MFG4991g (Phase 1 study in Patients with Advanced Solid Tumors) 
Study MFG4991g was an open-label, multicenter, Phase 1 study in 26 subjects with 
advanced solid tumors, of which 10 subjects had UCC. The safety and PK of escalating doses 
of vofatamab were evaluated following IV infusion of vofatamab to subjects once every 28 
days (on Day 1 of each cycle), with an additional loading dose on Day 8 of Cycle 1 only. 
Doses of 2, 4, 8, 15, and 30 mg/kg of vofatamab were evaluated in 26 subjects. The study 
was terminated early by the Sponsor for reasons unrelated to efficacy or safety. All 26 
subjects enrolled were in the dose-escalation stage, and the maximum tolerated dose was not 
reached. The maximum administered dose was 30 mg/kg on a 28-day schedule, and the 
median number of doses administered for all subjects was 3 (range 1-16).  
Overall, vofatamab administered as an IV infusion at doses up to 30 mg/kg on a 28-day 
schedule was well-tolerated in subjects with advanced solid tumors. Two deaths due to 
disease progression were reported, and no deaths due to treatment-related adverse events 
(AEs) were reported. Only one dose-limiting toxicity (DLT) was observed in the study; and 
was reported by one subject in the 30 mg/kg cohort (Grade 4 thrombocytopenia which 
occurred on Day 4 of treatment and was attributed by the investigator as possibly due to 
concomitant treatment with levofloxacin).  
The AEs assessed as related to vofatamab and occurring in ≥ 10% of the subjects were 
fatigue (19.2%) and mucosal inflammation (11.5%). The majority of vofatamab-related AEs 
reported were Grade 1 or 2 in severity. Ten (38.5%) subjects experienced Grade ≥ 3 AEs, 
with 1 (3.8%) having Grade 4 thrombocytopenia and 1 (3.8%) having Grade 3 white blood 
cell (WBC) count decreased assessed as related to vofatamab. Eleven serious adverse events 
(SAEs) were reported in 8 (30.8%) subjects, with 1 (3.8%) subject experiencing one SAE 
assessed as related to vofatamab. 
Serum exposure of vofatamab was approximately dose-proportional and increased with dose 
across the dose range of 2−30 mg/kg.  
All 26 subjects enrolled in the study had evaluable anti-vofatamab antibodies (ATA) samples 
after treatment, and all tested negative for antibodies to vofatamab. 
A total of 10 subjects (38%) had stable disease (SD) as their best clinical response on study. 
Furthermore, a post-hoc analysis comparing progression-free survival (PFS) of high-dose 
vofatamab (30 mg/kg) vs. low doses of vofatamab (< 30 mg/kg) showed greater PFS in the 
high-dose subjects (Figure 1). This finding was most notable in the evaluable UCC 
subpopulation, which had a median PFS of 5.7 months for the high-dose group (n = 5) 
compared with a median PFS of 1.7 months in the low-dose group (n = 3). Two subjects with 
UCC were not considered evaluable and were not included in this analysis. 

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Figure 1: 
Progression-Free Survival in Subjects with UCC (Study MFG4991g) 
 
Note: This data set excludes one subject who received escalating doses of vofatamab (anti-FGFR3), 
4 mg/kg up to 30 mg/kg, and a 2nd subject dosed at 30 mg/kg who died after Day 4 of the study due to 
disease progression 
^ Subject had a single dose of vofatamab (anti-FGFR3) and dropped out of the study due to 
thrombocytopenia, possibly related to levofloxacin. 
 
1.2.2.2 
Study MFG4809g (Phase 1 Study in Patients with Multiple Myeloma) 
Study MFG4809g was an open-label, multicenter, Phase 1 study in subjects with relapsed or 
refractory t(4;14)-positive multiple myeloma. The safety and PK of escalating doses of 
vofatamab were evaluated following IV infusion of vofatamab to subjects weekly for 3 
weeks (Days 1, 8, and 15 of a 28-day cycle), followed by a single infusion of the same dose 
on Day 1 of the subsequent cycles. Doses of 1, 2, 4, 8, and 15 mg/kg of vofatamab were 
evaluated in 14 subjects. The median number of cycles administered was 1.5 and the median 
number of doses administered was 3.5. The study was terminated early by the Sponsor due to 
unsatisfactory enrollment.  
All subjects had discontinued from the study at the time of study termination for the 
following reasons: 10 (71.4%) subjects due to disease progression, 3 (21.4%) subjects died 
(including 2 subjects who died due to disease progression and 1 subject who died due to 
disease progression with Grade 5 intracranial hemorrhage), and 1 (7.1%) subject due to 
subject/legal guardian decision to withdraw. All 14 subjects experienced at least one AE. 
The most common AEs irrespective of study drug attribution were fatigue experienced by 
6 (42.9%) subjects; anemia and nausea experienced by 4 (28.6%) subjects each; diarrhea, 
dyspnea, headache, and thrombocytopenia experienced by 3 (21.4%) subjects each; and 
confusional state, cough, decreased appetite, hypercalcemia, neutropenia, peripheral edema, 
platelet count decreased, pyrexia, and urinary tract infection experienced by 2 (14.3%) 

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subjects each. A total of 6 subjects experienced 9 SAEs between Cycle 1 Day 1 and 90 days 
after the last administration of vofatamab, including one SAE of Grade 5 intracranial 
hemorrhage and one SAE of Grade 2 pyrexia, which was deemed related to vofatamab. All 
other SAEs were considered unrelated to vofatamab. There were no AEs of special interest, 
and there were no additional AEs of interest identified during the conduct of the study. 
Furthermore, no events were identified as a DLT and the maximum tolerated dose (MTD) 
was not reached prior to the Sponsor’s decision to stop enrollment.  
Given the small sample size, no definitive conclusions regarding anti-tumor activity could be 
drawn. The best overall response achieved was that of SD, which was reported in 7 of 
14 subjects. 
Exposure to vofatamab increased with increasing dose. Increases in exposure were non-dose 
proportional in the lower dose groups of 1 and 2 mg/kg, and approximately dose proportional 
at all other dose groups (i.e., 4, 8, and 15 mg/kg). FGFR3 levels did not appreciably change 
upon vofatamab treatment, regardless of dose. 
1.2.2.3 
A Dose Escalation, Expansion Study of Vofatamab (B-701) Alone, Plus 
Docetaxel, or Versus Docetaxel in Subjects with Locally Advanced or 
Metastatic Urothelial Cell Carcinoma who have Relapsed After, or are 
Refractory to Standard Therapy (Study B-701-U21) 
Enrollment is complete of the study. In the Phase 1b, 20 subjects have been enrolled of 
whom 19 subjects have received at least one dose of study drug. No protocol-defined dose 
limiting toxicities were observed during the safety window in Cohort 1. The dosing regimen 
of 25 mg/kg of vofatamab and 75 mg/m2 of docetaxel every 3 weeks has been selected as the 
recommended dosing regimen for the remaining subjects on study. 
Of the 19 evaluable subjects in the Phase 1b safety population, subjects had a mean age of 65 
years (range 57-76), were predominately white (95%), and the majority were male (74%) and 
had an ECOG performance status of 1 (58%).  
All subjects received at least 1 line of chemotherapy and most subjects had received 2 or 
more prior treatments (73.7%), with 42.1% refractory to the last line of therapy. At study 
enrollment, 10.5% of subjects had liver metastases. Thirteen subjects had FGFR3 WT and 
6 subjects had FGFR3 Mut/Fus, with similar pretreatment characteristics between the 2 
groups. The median number of days of exposure was 96, with a clear difference in exposure 
based on Mut/Fus versus WT (147 vs 22 days).  
All subjects in Cohort 1 have discontinued study treatment, predominantly due to disease 
progression (12/19 subjects/63%). 
Phase 2 consisted of two cohorts, cohort 2 of subjects who received vofatamab in 
combination with docetaxel, and cohort 3 of subjects who were treated with vofatamab 
monotherapy. All subjects had an FGFR3 mutation or fusion. Cohorts 2 and 3 have 
completed accrual (as of 01 October 2018) and 21 subjects have been enrolled in each cohort. 
An interim analysis with cut-off data 25 April 2019 was conducted. The study is currently 

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ongoing. For further information, including safety information, please refer to the 
Investigator’s Brochure. 
 
1.2.2.4 
A Phase 1b/2, Multi-Center, Open-Label Phase 1b/2 Study of a Novel 
FGFR3 Inhibitor (B-701) Combined with Pembrolizumab in Subjects with 
Locally Advanced or Metastatic Urothelial Carcinoma who have 
Progressed Following Platinum-based Chemotherapy (Study B-701-U22) 
FIERCE-22 is a multi-center, open-label study to determine the safety, tolerability, and 
efficacy of vofatamab plus pembrolizumab in the treatment of subjects with locally advanced 
or mUCC, who have progressed following platinum-based chemotherapy or are not eligible 
for cisplatin-containing chemotherapy, and who have not received prior immune checkpoint 
inhibitor or FGFR inhibitor-targeted therapy. The study consists of 2 parts: a Phase 1b lead-
in phase enrolling six (6) to 18 subjects and a Phase 2 dose expansion phase enrolling up to 
74 subjects. Patients in the Phase 1b were unselected for FGFR3 status, whereas patients in 
the Phase 2 are assigned to Cohort 1 if their tumor is FGFR3 WT and to Cohort 2 if their 
tumor is FGFR3 mut/fus. Patients are treated with vofatamab 25 mg/kg IV monotherapy as a 
2-week cycle (Cycle 0) and vofatamab 25mg/kg IV in combination with pembrolizumab as a 
3-week cycle (Cycle 1 and following cycles). 
 
The Phase 1b study initiated enrollment on October 2017 with the last subject enrolled in this 
cohort in February 2018. There was 1 subject enrolled under amendment 1 who received 
1 dose of vofatamab and was taken off study after a program wide safety hold. This subject 
was not included in the DLT analysis as they never received the combination therapy but was 
included in the safety analysis. 
After review of safety data and an amendment to the protocol (amendment 2), the program 
resumed enrollment. A total of 7 additional subjects were enrolled in Phase 1b. Six subjects 
were evaluable, and 1 subject was replaced due to disease progression and the need for 
palliative treatment during the DLT safety window.  
Of the 8 subjects in the Phase 1b safety population, subjects had a mean age of 62 years 
(range 44-78), all (100%) were white and male and the majority (75%) had an ECOG 
performance status of 1. Among the 7 subjects enrolled after amendment 2, there were 6 
subjects with FGFR3 wild-type and 1 with Mut/Fus (pending confirmation by Foundation 
Medicine, Inc.). 
Phase 1b of the study has been completed, Cohort WT was fully enrolled (as of 14 August 
2018). The study is currently ongoing. For further information, including safety information, 
please refer to the Investigator’s Brochure. 
 
1.3 
Background on Pembrolizumab 
Pembrolizumab (Keytruda®) is a programmed death protein 1 (PD-1) blocking antibody that 
is approved by the FDA for the of treatment of patients with locally advanced or metastatic 

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UCC who have disease progression during or following platinum -containing chemotherapy 
or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-
containing chemotherapy. Pembrolizumab is also approved by the FDA for the treatment of 
patients with locally advanced or metastatic UCC who are not eligible for 
cisplatin -containing chemotherapy. 
The regular approval for the second-line indication was based on data from Trial 
KEYNOTE-045, a multicenter, randomized, active-controlled study in patients with locally 
advanced or metastatic urothelial carcinoma with disease progression on or after platinum 
containing- chemotherapy. Patients were randomly assigned (1:1) to receive either 
pembrolizumab 200 mg once every 3 weeks (Q3W; n = 270) or investigator’s choice of a 
chemotherapy regimen (paclitaxel [n = 84], docetaxel [n = 84], or vinflunine [n = 87]) Q3W 
(n = 272). The study demonstrated statistically significant improvements in overall survival 
(OS) and objective response rate (ORR) for patients assigned to pembrolizumab compared 
with chemotherapy. Median OS was 10.3 and 7.4 months in the pembrolizumab and 
chemotherapy arms, respectively (HR: 0.73; 95% CI: 0.59, 0.91, p = 0.004). ORR was 21% 
for pembrolizumab and 11% for chemotherapy (p = 0.002). No statistically significant 
difference in progression-free survival (PFS) between the two arms was observed.  
The accelerated approval for the first-line indication was based on data from 
KEYNOTE--052, a single-arm, open-label study in 370 patients with locally advanced or 
metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing 
chemotherapy. Patients received pembrolizumab 200 mg Q3W. With a median follow-up 
time of 7.8 months, the ORR was 28.6% (95% CI 24, 34) and the median response duration 
was not reached (range: 1.4+, 17.8+ months). 
The most common adverse reactions reported for at least 20% of pembrolizumab-treated 
patients in either of the two studies included fatigue, musculoskeletal pain, pruritus, 
decreased appetite, nausea, diarrhea, constipation, and rash. Discontinuation of 
pembrolizumab secondary to adverse reactions occurred in 8% of patients in KEYNOTE-045 
and in 11% in KEYNOTE-052. Dose interruption of pembrolizumab occurred in 
approximately 20% of patients in either study. Serious adverse reactions occurred in 
approximately 40% of pembrolizumab-treated patients. Immune-mediated adverse reactions, 
including pneumonitis, colitis, hepatitis, endocrinopathies (hypophysitis, hyperthyroidism, 
hypothyroidism, and Type 1 Diabetes mellitus), and renal dysfunction, were reported in the 
studies and were managed according to guidelines in Warnings and Precautions of the label 
for pembrolizumab. 
Complete information on dosage and administration, safety information, non-clinical and 
clinical studies is contained in the FDA approved label for pembrolizumab (available at:  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf). 
1.4 
Rationale for Combining Vofatamab and Pembrolizumab 
To date, several FDA-approved second-line therapies for the treatment of bladder cancer are 
available, including the immune checkpoint inhibitors (CPIs) such as atezolizumab, 
avelumab, durvalumab, nivolumab, and pembrolizumab. Although immune CPIs have the 

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potential to be a major advance in the second-line treatment of UCC, the inhibition of the 
programmed cell death protein (PD-1) pathway by CPIs depends on an immune response 
against tumor cells for efficacy. Consequently, emerging clinical and non-clinical data 
suggest that tumors with a non-inflamed phenotype are less likely to respond to immune CPI 
therapy. Moreover, while CPIs are highly effective in a small subset of patients whose 
tumors express PD-1, the majority of patients have disease which will progress while 
receiving this therapy. Thus, a significant unmet medical need exists for patients with 
relapsed or refractory metastatic UCC, especially for those tumors that do not have an 
inflammatory signature. 
Recent work using gene expression profiling suggests there are at least two main intrinsic 
subtypes of UCC, which differ in their response and benefit to systemic chemotherapy 
(Choi 2014; McConkey 2016; Cancer Genome Atlas Research Network 2014). The basal 
subtype, which is typically associated with markers associated with stem cells, CK 5/6 
positivity, and rapid proliferation, in addition to markers of angiogenesis, and markers of the 
immune system has a worse prognosis compared with luminal tumors which are typically 
associated with uroplakin markers, GATA3 positivity on immunohistochemistry (IHC), 
FGFR3 overexpression and mutations, and lower proliferation with an improved prognosis 
compared with untreated basal tumors. Using gene expression profiling the basal subtype 
was found to be predictive of improved survival outcomes when treated with neoadjuvant 
chemotherapy (McConkey 2016). This is the first clinical data which suggests that bladder 
cancer is not just one disease, and that with subtyping we may select patients most likely to 
benefit from specific therapies. 
Overexpression of FGFR and FGFR3 mutations are most commonly observed in luminal 
type I tumors, and are often associated with downstream markers of pathway activation 
including PPARGamma expression (Choi 2014; Cancer Genome Atlas Research 
Network 2014). FGFR3 positive luminal tumors also lack immune cell infiltration, and the 
typical inflammatory markers associated with immune system sensitivity, leading us to 
predict that this subtype would also be resistant to immune checkpoint inhibition 
(Sweis 2015). Recent data from Rosenberg et al. support the hypothesis that the luminal 
subtype 1 is associated with the lack of response and benefit from PD-L1 inhibition 
(Rosenberg 2016). Therefore, inhibiting the FGFR3 pathway may overcome the immuno-
silencing noted in the luminal I subtype. 
Vofatamab is a novel fully human monoclonal antibody specific for FGFR3 that is being 
developed to target FGFR3-positive tumors. Non-clinical studies have also shown that 
vofatamab suppresses FGFR3 mediated cell proliferation and exerts strong anti-tumor 
activity in mouse xenograft models of bladder cancer. Clinical data demonstrate that the 
majority of patients with UCC express FGFR3 on the tumor cell surface (Cancer Genome 
Atlas Research Network 2014; Carneiro 2015). 
This study is evaluating the safety, tolerability and efficacy of combining vofatamab with 
pembrolizumab. It is designed to assess whether vofatamab enhances immune cell infiltration 
or increase markers of immune system activation in subjects which in turn will enhance the 
efficacy of pembrolizumab. In addition, it will explore the impact of vofatamab on the tumor 
cell microenvironment. There is pre-clinical data suggesting that treatment of luminal cell 

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lines with FGFR inhibition may bring out features that will make tumors more susceptible to 
immunotherapy, providing the rationale for sequential and or combination treatment with 
FGFR3 and PD-1 inhibition. 
   

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2 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Phase 1b 
2.1.1.1 
Primary Objective 
• To establish the initial safety and to identify the recommended Phase 2 dose (RP2D) of 
vofatamab and pembrolizumab 
2.1.2 
Phase 2 and Phase 2 Expansion 
2.1.2.1 
Primary Objectives (Cohorts 1, 2, and 3) 
• To evaluate the safety and tolerability of vofatamab plus pembrolizumab in subjects with 
UCC. 
• To evaluate the efficacy of vofatamab in combination with pembrolizumab in the 
treatment of subjects with UCC as measured by objective response rate (ORR) by 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)  
2.1.2.2 
Secondary Objectives 
• To evaluate the efficacy of vofatamab in combination with pembrolizumab in the 
treatment of subjects with UCC as measured by duration of objective response 
(DOR), progression free survival (PFS), and disease control rate (DCR) by RECIST 
1.1, and overall survival (OS) 
• To describe the impact of FGFR3 status at enrollment [wildtype (WT), mutation 
and/or fusion (Mut/Fus)] on the safety and efficacy after one cycle of B-701 alone, 
followed by B-701in combination with pembrolizumab in subjects with advanced 
UCC 
• To evaluate the change in patient reported outcome (PRO) using quality of life 
measurements over time by the European Organization for Research and Treatment  
Quality of Life Questionnaire (EORTC QLQ-C30) 
• To evaluate the change in expression of markers associated with tumor subtype, 
immune cell infiltrate, and immune response when B-701 is administered alone 
during the 14-day lead-in period (Cohorts 1 and 2) 
• To evaluate the change in expression of markers associated with luminal tumor 
subtype, immune cell infiltrate, and immune response using a different timepoint for 
the 2nd biopsy only for Cohort 3 (at the end Cycle 1, Week 5) 
2.1.2.3 
Exploratory Objectives (Cohorts 1, 2 and 3) 
• To evaluate the pharmacokinetics (PK) of vofatamab in subjects with UCC 
• To assess the immunogenicity of vofatamab in subjects with UCC 

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• To determine if other molecular markers predict treatment response 
• To evaluate the efficacy of vofatamab in combination with pembrolizumab in the 
treatment of subjects with UCC as measured by ORR, DOR, OS, PFS, and DCR per 
iRECIST 
2.1.2.4 
Secondary Objectives (Cohort 4): 
• To evaluate the efficacy of vofatamab in combination with pembrolizumab in the 
treatment of unselected subjects with UCC as measured by duration of objective 
response (DOR), progression free survival (PFS), and disease control rate (DCR) by 
RECIST 1.1, and overall survival (OS)  
• To evaluate the change in patient reported outcome (PRO) using quality of life 
measurements over time by the European Organization for Research and Treatment 
Quality of Life Questionnaire (EORTC QLQ-C30) 
2.1.2.5 
Exploratory objective (Cohort 4): 
• To evaluate the efficacy of vofatamab in combination with pembrolizumab in the 
treatment of  unselected subjects with UCC as measured by ORR, DOR, PFS, and 
DCR per iRECIST 
 
2.2 
Endpoints 
2.2.1 
Phase 1b 
• DLTs within the 35-day observation period. 
 
2.2.2 
Phase 2 (Cohorts 1, 2, 3, and 4) 
2.2.2.1 
Primary Endpoints 
• Safety and tolerability measurements of AEs, physical examination findings, 
laboratory test results, and vital signs over time. 
• ORR defined as the percentage of subjects who have baseline measurable disease and 
who achieve a best response of either complete response (CR) or partial response 
(PR) (as defined by RECIST 1.1) 
 
2.2.2.2 
Secondary Endpoints: 
• Efficacy Endpoints 
 
Assessed by the investigator using RECIST 1.1 criteria (for progression) 
▪ DOR defined as the time from first occurrence of a documented, objective 
response until the time of relapse or death from any cause.  

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▪ DCR defined as the percentage of subjects who achieve either CR or PR or 
stable disease (SD). 
• 
DCR (90), defined as the absence of disease progression and death 
90 days from the time of first study drug administration. 
• 
DCR (180), defined as the absence of disease progression and death 
180 days from the time of first study drug administration.  
▪ PFS defined as the time from a first study treatment dose to first occurrence 
of disease progression (per RECIST 1.1) or death from any cause, 
whichever occurs first. 
▪ OS defined as the time from first study drug administration to death from 
any cause. 
▪ The change over time in subject-reported quality of life as measured by the 
EORTC QLQ-C30 
▪ The change following vofatamab 14-day lead-in period (Cohort 1 and 
Cohort 2) and after combination treatment with vofatamab and 
pembrolizumab (Cohort 3 and in Cohort 4 if biopsy material is available) 
on the immune infiltration of tumors in subjects with UCC by evaluating 
the expression of markers associated with tumor sub-type, immune cell 
infiltrates and cytokine expression  
▪ 
The impact of FGFR3 status at enrollment (WT or Mut/Fus) on the safety 
and efficacy of vofatamab alone and in combination with pembrolizumab 
in subjects with advanced UCC.  
 
2.2.2.3 
Exploratory Endpoints 
o 
The PK of vofatamab  
o 
The immunogenicity of vofatamab as measured by ATA levels  
o 
The safety and efficacy of vofatamab in combination with pembrolizumab by 
bladder cancer subtype 
o 
The impact of molecular markers on treatment response 
o 
The efficacy of vofatamab in combination with pembrolizumab in the 
treatment of subjects with UCC as measured by ORR, DOR, PFS, and DCR 
per iRECIST 

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3 
STUDY DESIGN 
3.1 
Summary of Study Design 
This is a Phase 1b/2 multi-center, open-label study to determine the safety, tolerability, and 
efficacy of vofatamab plus pembrolizumab in the treatment of subjects with locally advanced 
or metastatic UCC, who have progressed following platinum-based chemotherapy, and who 
have not received prior immune checkpoint inhibitor or FGFR inhibitor targeted therapy. The 
study consists of 3 parts: 
4. A Phase 1b which planned to enroll up to 18 patients in a 6+6 design. 8 subjects, 
7 WT and 1 Mut/Fus were enrolled (study completed). 
5. A Phase 2 enrolling 60 subjects: 20 WT (Cohort 1), 20 Mut/Fus (Cohort 2), and 
20 with tumors showing luminal biology (Cohort 3). Of these, 20 WT and 8 
Mut/Fus subjects have already been enrolled. No further WT patients will be 
enrolled; a further 12 Mut/Fus and 20 with luminal biology will be enrolled. 
6. A Phase 2 expansion enrolling 30 unselected patients (independent of their 
FGFR3 status) (Cohort 4)  
Prior to study enrollment, the availability of an archival tumor sample must be requested 
from participants and availability must be confirmed during screening. A blood sample may 
be substituted to determine FGFR3 genetic status archival tumor is not available. If an 
archival biopsy is not available, during the screening window a pre-treatment diagnostic 
biopsy within 56 days of first study treatment may be obtained to satisfy this requirement, if 
submitted for additonal required studies. A second biopsy will be taken during treatment for 
cohorts 1, 2 and 3 or if an expansion phase patient opts in. Study biopsies may not be 
obtained from lung, bone, or brain .  
For the Phase 2 expansion (Cohort 4), the paired biopsies are optional, but if they are taken, 
the second biospywill be taken at end of cycle 1, Week 5. Subjects will be required to sign a 
separate consent form and must confirm their decision to opt-in. 
 
Phase 1b: 
Enrolled subjects in Phase 1b will have a biomarker tumor biopsy taken prior to Cycle 0 
(lead-in cycle)  
• Within 7 days prior if an archival sample is available for screening 
• If an archival sample is not available, a biopsy should be obtained within the 28-days 
screening window. If the sample is adequate, it may be substituted for the initial (pre-
treatment) Cycle 0 biomarker biopsy.   
After this first on-study biopsy, subjects will be treated in Cycle 0 with an intravenous (IV) 
infusion of vofatamab alone. The second biomarker tumor biopsy should be obtained within 
3 days of Cycle 1 Day 1 infusion of vofatamab plus pembrolizumab. If the biopsy is on Cycle 
1 Day 1, it should be obtained prior to the start of infusion of vofatamab with 
pembrolizumab.  

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The first cohort of 6 subjects will be treated with vofatamab 25 mg/kg IV monotherapy as a 
2-week cycle (Cycle 0) and vofatamab 25mg/kg IV in combination with pembrolizumab 
(200mg) as a 3-week cycle (Cycle 1). Subjects will be followed for at least a 35-day dose-
limiting toxicity (DLT) window from first dose of vofatamab (14 days of vofatamab 
monotherapy and 21 days of combination therapy). If ≤ 1 subject experiences a DLT (a 
Grade 3 or higher AE attributed to vofatamab and/or pembrolizumab), then 25 mg/kg will be 
declared the RP2D. If 2 or more subjects experience a DLT, then the dose of vofatamab will 
be de-escalated as outlined in Table 2. 
Table 2 
Dosing for Dose De-escalation 
 
Dose Level 0 
Dose Level -1 
Dose Level -2 
Vofatamab 
25 mg/kg IV q 3 weeks 
(n=6) 
20 mg/kg IV q 3 weeks 
(n=6) 
15 mg/kg IV q 3 weeks 
(n=6) 
 
On Cycle 1 Day 1, Phase 1b subjects will receive treatment of vofatamab (25 mg/kg [or the 
RP2D if different than 25 mg/kg])) plus pembrolizumab (200 mg) once every 3 weeks 
(Q3W) until disease progression, death, withdrawal of patient consent, investigator 
discretion, or study termination, or the completion of 2 years of vofatamab and 
pembrolizumab therapy. Subjects who do not experience a study defined DLT but do not 
complete the 35-day observation window may be replaced. As of April 03, 2018, the Phase 
1b portion of the study was completed with no protocol-defined DLTs reported. 
Phase 2 and Phase 2 expansion:  
Phase 2 opened on April 04, 2018 following review of the aggregate adverse event (AE) and 
serious adverse event (SAE) by the vofatamab program Safety Steering Committee (SSC) 
after the 35-day DLT observation period in the Phase 1b subjects. The dose of vofatamab 
selected was dose level 0 (25 mg/kg given every 3 weeks) for the RP2D as no subjects met 
the study DLT definition of a Grade 3 or higher AE attributed to vofatamab and/or 
pembrolizumab. 
For Phase 2, subjects will be assigned to one of three cohorts by either baseline FGFR3 status 
of WT (Cohort 1) or Mut/Fus (Cohort 2), or by bladder cancer subtype (luminal biology, 
Cohort 3). As of December 31, 2018, the WT cohort has been fully enrolled and is closed. 
For Cohort 2, Mut/Fus status must be confirmed prior to initiation of treatment. Cohort 3 will 
be enrolled at selected limited sites based on their tumor showing luminal biology, to study 
the molecular changes in the tumor after the first dose of combination treatment of vofatamab 
and pembrolizumab. 
All subjects in Phase 2 (Cohorts 1, 2 and 3) will have a biomarker tumor biopsy taken within 
14 days prior to Cycle 0 (lead-in cycle). If the subject has undergone a diagnostic tumor 
biopsy procedure within 56 days of enrolling in the study, and the biopsy has adequate 
material, this sample may be used in place of the first biomarker biopsy. Biopsies will not be 
required for any patient enrolled in Phase 2 expansion, Cohort 4. If a second biopsy is 
performed, it will be at end of cycle 1, Week 5. 

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Subjects will be treated in Cycle 0 with an IV infusion of vofatamab alone (without 
pembrolizumab).  
For Phase 2, Cohort 1 and Cohort 2, a second tumor biopsy will be obtained 14 days after 
Cycle 0 Day 1 of vofatamab. The second tumor biopsy should always occur within 3 days 
before Cycle 1 Day 1 infusion and prior to the first dose of vofatamab and pembrolizumab. 
For patients enrolled in Cohort 3, the second tumor biopsy will occur at the end of cycle 1. 
Week 5, within 3 days before Cycle 2, Day 1 and prior to the administration of the second 
combination dose of vofatamab and pembrolizumab. Disease re-staging will occur following 
cycle 1 for biomarker correlation but will not be utilized for RECIST evaluation. 
On Cycle 1 Day 1, subjects will receive combined treatment of vofatamab (25 mg/kg) plus 
pembrolizumab (200 mg) . Subjects will continue to receive vofatamab plus pembrolizumab 
Q3W until disease progression, death, decision to discontinue treatment, investigator 
discretion, or study termination. 
Subjects may continue vofatamab and/or pembrolizumab treatment beyond radiological 
disease progression following discussion with the medical monitor and based on clinical 
judgement of the investigator that the subject is experiencing clinical benefit. It is highly 
encouraged that prior to discontinuation of any subject whom is receiving clinical benefit that 
a consultation occur with the study PI or medical monitor.  
Subjects who discontinue vofatamab may continue on study and receive pembrolizumab 
alone until disease progression, death, withdrawal of patient consent, investigator discretion, 
or study termination. Subjects who discontinue pembrolizumab may continue on study and 
receive vofatamab alone (25 mg/kg Q3W [or RP2D if different than 25 mg/kg]) until disease 
progression, death, withdrawal of patient consent, investigator discretion, or study 
termination. 
 

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Figure 2:  
Study Design 
 
 
 
FGFR3 = fibroblast growth factor receptor 3; Mut/Fus = mutant/fusion; Q3W = once every 3 weeks; WT = 
wild type. 
*As of April 03 2018, Phase 1b of the study is complete. 
**As of Dec 31 2018, 28 subjects (20 WT and 8 Mut/Fus) have already been enrolled in Phase 2. A total of 
27 subjects will be added, 12 Mut/Fus (Cohort 2) and 15 with luminal biology (Cohort 3). No further WT 
subjects will be enrolled.  
 
In Phase 2, Cohort 1 and Cohort 2 of the study, subjects will be assigned to a cohort by baseline FGFR3 
status of 1) WT or 2) Mut/Fus; in Phase 2, Cohort 3, at selected sites, the patient’s bladder cancer sub-type 
will be luminal enriched as determined by IHC testing for GATA3 and post enrollment by the Decipher 
Bladder test or acceptable comparable test on samples that were obtained at or after the time when the 
subject was found to have muscle invasive / metastatic disease.  
 
 

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3.2 
Discussion and Rationale for Study Design 
3.2.1 
Selection of Dose and Dosing Schedule  
Pembrolizumab will be used at the dose regimen indicated on its package insert for 
metastatic UCC. The dose regimen of vofatamab is based on the Phase 1 clinical PK and 
safety data in advanced solid tumors and should ensure > 90% patients achieve the estimated 
efficacious exposure. Since each drug has distinct and non-overlapping targets and 
suppression of each target to the fullest extent possible is desirable, both drugs will be used at 
full dose from the beginning of the study with the option for de-escalation of vofatamab if 
unanticipated safety events are observed.  
To safeguard the interests of study participants, the toxicity of vofatamab plus 
pembrolizumab will be monitored closely by a Safety Steering Committee (SSC) (Section 
3.2.2). 
3.2.1.1 
Vofatamab 
The vofatamab dose and schedule in this study is consistent with study drug administration in 
the ongoing Phase 2 study and based on safety and PK data obtained from completed Phase 1 
studies. The dosing regimen of vofatamab at 25 mg/kg every 21 days was selected since it is 
estimated to provide a steady-state area under the concentration curve (AUC) comparable to 
30 mg/kg every 28 days, a dose and regimen that was administered and found to be generally 
safe and well-tolerated in the completed Phase 1 study in advanced solid tumors. The safety 
of this dose in combination with pembrolizumab will be confirmed in the Phase 1b portion of 
this protocol. 
From an efficacy perspective, this dose is anticipated to be sufficient based on extrapolation 
from preclinical PK/pharmacodynamic analyses. Furthermore, the 14-day dosing period in 
phase 1b and initial phase 2 prior to initiating pembrolizumab therapy provides a window for 
immune cell recruitment without delaying the onset of immune checkpoint therapy for an 
extended period. 
Additional supporting details: 
• Murine PK modeling indicated a steady-state AUC of 850 day × µg/mL on a weekly 
basis, or 3400 day × µg/mL with administration every 4 weeks was needed for 
efficacy. Using compartmental PK analysis, IV administration of 20 mg/kg and 30 
mg/kg of vofatamab every 21 days are expected to have steady state AUC of 3529 
day × µg/mL and 5293 day × µg/mL, respectively. Thus, 25 mg/kg every 21 days is 
predicted to provide adequate doses for efficacy.  
• In a Phase 1 study, administration of vofatamab across the dose range of 2 -30 mg/kg 
every 28-days was well-tolerated in subjects with advanced solid tumors. Serum 
exposure of vofatamab was approximately dose-proportional and increased with dose 
across the range tested. Six of the 10 subjects who had SD as their best clinical 
response on study were treated with 30 mg/kg vofatamab every 28-days. 

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Based on a population PK analysis, the post-hoc estimate of steady-state AUC for 
30 mg/kg every 28-days was 5021 day × µg/mL 
3.2.1.2 
Pembrolizumab  
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, 
inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in 
some tumors and signaling through this pathway can contribute to inhibition of active T-cell 
immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to PD-1 
and blocks its interaction with PD-L1 and PD-L2, releasing the PD-1 pathway-mediated 
inhibition of the immune response, including the anti-tumor immune response. In syngeneic 
mouse tumor models, blocking the PD-1 pathway activity resulted in decreased tumor 
growth. In clinical studies, blocking the PD-1 pathway resulted in efficacious treatment of 
melanoma, non-small cell lung cancer, renal cell carcinoma and bladder cancer. 
The recommended clinically approved dose of pembrolizumab for the treatment of UCC is 
200 mg IV over 30 minutes Q3W. At this dose pembrolizumab has activity in advanced UCC 
with an ORR of 29% in patients ineligible for platinum therapy and 22% in patients 
post-platinum therapy.  
3.2.2 
Safety Monitoring Rules and the Safety Steering Committee 
The toxicity of vofatamab plus pembrolizumab will be monitored by an SSC, composed of a 
Rainier medical representative and three independent UCC specialists. SSC review meetings 
will be defined in an approved SSC charter.  
Standard safety monitoring will be employed for DLT assessment and dose de-escalation 
decisions. All AEs will be considered during the DLT assessment period (Day 1 through Day 
35) unless an event is clearly unrelated to trial treatment. Before dose de-escalation 
(if applicable) at each dose level of vofatamab and at any other time that safety data warrant 
review, the Rainier MM will review safety data in consultation with the SSC, as appropriate. 
For study monitoring and decisions about treatment, a subject in Phase 1b will be determined 
to have a DLT defined as follows: 
The subject experiences any Grade 3 or higher treatment-emergent AE that is possibly or 
definitely related to either vofatamab and/or pembrolizumab received on this protocol and 
occurs up to 35 days after Cycle 0 Day 1. The exception is that a treatment-emergent AE that 
is potentially treatable with steroids will only count as a DLT if it does not improve to Grade 
1 or better within 2 weeks after starting steroids. 
3.2.3 
Selection of Study Population 
This study will be conducted in subjects with locally advanced or metastatic UCC who have 
progressed following treatment with platinum-based chemotherapy or who are not eligible 
for cisplatin-containing chemotherapy. This population was chosen on the basis of high 
unmet need, consistency with the current pembrolizumab label, and preclinical and clinical 
evidence that vofatamab administered with a PD-1 inhibitor has promising therapeutic 

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potential in this indication. After the initial safety run (Phase 1b), subjects will be assigned to 
one of three cohorts in Phase 2 based on either baseline FGFR3 status of WT (Cohort 1) or 
Mut/Fus (Cohort 2), or by bladder cancer subtype (luminal biology, Cohort 3; at selected 
limited sites), subjects with unselected tumors will be enrolled into the Phase 2 expansion 
(Cohort 4). 
3.2.4 
Blinding 
This is an open-label study. 
3.2.5 
Duration of Subject Participation 
The study period will include a 4-week screening period, and may include a 2 -week 
treatment period of vofatamab, followed by a treatment period of vofatamab plus 
pembrolizumab to complete 2 years of combination vofatamab and pembrolizumab therapy 
(21-days per cycle for combination treatment), End of Treatment visit, and telephone follow-
up to monitor survival. 
3.2.6 
Definition of End of Study 
The end of the study (i.e., the last visit) will occur due to Sponsor decision or when the last 
subject experiences disease progression, dies, or is discontinued from study treatment due to 
withdrawal of consent of investigator discretion. 

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4 
STUDY POPULATION AND WITHDRAWAL 
4.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Have locally advanced (on TNM staging: T4b and any N, or any T and N2-3) or 
metastatic transitional cell carcinoma of the urothelium, including the urinary bladder, 
urethra, ureter, and/or renal pelvis. The diagnosis must be histologically or 
cytologically confirmed.  
For subjects in the Phase 2, Cohort 2 (Mut/Fus), tumors must have at least one of the 
following FGFR3 mutations: R248C, S249C, G370/2C, S371/3C, Y373/5C, 
G380/82R, F384/6L, K650/2X (X=E,T or M) or FGFR3- TACC3 fusion, as shown 
by tests performed by a CAP or CLIA certified laboratory (or equivalent outside of 
the US) on samples that were obtained at or after the time when the subject was found 
to have muscle invasive / metastatic disease or high grade papillary non-muscle 
invasive disease.  
In the absence of pre-existing genetic test results, subjects can submit archival tissue 
(obtained at or after the time subject was found to have muscle invasive / metastatic 
disease) for genetic testing. If no suitable tissue is available, a blood sample may be 
used to determine FGFR3 genetic status.  
Subjects in Phase 2, Cohort 3 (luminal biology) must have a tumor that appears to 
show luminal biology as determined by IHC (GATA3 positive and absence of 
KRT14), or acceptable comparable test on samples that were obtained at or after the 
time when the subject was found to have muscle invasive / metastatic disease or high 
grade papillary non-muscle invasive disease.  
Subjects in the Phase 2 expansion cohort (Cohort 4) will have FGFR3 mutation 
fusion status determined for analysis but this will not be used to assign treatment, but 
used for analysis purposes  
 
2. Have progression during or following platinum-containing chemotherapy in 
metastatic setting or within 12 months of neoadjuvant or adjuvant treatment with 
platinum-containing chemotherapy 
3. Have available archival tumor or be willing to undergo diagnostic biopsy at screening  
4. Have measurable disease according to Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST 1.1). 
5. Male and female subjects, age ≥ 18 years. 
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1. 
7. Willingness to avoid pregnancy or fathering children based on the criteria below: 
a. Women of non-childbearing potential (i.e., surgically sterile with a hysterectomy 
and/or bilateral oophorectomy OR chemically sterile OR ≥ 12 months of 

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amenorrhea in the absence of chemotherapy, anti-estrogens, or ovarian 
suppression). Women of non-childbearing potential need not undergo pregnancy 
testing. 
b. Women of childbearing potential who have a negative urine or serum pregnancy 
test at Screening and before the first dose of study drug on Cycle 0 Day 1 and 
who agree to take appropriate precautions to avoid pregnancy (with 
approximately 99% certainty) from Screening through 120 days after the last dose 
of study drug. Permitted methods of contraception that are approximately 99% 
effective in preventing pregnancy should be communicated to the subject, and the 
subject’s understanding confirmed.  
c. Men who agree to take appropriate precautions to avoid fathering children (with 
at least 99% certainty) from Screening through 120 days after the last dose of 
study drug. Permitted methods of contraception that are approximately 99% 
effective in preventing pregnancy should be communicated to the subject, and the 
subject’s understanding confirmed. 
8. Ability to understand and sign informed consent form (ICF) and comply with all 
study procedures 
9. Have adequate hematologic and end organ function defined by the following 
laboratory results obtained within 14 days prior to the first dose of study treatment: 
a. Absolute neutrophil count ≥ 1,500/µL. 
b. Platelet count ≥ 100,000/µL. 
c. Hemoglobin ≥ 9.0 g/dL without transfusion. 
d. Albumin ≥ 2.5 g/dL. 
e. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline 
phosphatase (ALP) ≤ 2.5 × upper limit of normal (ULN), with the following 
exception: ALP ≤ 5 × ULN for subjects with documented bone metastases. 
i. 
Creatinine clearance ≥ 30 mL/min on the basis of the Cockroft-Gault 
glomerular filtration rate estimation: 
(140 −𝑎𝑔𝑒) × (𝑤𝑒𝑖𝑔ℎ𝑡 𝑖𝑛 𝑘𝑔) × (0.85 𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒) 
72 × (𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝑖𝑛 𝑚𝑔/𝑑𝐿)
 
Note: Creatine clearance < 30 mL/min may have confirmatory re-
testing done using a 24-hour creatinine clearance by Cockroft-Gault 
estimation or direct measurement 
f. Prothrombin time/international normalized ratio (PT/INR) and partial 
thromboplastin time (PTT) must be ≤ 1.5 × ULN. 
 
4.2 
Exclusion Criteria 
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 

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1. 
Participants with a history of idiopathic pulmonary fibrosis, organizing pneumonia, 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on the Screening chest CT scan.  
2. 
Prior therapy with an anti-programmed cell death 1 (PD-1) or anti-PD-Ligand 1 
agent, or with an agent directed to another co-inhibitory T-cell receptor or FGFR 
inhibitor. 
3. 
Patients with autoimmune disease or medical conditions that required systemic 
corticosteroids (> 10 mg/day prednisone or its equivalent) or other 
immunosuppressive medications or any other form of systemic immunosuppressive 
therapy within 7 days prior to the first dose of study treatment. Note Replacement 
therapy (e.g. physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment 
4. 
Prior anti-cancer therapy (e.g. biologic or other targeted therapy, chemotherapy or 
hormonal therapy) within 14 days prior to the first dose of study medication. 
A washout of less than 14 days may be allowed after discussion with the Medical 
Monitor, provided that the subject has recovered from any clinically relevant toxicity 
(Exception: participants with neuropathy of Grade 1 will be allowed study entry). 
5. 
Acute clinical AEs, except for alopecia, from any previous treatments must have 
resolved to ≤ Grade 1 or chronic defined as present for more than 6 months without 
worsening and not greater than Grade 2. 
6. 
Laboratory AEs from any previous treatments must have resolved to ≤ Grade 1 or to 
within 10% of baseline prior to the first dose of study treatment. 
7. 
Participants who are receiving or have received any other investigational drugs or 
devices within the 2 weeks prior to the first dose of study medications. 
8. 
Participants with a diagnosis of immunodeficiency. 
9. 
Primary central nervous system (CNS) malignancy or CNS metastases (past or 
current).  
10. Participants with a history of allergic reactions attributed to monoclonal antibody 
therapy (or recombinant antibody-related fusion proteins). 
11. History of major bleeding (requiring a blood transfusion ≥ 2 units) not related to a 
tumor within the past 12 months. 
12. History of clinically significant coagulation or platelet disorder in the past 12 
months. 
13. Participants who have not recovered adequately from the toxicity and/or 
complications from the interventions prior to starting therapy.  
14. Incomplete healing from wounds from prior surgery (wounds larger than 2 cm in 
length) within 28 days prior to first dose of study treatment. 
15. Participants with an active uncontrolled infection requiring systemic therapy (e.g., 
IV antibiotics or antifungal therapy). 

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Note: The use of oral anti-infectious agents for prophylaxis or treatment of resolving 
infections is not considered exclusionary under this rule. 
16. Participants who have received a live vaccine within 30 days of planned start of study 
therapy. 
Note: Seasonal influenza vaccines with inactivated flu vaccines are allowed; 
however, live attenuated vaccines such as intranasal influenza vaccines 
(e.g., Flu-Mist®) are not allowed. 
 
17. Participants with uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection, symptomatic congestive heart failure, unstable angina 
pectoris, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
18. Participants with a history of other malignancy which could affect compliance with 
the protocol or interpretation of results. Individuals with a history of curatively 
treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, 
and definitively treated prostate cancer discovered incidentally at surgery are allowed. 
Participants with other malignancies that have been treated with curative intent will 
also be allowed if the malignancy has been in remission without treatment for ≥ 2 
years prior to Cycle 0 Day 1 (prior to first dose of study treatment). 
19. Pregnant and breast-feeding women are excluded from this study because the risks 
with vofatamab and pembrolizumab are unknown. Because there is an unknown but 
potential risk for AEs in nursing infant(s) secondary to treatment of the mother with 
vofatamab and pembrolizumab, breastfeeding should be discontinued.  
20. Presence of positive test results for Hepatitis B (Hepatitis B surface antigen [HBsAg] 
and/or total Hepatitis B core antibody [HBcAb]), Hepatitis C (Hepatitis C virus 
antibody serology testing [HCV Ab]), human immunodeficiency virus (HIV1/2 
antibody +), and /or evidence of active tuberculosis (history and/or radiology 
findings).  
Note: Subjects positive for Hepatitis core antibody [HBcAb] are eligible only if 
confirmatory polymerase chain reaction (PCR) is negative for evidence of Hepatitis B 
Virus DNA (within the Institution cutoff value) and for study purposes the reported 
positive antibody testing will be considered to be a false positive test result. 
 
4.3 
Removal of Subjects for Therapy or Assessment 
4.3.1 
Subject Discontinuation from the Study or Treatment 
Subjects must be withdrawn from the study if they experience disease progression (defined 
using RECIST 1.1 in Appendix 2). Subjects may continue vofatamab and/or pembrolizumab 
therapy beyond progression following discussion with the medical monitor and based on 
clinical judgement of the investigator that the subject is experiencing clinical benefit. It is 
highly encouraged that prior to discontinuation of any subject whom is receiving clinical 
benefit that a consultation occur with the study PI or medical monitor.  

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Subjects may discontinue treatment with vofatamab and/or pembrolizumab early (i.e., for 
reasons other than disease progression) for reasons such as subject/investigator decision or 
unacceptable toxicity. The reasons for early discontinuation of treatment must be 
documented on the appropriate case report form (CRF). Subjects who discontinue vofatamab 
or pembrolizumab should continue on study and receive the other agent alone until disease 
progression, death, decision to discontinue treatment, investigator discretion, or study 
termination.  
Subjects must be withdrawn from study treatment if they become pregnant. 
The investigator has the right to discontinue a subject from the study for any medical 
condition that the investigator determines may jeopardize the subject’s safety, for reasons of 
noncompliance (e.g., missed doses [≥ 2 doses], visits), or if the investigator determines it is 
in the best interest of the subject. 
The End of Treatment visit assessments should be performed on subjects who prematurely 
withdraw from the study during the treatment period. Subjects should be followed for safety 
outcomes for 30 days following the subject’s last dose of study drug or until the subject 
receives another anti-cancer therapy, whichever occurs first.  
Upon discontinuation of study treatment (vofatamab and pembrolizumab), subjects will be 
followed for overall survival every 3 months via telephone until death or full withdrawal of 
consent. 
4.3.1.1 
Subject Replacement 
Subjects who discontinue the study early will not be replaced with the exception of patients 
enrolled in the phase 1b portion of the trial whom discontinued for a reason other than DLT. 
4.3.2 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the 
study may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects. 
• Subject enrollment is unsatisfactory 
• Evidence that either cohort is providing no potential benefit over current therapies. 

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5 
TREATMENT OF SUBJECTS 
5.1 
Treatment Regimens 
For subjects participating in Cycle 0, vofatamab (25 mg/kg or the RP2D) monotherapy will 
be administered on Cycle 0 Day 1 by IV infusion over 90 (± 15) minutes.  
Subjects will begin combination treatment with vofatamab plus pembrolizumab on 
approximately Day 15 (i.e., Cycle 1 Day 1). Subjects will receive pembrolizumab (200 mg) 
by IV infusion over 30 (-5/+10) minutes followed by vofatamab (25 mg/kg) by IV infusion 
over 90 (± 15) minutes. If Cycle 0 and Cycle 1vofatamab infusions have been well-tolerated, 
subsequent doses of vofatamab may be administered over 30 (± 10) minutes, followed by a 
30-minute observation period post-infusion. The vofatamab infusion will begin 
approximately 30 minutes after completion of the pembrolizumab infusion. Thereafter, 
combination vofatamab plus pembrolizumab treatment will be administered Q3W (Day 1 of 
each cycle ± 7 days) until disease progression, death, decision to discontinue treatment, 
investigator discretion, or study termination. 
Dosing guidelines for vofatamab and pembrolizumab are summarized in Table 3. 
Table 3 
Study Drug Dosing Guidelines 
Agent 
Dose 
Route 
Schedule 
Pembrolizumab 200 mg 
IV over 30 (−5/+10) minutes b 
Day 1 (± 3 days) of Cycle 1 and Day 1 (± 7 
days) of Cycles 2+ 
Vofatamab 
25 mg/kga 
IV over 90 (± 15) minutes b 
Day 1 of Cycle 0 (if applicable), Day 1 (± 3 
days) of Cycle 1, and Day 1 (± 7 days) of 
Cycles 2+ 
Note: Cycle 0 is 14 days and Cycles 1+ are 21 days. 
a. Or the recommended Phase 2 dose if different than 25 mg/kg. 
b. If no infusion reactions are observed in Cycles 0 ( if applicable) and Cycle 1, subsequent doses of vofatamab 
may be infused over 30 ± 10 minutes. 
 
The rules for continued dosing are provided in Section 5.1.1, and dose modification 
instructions are provided in Section 5.1.2. Additional drug administration details are provided 
in the pembrolizumab package insert. 
5.1.1 
Guidelines for Continued Dosing 
Once enrolled and on study, subjects must meet the following criteria for ongoing clinical 
benefit and acceptable toxicity to be eligible to receive additional cycles of study treatment: 
• Ongoing clinical benefit: Subjects must have no signs or symptoms of progressive 
disease (PD). Subjects with PD (as defined by RECIST 1.1 in Appendix 2), will be 
ineligible to receive further treatment with study drug. The end of Cycle 1 scan will 
be used for biomarker correlation, but will not be used to determine disease 
progression per RECIST. Limited Exception: Subjects may continue vofatamab and 

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pembrolizumab treatment beyond progression if the investigator feels they are 
experiencing benefit. This decision will be made in consultation with the medical 
monitor.  
Acceptable toxicity: All study drug-related AEs from prior infusions must have decreased 
to Grade 1 or baseline grade on or before the day of the next infusion. Exceptions on the 
basis of ongoing clinical benefit may be allowed after a careful assessment and 
discussion of risk versus benefit with the subject by the investigator and approval from 
the Medical Monitor, with the option of dosing vofatamab at the full dose of 25 mg/kg or 
reducing the dose of vofatamab to 20 mg/kg (Dose Level -1) or to 15 mg/kg (Dose Level 
-2). No further dose de-escalation may be done in this study, and the subject should be 
discontinued for unacceptable toxicity if 15 mg/kg is not tolerated. In addition, delay of 
therapy due to toxicities not attributed to study drug may not require discontinuation and 
must be discussed with the Medical Monitor. This may also apply to pembrolizumab with 
the following caveats: hypothyroidism, adrenal insufficiency, and hypopituitarism which 
all may require hormone replacement and are likely irreversible. Subjects with 
asymptomatic elevations of amylase and lipase have been observed, and may continue on 
pembrolizumab as long as amylase and lipase levels are < Grade 4 using CTCAE. 
5.1.2 
Dose Modification 
There are currently no AEs that are more likely attributed to vofatamab than to 
pembrolizumab. 
Subjects will be closely monitored for platelets and coagulation factors including aPTT, 
PT/INR, and fibrinogen (see Table 1 for the timing of assessments). If either aPTT or 
PT/INR exceeds 1.5 × ULN or if fibrinogen falls below the LLN, all study drug treatment 
should be held until these factors return to baseline levels before re-dosing. Exceptions may 
be allowed upon discussion with the Medical Monitor and Investigator. 
5.1.2.1 
Vofatamab Dose Modification 
Subjects in whom toxicities have not reversed sufficiently by the scheduled day of infusion 
(for Cycle 1 and beyond) may have their dose of vofatamab delayed by up to 21 days. If all 
study drug–related toxicities have reversed sufficiently and the additional criteria described 
in Section 5.1.1 have been met, then the subject may receive the subsequent dose of 
vofatamab.  
Subjects who do not fulfill the criteria for dosing after 21 days have elapsed will be 
discontinued from vofatamab, but may continue on study and receive pembrolizumab alone 
until disease progression, death, withdrawal of patient consent, investigator discretion, or 
study termination. Exceptions on the basis of ongoing clinical benefit may be allowed 
following a careful assessment and discussion of risk versus benefit with the subject by the 
investigator and approval from the Medical Monitor, with the option of dosing vofatamab at 
the full dose of 25 mg/kg or reducing the dose of vofatamab to 20 mg/kg (Dose Level -1) or 
to 15 mg/kg (Dose Level -2). No further dose de-escalation may be done in this study, and 
the subject should be discontinued for unacceptable toxicity if 15 mg/kg is not tolerated. In 

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addition, delay of therapy because of toxicities not attributed to study drug may not require 
discontinuation and will be discussed with the Medical Monitor. 
The SSC will review the overall safety data from dosed subjects and DLTs, and can make 
recommendations to stop the study. Safety analyses will be performed by the SSC based on 
guidelines outlined in the SSC Charter. 
5.1.2.2 
Pembrolizumab Dose Modification 
Pembrolizumab dosing delays or dose modifications will be performed consistent with the 
pembrolizumab package insert. Refer to Warnings and Precautions sections of the 
FDA-approved package insert for additional information. Vofatamab may be continued after 
consultation with the medical monitor. 
Subjects who experience any of the following should have pembrolizumab withheld until 
resolution of the toxicity to Grade 0 or 1: 
• Grade 2 pneumonitis 
• Grade 2 or 3 colitis 
• Grade 3 or 4 endocrinopathies 
• Grade 2 nephritis 
• Grade ≥ 3 hyperthyroidism 
• AST or ALT greater than 3 and up to 5× ULN 
• Total bilirubin greater than 1.5 and up to 3× ULN 
• Any other severe or Grade ≥3 treatment-related adverse reaction 
Pembrolizumab should be permanently discontinued if any of the following are observed and 
deemed by the investigator to be most likely due to pembrolizumab treatment: 
• Any life-threatening adverse reaction (excluding endocrinopathies controlled with 
hormone replacement therapy) 
• Grade 3 or 4 pneumonitis or recurrent pneumonitis of Grade 2 severity 
• Grade 3 or 4 nephritis  
• AST or ALT greater than 5× ULN or total bilirubin greater than 3× ULN 
• Grade 3 or 4 infusion-related reactions 
• Inability to reduce corticosteroid dose to 10 mg/day or less of prednisone or 
equivalent per day within 12 weeks 

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• Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy) that do not recover to Grade 0-1 within 12 weeks after 
last dose of pembrolizumab 
• Any severe or Grade 3 treatment-related adverse reaction that recurs 
Pembrolizumab dose modification guidelines for drug-related AEs are summarized in the 
pembrolizumab package insert. 
5.1.3 
Post-Study Access to Study Drug 
The Sponsor does not have any plans to provide vofatamab, pembrolizumab, or other study 
interventions to subjects after the end of the study (defined in Section 3.2.6).  
5.2 
Preparation, Administration, and Storage of Study Drug 
5.2.1 
Vofatamab 
5.2.1.1 
Preparation and Administration 
Vofatamab is provided as a sterile lyophilized powder and contains no preservatives. After 
reconstitution with sterile water for injection, the drug product is formulated as 10 mg/mL 
vofatamab in 200 mM arginine succinate, 0.02% polysorbate 20, pH 5.5. The drug product 
will be delivered at a final concentration of ≥ 3 mg/mL. 
Drug product will be delivered using standard medical syringes and syringe pumps or IV 
bags. Delivery will be carried out with a 0.22 μm in-line filter on either the syringe-pump 
extension set or the IV infusion set 
The initial dose of vofatamab (Cycle 0 and Cycle 1) will be administered over 90 (± 15) 
minutes to well-hydrated subjects. The infusion may be slowed or interrupted for subjects 
experiencing infusion-associated symptoms. Following the initial dose, subjects will be 
observed for 90 minutes for fever, chills, rigors, hypotension, nausea, or other infusion-
associated symptoms. If prior infusions have been well-tolerated, subsequent doses of 
vofatamab (Cycle 2+) may be administered over 30 (± 10) minutes, followed by a 30-minute 
observation period post-infusion. Additional instructions on study drug preparation and 
administration are provided in the Pharmacy Manual. 
5.2.1.2 
Storage 
Vofatamab vials must be refrigerated at 2ºC–8ºC (36ºF-46ºF) upon receipt until use. 
Vofatamab should not be used beyond the expiration date provided by the manufacturer. The 
lyophilized vofatamab vials should be reconstituted with sterile water for injection the day of 
use. Vial contents should not be frozen or shaken and should be protected from direct 
sunlight. Vofatamab solutions may be stored at refrigerated (2-8ºC) for 24 hours or at room 
temperatures (25ºC [77ºF]) for up to 8 hours prior to use, total time at both temperatures not 
to exceed 24 hours. 

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Additional vofatamab dosage, administration, and storage instructions are provided in the 
Pharmacy Manual. 
5.2.1.3 
Precautions 
Infusion reactions have been reported with the use of vofatamab alone or in combination with 
chemotherapy. The majority of these infusion reactions have been mild, however, severe life- 
threatening allergic reactions have been observed. The administration of vofatamab should be 
performed in a setting with access to emergency equipment and staff who are trained to 
monitor and respond to medical emergencies. Subjects will be monitored during and after 
each vofatamab infusion for 90 minutes after the Cycle 0 (if applicable) and Cycle 1 and for 
30 minutes after subsequent infusions in the absence of infusion--related AEs. Subjects who 
experience infusion-related symptoms should be managed as directed in Table 4 below. 
Table 4 
Management of Infusion-Related Symptoms (e.g., fever, chills/rigors, 
nausea, vomiting, pruritus, headache, rhinitis, rash, hypotension, 
hypersensitivity, anaphylaxis, dyspnea, wheezing, bronchospasm, 
tachycardia, reduced oxygen saturation, or respiratory distress) 
Infusion-Related Symptoms a 
Guidance 
Grade 1−2 
• 
Slow or hold infusion. 
• 
Give supportive treatment b. 
• 
Upon symptom resolution, may resume infusion rate escalation 
at the investigator’s discretion c. 
Grade 3-4 
• 
Discontinue infusion immediately, treat symptoms aggressively, 
and do not restart drug. 
a 
Refer to National Cancer Institute Common Terminology Criteria for Adverse Events, v4.0, 
for the grading of symptoms. This table does not refer to management of IgE-mediated allergic reactions, 
which should be managed as directed in text following this table. 
b 
Supportive treatment: Subjects should be treated with acetaminophen/paracetamol and an antihistamine 
such as diphenhydramine if they have not been received in the last 4 hours. Intravenous saline may be 
indicated. For bronchospasm, urticaria, or dyspnea, subjects may require antihistamines, oxygen, 
corticosteroids (e.g., 100 mg IV prednisolone or equivalent), and/or bronchodilators. For hypotension, 
subjects may require vasopressors. 
c 
Infusion rate escalation after re-initiation: Upon complete resolution of symptoms, the infusion may be 
resumed at 50% of the rate achieved prior to interruption. In the absence of infusion-related symptoms, 
the rate of infusion may be escalated in increments of 50 mg/h every 30 minutes. 
 
Subjects who experience vofatamab infusion-related temperature elevations of > 38.5C or 
other minor infusion-related symptoms may be treated symptomatically with acetaminophen 
(≥ 500 mg) and/or H1 and H2 histamine-receptor antagonists (e.g., diphenhydramine, 
ranitidine). Serious infusion-related events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be 
managed with additional supportive therapies (e.g., supplemental oxygen, 2-agonists, and/or 
corticosteroids) as clinically indicated according to standard clinical practice. 
Infusion-related reaction (IRR) prophylaxis with medications (e.g., acetaminophen, 
antihistamines, and/or corticosteroids) may be instituted at any point in the study that it is 

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determined to be in the best interest of subjects due to the observation of IRRs in a 
significant number of subjects. 
In the event of a life-threatening infusion-related reaction (which may include pulmonary or 
cardiac events) or immunoglobulin (Ig) E-mediated anaphylactic reaction, vofatamab should 
be discontinued and no additional vofatamab should be administered. Subjects who 
experience these reactions should receive aggressive symptomatic treatment and should be 
discontinued from study treatment. 
Precautions and procedures for suspected anaphylactic reaction during study drug infusions 
are provided in Appendix 3. Prophylactic administration with acetaminophen and 
antihistamine may be used at investigator discretion. 
5.2.2 
Pembrolizumab  
Complete preparation, administration, and storage instructions for pembrolizumab are 
provided in the Pharmacy Manual. 
Subjects should be monitored for signs and symptoms of pembrolizumab-related 
pneumonitis, colitis, hepatitis, and endocrinopathies; and changes in liver function, renal 
function, and thyroid function. Subjects who experience any of the above pembrolizumab-
related toxicities should have the dose of pembrolizumab modified as described in 
Section 5.1.2.2.  
5.3 
Study Drug Accounting 
5.3.1 
Receipt of Drug Supplies 
Upon receipt of the study treatment supplies, an inventory must be performed and a drug 
receipt log filled out and signed by the person accepting the shipment. It is important that the 
designated study staff counts and verifies that the shipment contains all the items noted in the 
shipment inventory. Any damaged or unusable study drug in a given shipment (active drug or 
comparator) will be documented in the study files. The investigator must notify study 
sponsor of any damaged or unusable study treatments that were supplied to the investigator’s 
site. 
5.3.2 
Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation 
form, signed and dated. Any discrepancies noted will be investigated, resolved, and 
documented prior to return or destruction of unused study drug. Drug destroyed on site will 
be documented in the study files. 

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5.4 
Concomitant and Prohibited Therapies 
5.4.1 
Concomitant Therapy 
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a subject between the signing of the Informed Consent Form and the end of study 
visits. All concomitant medications and therapies should be reported to the investigator and 
recorded on the appropriate CRF. 
Subjects who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use. Concomitant use of hematopoietic growth factors is 
allowed in accordance with instructions provided in the package inserts. 
5.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study: 
• Cytotoxic chemotherapy 
• Radiotherapy (unless for palliative care of a solitary non-target lesion) 
• Immunotherapy 
• Hormone therapy (other than contraceptives, hormone-replacement therapy, hormone 
therapy for adjuvant breast cancer therapy or megestrol acetate) 
• Biologic agents (other than hematopoietic growth factors, which are allowed if 
clinically indicated and used in accordance with instructions provided in the package 
inserts) 
• Any therapies intended for the treatment of UCC, whether approved by local regulatory 
authorities or investigational 
Subjects who require the use of any of these agents will be discontinued from treatment with 
vofatamab and/or pembrolizumab. See Section 6.1.5 for assessments that are to be performed 
for subjects who discontinue from the study early. 
5.5 
Treatment Compliance 
Subject compliance with treatment is not applicable since study site personnel will administer 
study drug. 

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6 
STUDY PROCEDURES (PHASE 1B AND 2 INCLUDING EXPANSION 
COHORT) 
The Schedule of Assessments, Screening through End of Study, is presented in Table 1.  
All screening evaluations must be completed and reviewed by the Medical Monitor to 
confirm that subjects meet all eligibility criteria and are approved for enrollment before the 
first infusion of study drug.  
All visits should occur on the scheduled days. However, visits after Cycle 1 may occur ± 7 
days from the scheduled date if a change is required for logistical/scheduling reasons. 
Assessments scheduled on the day of study drug administration (Day 1) of each cycle should 
be performed prior to study drug infusion, unless otherwise noted.  
Local laboratory assessments may be performed within 72 hours preceding study drug 
administration on Day 1 of each cycle, unless otherwise specified. Results must be reviewed 
and the review documented prior to study drug administration. 
6.1 
Assessments by Study Visit 
6.1.1 
Screening 
The following Screening evaluations will be performed within 28 days preceding the first 
dose of study drug, unless otherwise specified.  
• Written informed consent must be signed before any study-specific procedures are 
performed (described in Section 7.1.1).  
• Confirm availability and request archival tumor tissue (described in Section 7.1.3) or 
undergo diagnostic biopsy during Screening window 
• Review inclusion/exclusion criteria (described in Section 7.1.4) 
• Medical history and demographics (described in Section 7.1.5) 
• Complete physical examination (described in Section 7.2.2) 
• Height and weight (described in Section 7.2.2) 
• Vital signs (described in Section 7.2.3) 
• ECOG PS (see Appendix 1) 
• Concomitant medications and therapies 
• Tumor assessment: A documented standard-of-care tumor assessment performed within 
56 days prior to Cycle 0, Day 1 may be used for the screening assessment (described in 
Section 7.3.1 and Appendix 2). The same imaging methods used at screening should be 
used throughout the study for each subject where possible. 

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• Hematology (described in Section 7.2.4.1) 
• Viral serology (HIV -1/2, HBsAg and  HBcAb, (HBV DNA by PCR if required) and 
HCV Ab) 
• Serum chemistry (described in Section 7.2.4.1 
• Urinalysis (described in Section 7.2.4.1) 
• Electrocardiogram (ECG; described in Section 7.2.5) 
• Coagulation (i.e., activated partial thromboplastin time [aPTT] or partial thromboplastin 
time PTT, prothrombin time [PT]/international normalized ratio [INR], and fibrinogen; 
described in Section 7.2.4.1) 
• Urine  or serum pregnancy test within 14 days prior to first study treatment (described in 
Section 7.2.4.1) 
• EORTC QLQ-C30 
 
6.1.2 
Cycle 0 
6.1.2.1 
Day 1 of Cycle 0 
Note: Study-related biopsies should not be obtained from lung, bone, or brain at any point 
during the study. 
The following assessments should be performed prior to study drug infusion: 
• Targeted physical examination (described in Section 7.2.2) 
• Biomarker tumor biopsy (optional for Phase 2 expansion, Cohort 4) (described in Section 
7.1.2) 
• Weight 
• Vital signs (described in Section 7.2.3) 
• ECOG PS (see Appendix 1) 
• Concomitant medications and therapies 
• Hematology (described in Section 7.2.4.1) 
• Serum chemistry (described in Section 7.2.4.1) 
• Urinalysis (described in Section 7.2.4.1) 
• Coagulation (i.e., aPTT, PT/INR, and fibrinogen; described in Section 7.2.4.1) 
• Urine or serum pregnancy test (described in Section 7.2.4.1) 

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• ECGs (described in Section 7.2.5) 
• PK blood samples collected before vofatamab administration (described in Section 7.4) 
• ATA and biomarker blood samples (described in Sections 7.5 and 7.6, respectively) 
• For Phase 2 only: 
▪ Assign subject to a cohort by baseline FGFR3 status (WT or Mut/Fus) (described in 
Section 7.1.3). 
For Phase 2 and Phase 2 expansion:  
▪ Patient reported outcome (PRO) assessment/ EORTC QLQ-C30 (described in 
Section 7.3.3) 
 
Study drug administration: 
• Subjects should be well-hydrated prior to study drug administration. Subjects will receive 
Cycle 0 and Cycle 1 infusions of vofatamab over 90 (± 15) minutes. The infusion will be 
followed by a 30-minute observation period (described in Section 5.2) 
• Vital signs should be assessed every 15 (± 5) minutes during the vofatamab infusion, and 
at the end of the vofatamab infusion (described in Section 7.2.3) 
 
AEs should be collected and recorded while the subject is receiving study drug (described in 
Section 7.2.1) 
The following assessment(s) should be performed after study drug infusion has been 
completed: 
• Vital signs should be assessed every 30 (± 10) minutes for 90 minutes post-vofatamab-
infusion (i.e., 30 [± 10] minutes, 60 [± 10] minutes, and 90 [± 10] minutes post-infusion; 
described in Section 7.2.3) 
• PK blood samples collected within 30 (± 15) minutes after the completion of vofatamab 
administration (described in Section 7.4) 
 
AEs: Subjects should be monitored for 90 minutes following completion of the infusion 
(described in Section 7.2.1) 
6.1.3 
Day 1 of Cycle 1 (± 3 days) 
Biomarker tumor biopsy (described in Section 7.1.2): For subjects in Phase 2, Cohort 1 and 
Cohort 2, this procedure should occur approximately 2 weeks after the first vofatamab 
infusion and no more than 3 days before the Cycle 1 Day 1 visit.   
The following assessments should be performed prior to study drug infusion: 

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• Targeted physical examination (described in Section 7.2.2) 
• Biomarker tumor biopsy Phase 2, Cohorts 1 and 2 only (described in Section 7.1.2) 
• Weight 
• Vital signs (described in Section 7.2.3) 
• ECOG PS (see Appendix 1) 
• AEs since the previous visit (described in Section 7.2.1) 
• Concomitant medications and therapies 
• Tumor assessments (described in Section 7.3.1) 
• Hematology (described in Section 7.2.4.1) 
• Serum chemistry (described in Section 7.2.4.1) 
• Urinalysis (described in Section 7.2.4.1) 
• Coagulation (i.e., aPTT, PT/INR, and fibrinogen; described in Section 7.2.4.1) 
• Urine or serum pregnancy test (described in Section 7.2.4.1) 
• ECG (Cycles 1 and 2 only; described in Section 7.2.5)  
• PK blood samples collected before pembrolizumab administration (described in 
Section 7.4) 
• ATA and biomarker blood samples (described in Sections 7.5 and 7.6, respectively) 
• Phase 2 and Phase 2 expansion only: PRO assessment/EORTC QLQ-C30 (described in 
Section 7.3.3) 
Note: The EORTC QLQ-C30 will be assessed at baseline during screening or prior to 
Cycle 0 and for Cycles 1 and 2, then every 2 cycles, and 30 days after discontinuation. 
 
Study drug administration: 
• Subjects should be well-hydrated prior to study drug administration. Subjects will receive 
one IV infusion of pembrolizumab over 30 (−5/+10) minutes, followed by one IV 
infusion of vofatamab. If prior vofatamab infusions have been well-tolerated, subsequent 
doses of vofatamab may be administered over 30 (± 10) minutes. The vofatamab infusion 
will begin approximately 30 minutes after completion of the pembrolizumab infusion. 
Vofatamab infusions will be followed by a 30-minute observation period (described in 
Section 5.2) 

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• Vital signs should be assessed every 15 (± 5) minutes during the vofatamab infusion, and 
at the end of the vofatamab infusion (described in Section 7.2.3). For infusions with 
pembrolizumab, vital signs should be assessed per institutional guidelines. 
AEs should be collected and recorded while the subject is receiving study drug (described in 
Section 7.2.1) 
The following assessment(s) should be performed after study drug infusion has been 
completed: 
• Vital signs should be assessed 30 (± 10) minutes post-vofatamab-infusion (described in 
Section 7.2.3) 
• PK blood samples collected within 30 (± 15) minutes after the completion of vofatamab 
administration (described in Section 7.4) 
 
AEs: Subjects should be monitored for 90 (± 10) minutes following completion of the 
infusion (described in Section 7.2.1) 
6.1.4 
Day 1 of Cycles 2+ (± 7 days) until Disease Progression 
All visits should occur on the scheduled days. However, visits may occur ± 7 days from the 
scheduled date, if a change is required for logistical/scheduling reasons.   
 
The following assessments should be performed prior to study drug infusion: 
• Targeted physical examination (described in Section 7.2.2) 
• Biomarker tumor biopsy Phase 2, Cohort 3 and Cohort 4 (optional) (described in Section 
7.1.2). The biopsy will be taken at end of cycle 1, Week 5. 
• Weight 
• Vital signs (described in Section 7.2.3) 
• ECOG PS (see Appendix 1) 
• AEs since the previous visit (described in Section 7.2.1) 
• Concomitant medications and therapies 
• Tumor assessments (described in Section 7.3.1) 
• Hematology (described in Section 7.2.4.1) 
• Serum chemistry (described in Section 7.2.4.1) 
• Urinalysis (described in Section 7.2.4.1) 

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• Coagulation (i.e., aPTT, PT/INR, and fibrinogen; described in Section 7.2.4.1) 
• Urine or serum pregnancy test (described in Section 7.2.4.1) 
• ECG (Cycles 1 and 2 only; described in Section 7.2.5)  
• PK blood samples collected before pembrolizumab administration (described in 
Section 7.4) 
• ATA and biomarker blood samples (described in Sections 7.5 and 7.6, respectively) 
• Phase 2 and phase 2 expansion only: PRO assessment/EORTC QLQ-C30 (described in 
Section 7.3.3) 
Note: The EORTC QLQ-C30 will be assessed  at baseline during screening or prior to 
Cycle 0 and for Cycles 1 and 2, then every 2 cycles, and 30 days after discontinuation. 
 
Study drug administration: 
• Subjects should be well-hydrated prior to study drug administration. Subjects will receive 
one IV infusion of pembrolizumab over 30 (−5/+10) minutes, followed by one IV 
infusion of vofatamab over 90 (± 15) minutes. The vofatamab infusion will begin 
approximately 30 minutes after completion of the pembrolizumab infusion. (Note: If 
prior vofatamab infusions have been well-tolerated, doses of vofatamab may be 
administered over 30 [± 10 minutes]). Infusions will be followed by a 30-minute 
observation period (described in Section 5.2) 
• Vital signs should be assessed prior to vofatamab infusion, and as clinically indicated 
during the infusion (described in Section 7.2.3). For infusions with pembrolizumab, vital 
signs should be assessed per institutional guidelines. 
AEs should be collected and recorded while the subject is receiving study drug (described in 
Section 7.2.1) 
The following assessment(s) should be performed after study drug infusion has been 
completed: 
• Vital signs should be assessed 30 (± 10) minutes post-vofatamab-infusion (described in 
Section 7.2.3) 
• PK blood samples collected within 30 (± 15) minutes after the completion of vofatamab 
administration (described in Section 7.4) 
 
AEs: Subjects should be monitored for 30 (± 10) minutes following completion of the 
infusion (described in Section 7.2.1) 

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6.1.5 
End of Treatment 
Subjects who complete the study or discontinue from study treatment early will be asked to 
return to the clinic within 30 days after the last study drug infusion for an End of 
Treatment/ET visit. The visit at which response assessment shows progressive disease may 
be used as the End of Treatment/ET visit. 
The following assessments should be performed: 
• Targeted physical examination (described in Section 7.2.2) 
• Weight 
• Vital signs (described in Section 7.2.3) 
• ECOG PS (see Appendix 1) 
• AEs (described in Section 7.2.1) 
• Concomitant medications and therapies 
• Tumor assessment; subjects will also be asked to provide any optional metastatic tumor 
tissue sample collected during end of treatment or at autopsy (described in Section 7.3.1). 
• Hematology (described in Section 7.2.4.1) 
• Serum chemistry (described in Section 7.2.4.1) 
• Urinalysis (described in Section 7.2.4.1) 
• Coagulation (i.e., aPTT, PT/INR, and fibrinogen; described in Section 7.2.4.1) 
• Urine or serum pregnancy test (described in Section 7.2.4.1) 
• ECG (described in Section 7.2.5) 
• PK blood sample (described in Section 7.4) 
• ATA and biomarker blood samples (described in Section 7.5 and 7.6, respectively), 
including blood for circulating tumor DNA at the time of progression 
• PRO assessment/EORTC QLQ-C30 (described in Section 7.3.3) 
 
6.1.6 
End of Study 
All subjects will be followed for survival until death or full withdrawal of consent (described 
in Section 7.3.2). After the end of treatment, subjects will be monitored for survival every 
3 months until the End of Study visit via telephone follow-up from the investigator. 

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7 
STUDY ASSESSMENTS 
7.1 
Screening/Baseline Assessments 
7.1.1 
Informed Consent 
The potential subject or legal guardian of a potential subject will be given a verbal 
explanation of the study and the procedures involved and will have all questions addressed. 
The subject or legal guardian must sign and date a consent form that has been approved by 
the appropriate Institutional Review Board (IRB)/Ethic Committee (IEC) before any 
study-specific procedures are initiated. The subject or legal guardian will be given a copy of 
the signed and dated informed consent form.  
Informed Consent Forms for subjects who are not subsequently enrolled will be maintained 
at the study site. Additional details are provided in Section 10.1. 
7.1.2 
Collection of Biomarker Tumor Biopsy Samples 
All subjects in Phase 1b will have a biomarker tumor biopsy taken prior to Cycle 0 (lead-in 
cycle) 
• Within 7 days prior if an archival sample is available for screening  
• If an archival sample is not available, a biopsy should be obtained within the 28-days 
screening window. If the sample is adequate, it may be substituted for the initial (pre-
treatment) Cycle 0 biomarker biopsy. 
• No study related biopsy may be obtained from lung, bone, or brain (study exclusion CNS 
disease) 
• Biopsies should be obtained using the least invasive procedure feasible (no major surgical 
procedure are to be done for study purposes)    
• If possible biopsies should not be performed in target lessions to allow for accurate ORR 
evaluations  
All subjects in Phase 2 (Cohorts 1, 2 and 3) will have a biomarker tumor biopsy taken within 
14 days prior to Cycle 0 (lead-in cycle). If the subject has undergone a diagnostic tumor 
biopsy procedure within 56 days of enrolling in the study, and the biopsy has adequate 
material, this sample may be used in place of the first biomarker. For the Phase 2 expansion 
(cohort 4), a biopsy is optional. Subjects will be required to sign a separate consent form and 
must confirm their decision to opt-in.  
For Phase 2, Cohort 1 and Cohort 2, a second tumor biopsy will be obtained 14 days after 
Cycle 0 Day 1 of vofatamab. The second tumor biopsy should always occur within 3 days 
before Cycle 1 Day 1 infusion and prior to the first dose of vofatamab plus pembrolizumab.  
For patients enrolled in Phase 2, Cohort 3 and Cohort 4 (optional), the second tumor biopsy 
will occur at the end of cycle 1, Week 5, within 3 days before Cycle 2, Day 1 and prior to the 
administration of the second combination dose of vofatamab and pembrolizumab. 

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Biopsies will be used to evaluate how treatment with vofatamab affects the FGFR3 signaling 
pathway relative to FGFR3 expression, immunological status of the tumor, and to explore 
what markers are associated with and predictive of response to vofatamab. Sample analysis 
may include any or all of the following: molecular profiling (RNA analysis), sequencing of 
cancer related genes, IHC on cancer related proteins and markers of immune cell infiltration. 
Sample analyses will be performed by a laboratory selected by the Sponsor. 
7.1.3 
Archival/Diagnostic Tissue Collection 
All subjects in this study must consent to submit archival tumor tissue that was obtained at 
the time or after the subject was found to have muscle invasive or metastatic disease. 
Availability of archival tumor tissue of suitable quality and quantity should be confirmed 
prior to study entry. If no suitable tissue is available, a blood sample may be used to 
determine FGFR3 genetic status. Subsequent to subject enrollment, blood samples used to 
determine FGFR3 status, or previous test results that were not provided by Foundation will 
be verified using archival tissue or the first biomarker tumor biopsy sample. If archival tumor 
tissue is not available, the subject may undergo a diagnostic tumor biopsy procedure within 
56 days of enrolling in the study. For Phase 2, Cohort 1 and Cohort 2, subjects will be 
assigned based on FGFR3 status of 1) WT or 2) Mut/Fus.  
Genetic sequencing of FGFR3, other cancer related genes, immune response related genes, 
and determination of mutation burden may also be performed by the Sponsor, a laboratory 
selected by the Sponsor or a participating institution. 
Detailed instructions will be provided in the Sample Collection & Processing Manual. 
7.1.4 
Subject Eligibility 
During the Screening visit, all subjects will be assessed for eligibility against the inclusion 
and exclusion criteria described in Section 4.1 and Section 4.2. 
7.1.5 
Medical History and Demographics 
Complete medical history will be recorded at the Screening visit. 
7.2 
Safety Assessments 
7.2.1 
Adverse Events 
7.2.1.1 
Definitions 
7.2.1.1.1 
Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether 
or not related to the medicinal (investigational) products. 

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All AEs resulting in discontinuation from the study should be followed until resolution or 
stabilization. Subjects who are discontinued from study drug will be followed for safety 
outcomes through the safety follow-up visit after the subject’s last dose of study drug or until 
the subject receives another anti-cancer therapy, whichever occurs first. 
Suspected Adverse Reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. For the purposes of expedited safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. 
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug. 
A life-threatening AE or life-threatening suspected adverse reaction is an AE or suspected 
adverse reaction that, in the view of either the investigator or Sponsor, places the subject at 
immediate risk of death. It does not include an AE or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
7.2.1.1.2 
Serious Adverse Event 
An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that at 
any dose, in the view of either the investigator or Sponsor, results in any of the following 
outcomes:  
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
Important medical events that may not result in death, be immediately life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in the definition.  
All AEs that do not meet any of the criteria for serious should be regarded as non-serious 
AEs. 
The definition of an SAE also includes any important medical event. Medical and scientific 
judgment should be exercised in deciding whether expedited 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 subject or may require intervention 
to prevent one of the other outcomes listed in the previous definition. These should also 
usually be considered serious. Examples of such events are 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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It is important to distinguish between serious and severe adverse events. Severity is a 
measure of intensity; however, an AE of severe intensity need not necessarily be considered 
serious. For example, nausea, which persists for several hours, may be considered severe 
nausea, but may not be considered an SAE. On the other hand, a stroke which results in only 
a limited degree of disability may be considered only a mild stroke, but would be considered 
an SAE. 
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself. 
7.2.1.1.3 
Adverse Event of Special Interest 
Bleeding and bleeding-related adverse events will be carefully followed. 
7.2.1.2 
Severity of Adverse Events 
Each AE and SAE should be graded as mild, moderate, severe, life-threatening, or death 
using the following definitions. The severity of all adverse events will be graded using the 
National Cancer Institute (NCI) CTCAE v4.0 in Table 5. 

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Table 5 
Adverse Event Severity Grading Scale 
Grade 
Severity 
Alternate Description a 
1 
Mild (apply event-specific NCI CTCAE 
grading criteria) 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated 
2 
Moderate (apply event-specific  
NCI CTCAE grading criteria) 
Minimal, local or noninvasive intervention 
indicated; limiting age-appropriate 
instrumental ADLb 
3 
Severe (apply event-specific  
NCI CTCAE grading criteria) 
Severe or medically significant but not 
immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; 
disabling; limiting self-care ADLc 
4 
Very severe, life threatening,  
or disabling (apply event-specific NCI 
CTCAE grading criteria) 
Life-threatening consequences; urgent 
intervention indicated 
5 
Death related to AE 
 
ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology Criteria for Adverse 
Events; NCI = National Cancer Institute. 
The NCI CTCAE v4.0 can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40. 
Note: Regardless of severity, some events may also meet regulatory serious criteria. Refer to definition of an 
SAE (see Section 7.2.1.1). 
a 
Use these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or reported AE is not 
in the NCI CTCAE listing. 
b 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
c 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
To make sure there is no confusion or misunderstanding of the difference between the terms 
"serious" and "severe," which are not synonymous, the following note of clarification is 
provided. The term "severe" is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may 
be of relatively minor medical significance (such as severe headache). This is not the same as 
"serious" which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject's life or functioning. Seriousness (not severity) serves as 
a guide for defining regulatory reporting obligations. 
7.2.1.3 
Relationship of Adverse Events to Study Drug 
The investigator will assess the potential relationship of each AE and SAE to vofatamab and 
to pembrolizumab using the following descriptions. 
• Unrelated: This category applies to an AE or SAE that is clearly not related to the 
investigational agent/procedure, beyond a reasonable doubt. That is, another cause of the 
event is most plausible; and/or a clinically plausible temporal sequence is inconsistent 

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with the onset of the event and the exposure to study drug and/or a causal relationship is 
considered biologically implausible. 
• Possibly Related: This category applies to an AE that follows a reasonable temporal 
sequence from administration of the study drug and that follows a known or expected 
response pattern to the suspected study drug, but that could readily have been produced 
by a number of other factors. 
• Related: This category applies to an AE that is certainly related to the investigational 
agent/procedure. That is, the AE has a temporal relationship to the administration of the 
investigational agent(s) or research intervention, which cannot be explained by 
concurrent disease or other drugs or chemicals; the response to withdrawal of drug is 
clinically plausible; and the event has been shown to be definitively pharmacologically or 
phenomenologically related using a satisfactory rechallenge procedure. 
 
Note: The investigator’s assessment of causality for individual AE reports is part of the study 
documentation process. Regardless of the “Yes” or “No” causality assessment for individual 
AE reports, the Sponsor will promptly evaluate all reported SAEs against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
investigators and applicable regulatory authorities.  
7.2.1.4 
Eliciting Adverse Events 
A consistent methodology of non-directive questioning for eliciting AEs at all subject 
evaluation time points should be adopted. Examples of non-directive questions include: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
7.2.1.5 
Adverse Event Reporting Period 
After informed consent, but prior to initiation of study drug, only SAEs caused by a 
protocol-mandated intervention will be collected (e.g., SAEs related to invasive procedures 
such as biopsies, medication washout, or no treatment run-in). All medical occurrences from 
the time of signing the informed consent that meet this definition should be recorded. Events 
preceding first study drug administration, however, should be recorded as medical history, 
not as AEs. 
After initiation of study drug, all AEs and SAEs regardless of attribution will be collected 
until 30 days following the last administration of study drug, 30 days after subject 
discontinuation, initiation of another anti-tumor therapy, resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause. After this 
period, investigators should report only SAEs that are felt to be related to prior study 
treatment (see Section 7.2.1.9). 

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7.2.1.6 
Recording of Adverse Events 
Information on all AEs should be recorded immediately in the source document, and in the 
appropriate adverse event module of the CRF. All clearly related signs, symptoms, and 
abnormal diagnostic procedure results should be recorded in the source document, grouped 
under one diagnosis. 
7.2.1.6.1 
Diagnosis versus Signs and Symptoms 
If known, a diagnosis should be recorded on the CRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded as an AE or SAE on the CRF. If a diagnosis is 
subsequently established, it should be reported as follow-up information. 
For this study, the NCI CTCAE terms “cytokine release syndrome” should not be used. If 
multiple signs or symptoms occur with a given event, each sign or symptom should be 
recorded separately with its level of severity. 
7.2.1.6.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause. For example, if severe diarrhea is 
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or 
SAE on the CRF.  
However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the Adverse Event CRF. 
For example, if a severe gastrointestinal hemorrhage leads to renal failure, both events should 
be recorded separately on the Adverse Event CRF. 
7.2.1.6.3 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be recorded on the General Medical History and Baseline Conditions CRF. 
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events 
on an Adverse Event CRF, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more frequent headaches”). 
7.2.1.6.4 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between subject 
evaluation time points. Such events should only be recorded once in the CRF unless their 
severity increases. If a persistent AE becomes more severe, it should be recorded as a new 
entry on the Adverse Event CRF. If a previously reported SAE increases in severity, it should 

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be reported on the previously submitted CRF as a follow-up or update and not as a new 
event. 
A recurrent AE is one that occurs and resolves between subject evaluation time points and 
subsequently recurs. All recurrent AEs should be recorded on an Adverse Event CRF. 
7.2.1.6.5 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the Adverse Event CRF (e.g., abnormalities that require study 
drug dose modification, discontinuation of study treatment, more frequent follow-up 
assessments, further diagnostic investigation, etc.). 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome  
(e.g., ALP and bilirubin 5  the ULN associated with cholecystitis), only the diagnosis  
(e.g., cholecystitis) needs to be recorded on the Adverse Event CRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the Adverse Event CRF. If the 
laboratory abnormality can be characterized by a precise clinical term, the clinical term 
should be recorded as the AE or SAE. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the Adverse Event CRF, unless their 
severity, seriousness, or etiology changes.  
7.2.1.6.6 
Worsening of Urothelial Cell Carcinoma  
Progression of underlying malignancy should not be reported as an AE if it is clearly 
consistent with the suspected progression of the underlying cancer, as defined by respective 
disease criterion or other criteria as determined by protocol. Hospitalization due solely to the 
progression of underlying malignancy should NOT be reported as an SAE. Clinical 
symptoms of progression may be reported as AEs, if the symptom cannot be determined as 
exclusively due to the progression of the underlying malignancy, or does not fit the expected 
pattern of progression for the disease under study.  
7.2.1.6.7 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE unless specifically instructed otherwise in this protocol.  
There are some hospitalization scenarios that do not require reporting as an SAE when there 
is no occurrence of an AE. These scenarios include a planned hospitalization or prolonged 
hospitalization to: 
• Perform an efficacy measurement for the study 

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• Undergo a diagnostic or elective surgical procedure for a preexisting medical condition 
that has not changed 
• Receive scheduled therapy for the target disease of the study 
 
7.2.1.6.8 
Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of UCC will be recorded only on the Study Discontinuation 
CRF. All other on study deaths, regardless of attribution, will be recorded on an Adverse 
Event CRF and expeditiously reported to the Sponsor.  
7.2.1.6.9 
Pregnancy 
Conditions of pregnancy and lactation are excluded from study participation. During the 
study, females of childbearing potential must contact the treating Investigator immediately if 
they suspect that they may be pregnant (a missed or late menstrual period should be reported 
to the treating Investigator).  
If an investigator suspects that a subject may be pregnant after the subject started study drug, 
study drug must immediately be withheld until the result of the pregnancy test is confirmed. 
If a pregnancy is confirmed, the study drug(s) must be immediately and permanently 
stopped, the subject must be discontinued from the study, and the Investigator must notify the 
study Sponsor within 24 hours of confirmation. 
If a female subject becomes pregnant while receiving investigational therapy or within 
120 days after the last dose of the study drug, a Pregnancy Report CRF should be completed. 
Pregnancy should not be recorded on the Adverse Event CRF. 
Abortion, whether therapeutic or spontaneous, should always be classified as serious (as the 
Sponsor considers these medically significant), recorded on an Adverse Event CRF, and 
expeditiously reported to the Sponsor. After the study period, such events should still be 
reported expeditiously to the Sponsor.  
Any congenital anomaly/birth defect in a child born to a female subject or female partner of a 
male subject exposed to the investigational product should be classified as serious, recorded 
on an Adverse Event CRF, and expeditiously reported to the Sponsor during the study period. 
After the study period, such events should still be reported expeditiously to the Sponsor 
recorded and reported as an SAE. 
7.2.1.7 
Expedited Reporting Requirements for Serious Adverse Events and Serious 
Drug Reactions 
7.2.1.7.1 
Reporting Requirements for All SAEs  
Investigators will submit reports of all SAEs, regardless of attribution, and all 
protocol-defined non-serious expedited AEs to the Sponsor within 24 hours of learning of the 

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events. For initial SAE and protocol-defined non-serious expedited AE reports, investigators 
should record all case details that can be gathered within 24 hours on an Adverse Event CRF 
and submit as follows: 
• 
To Parexel Drug Safety group. Complete the SAE report form and fax the documents 
to PAREXEL GMS using the PAREXEL SAE fax number: +1 781 434 5957 
Or 
• 
Complete the SAE report form and submit it to PAREXEL GMS via email utilizing 
the address: NorthAmerica_Medical@parexel.com 
 
and/or 
• 
In the event that the site staff is unable to complete the SAE form within 24 hours of 
their knowledge of the event, the investigators may report the SAE over the telephone 
and then provide the completed SAE form via fax or email within the next 24 hours. 
If questions arise regarding the reporting procedures or the specifics of the reporting 
of an event, sites may call utilizing the following number: +1 781 434 5010 
 
7.2.1.7.2 
IRB/IEC Notification by the Investigator 
Reporting of SAEs to the IRB/IEC will be done in compliance with the standard operating 
procedures and policies of the IRB/IEC and with applicable regulatory requirements. 
Adequate documentation must be obtained by Rainier showing that the IRB/IEC was 
properly and promptly notified as required. 
7.2.1.7.3 
Regulatory Agency Notification by the Sponsor 
The study sponsor or designee, shall notify all applicable regulatory agencies by telephone, 
by facsimile transmission, or registration in EudraVigilance database of any suspected 
unexpected serious adverse reaction (SUSAR) associated with the use of the drug as soon as 
possible but no later than 7 calendar days from the Sponsor’s original receipt of the 
information. 
If a previous AE that was not initially deemed reportable is later found to fit the criteria for 
reporting, the study sponsor will submit the AE in a written report to the appropriate 
regulatory agencies as soon as possible, but no later than 15 calendar days from the time the 
determination is made. 
7.2.1.8 
Type and Duration of Follow-Up after Adverse Events 
The investigator should follow all unresolved AEs and SAEs until the events are resolved to 
baseline grade, the event is assessed by the investigator as stable, new anti-cancer treatment 
is initiated, the subject is lost to follow-up, or it has been determined that the study treatment 
or participation is not the cause of the AE/SAE. Resolution of AEs and SAEs (with dates) 
should be documented on the appropriate Adverse Event CRF and in the subject’s medical 
record to facilitate source data verification (SDV) during the study period. 

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For some SAEs, the Sponsor or its designee may follow-up by telephone, fax, electronic 
mail, and/or a monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report). 
7.2.1.9 
Post-Study Adverse Events 
At the last scheduled visit, the investigator should instruct each subject to report to the 
investigator any subsequent SAEs that the subject’s personal physician believes could be 
related to prior study treatment.  
The investigator should notify the Sponsor of any death or other SAE occurring at any time 
after a subject has discontinued or terminated study participation if felt to be related to prior 
study treatment. The Sponsor should also be notified if the investigator should become aware 
of the development of cancer or of a congenital anomaly in a subsequently conceived 
offspring of a subject who participated in this study. The investigator should report these 
events to the Sponsor on the study Adverse Event CRF.  
7.2.2 
Physical Examination, Height, and Weight 
Complete physical examinations should include the evaluation of head, eye, ear, nose, and 
throat (HEENT), cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  
Targeted physical examinations may be limited to systems of primary clinical relevance  
(i.e., cardiovascular, respiratory, those systems associated with symptoms, and any system 
that might be associated with tumor assessment). 
Changes from baseline for all targeted physical examinations should be recorded at each 
subsequent physical examination. New or worsened abnormalities should be recorded as AEs 
if appropriate. 
Height should be measured only at the Screening visit and weight should be measured at the 
Screening visit and on Day 1 of each cycle. 
7.2.3 
Vital Signs 
Vital signs will include measurements of systolic and diastolic blood pressure, pulse rate, and 
body temperature. 
On Day 1 of Cycle 0 and Cycle 1, vital signs for vofatamab should be assessed pre-infusion, 
every 15 (± 5) minutes during the infusion, at the end of the infusion, and 30 (± 10) minutes, 
60 (± 10) minutes, and 90 (± 10) minutes post-infusion. On Day 1 of Cycles 2+, vital signs 
for vofatamab should be assessed pre-infusion, as clinically indicated during the infusion, 
and at the end of the vofatamab infusion. For infusions with pembrolizumab, vital signs 
should be assessed per institutional guidelines. 

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7.2.4 
Laboratory Assessments 
For the Screening visit, local laboratory assessments should be done within 14 days of Day 1 
of Cycle 0. After Cycle 0, local laboratory assessments may be performed within 72 hours 
preceding study drug administration on Day 1, unless otherwise specified. Results must be 
reviewed and the review documented prior to study drug administration. 
Detailed sample collection instructions will be provided in the Sample Collection & 
Processing Manual. 
7.2.4.1 
Local Laboratory Assessments 
Samples for hematology, serum chemistry, and pregnancy will be analyzed at the study site’s 
local laboratory. If an institution performs an equivalent test to those listed below (for 
example, urine albumin rather than urine protein) for study purposes, this may be acceptable 
as long as it is noted with institutional normal(s) and approved by the sponsor prior to subject 
enrollment: 
• Hematology: complete blood count (complete blood count [CBC]; including RBC, 
hemoglobin, hematocrit, WBC), platelet count, and percent and absolute differential 
count (neutrophils, bands, lymphocytes, eosinophils, monocytes, and basophils) 
• Coagulation: aPTT, PT/INR, and fibrinogen 
• Serum chemistry: sodium, potassium, chloride, bicarbonate, non-fasting glucose, blood 
urea nitrogen (BUN), creatinine, calcium, phosphate, magnesium, total and direct 
bilirubin, total protein, albumin, ALT, AST, ALP, lactate dehydrogenase, and uric acid 
• Urinalysis: Urinalysis includes Urinalysis includes macroscopic analysis (specific 
gravity, pH, protein, glucose, ketones, blood, bilirubin, leukocyte esterase, urobilinogen, 
and nitrite) and microscopic urinalysis (RBCs, WBCs, epithelial cells, casts, crystals, 
bacteria, and yeast) 
 
Pregnancy test: For women of childbearing potential, a urine or serum pregnancy test must 
be performed during Screening (within 14 days prior to first administration of study 
treatment), prior to administration of study drug on Day 1 of each cycle, and the End of 
Treatment/ET visit.  
7.2.5 
Electrocardiogram Assessments 
ECG measurements must be obtained from subjects who have been resting for at least 10 
minutes, either before or after drawing blood samples. One ECG reading should be obtained 
at each of the following time points: Screening, Cycle 0 Day 1 pre-treatment, Cycle 1 Day 1 
pre-treatment, Cycle 2 Day 1 pre-treatment, and at the End of Treatment/ET visit (described 
in Section 6.1 and Table 1).  

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7.3 
Response/Efficacy Assessments 
7.3.1 
Tumor and Response Assessments 
For subjects with measurable disease, response will be assessed by the investigator per 
RECIST 1.1 (see Appendix 2). 
All evaluable and measurable disease must be documented at the Screening visit, at the end 
of Cycle 1, and every 9 weeks (± 7 days) thereafter (i.e., every third cycle beginning after 
Cycle 1) until disease progression or lack of tolerability; and will include the following 
measures: 
• CT scans of the chest, abdomen, and pelvis, and all known or suspected sites of disease  
• Brain scan (CT or magnetic resonance imaging [MRI]) at Screening only 
• Bone scans (CT or MRI), if clinically indicated 
Scans performed at End of Cycle 1 will not be used to determine progression per RECIST 
1.1. Progression per RECIST 1.1 will be determined using radiographic assessments taken at 
end of Cycle 3 onward.  
Additional methods of assessment of measurable disease per RECIST 1.1 may be used in 
addition to those listed above. The same imaging methods used at screening must be used 
throughout the study for each subject. Additional tumor assessments may be conducted as 
clinically indicated during the study. Results must be reviewed prior to study drug infusion at 
the next cycle to assess whether a subject is eligible to continue treatment. 
Subjects may continue vofatamab and/or pembrolizumab treatment beyond radiological 
disease progression following discussion with the medical monitor and based on clinical 
judgement of the investigator that the subject is experiencing clinical benefit. It is highly 
encouraged that prior to discontinuation of any subject whom is receiving clinical benefit that 
a consultation occur with the study PI or medical monitor. 
A tumor assessment scan should be performed if the subject is discontinuing the study early. 
In addition, conﬁrmation scans are required of any patient exhibiting PR or CR. 
 
At the End of Treatment/ET visit or at autopsy, subjects will be asked to provide any optional 
metastatic tumor tissue samples collected during the study or at autopsy. 
7.3.2 
Survival 
Upon discontinuation of study treatment (vofatamab and pembrolizumab), subjects will be 
followed for overall survival every 3 months via telephone until death or full withdrawal of 
consent. 
The End of Study visit assessment should be performed by telephone call. 

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7.3.3 
Patient-Reported Outcome/European Organization for Research and 
Treatment Quality of Life Questionnaire 
In Phase 2 and expansion phase of the study, the EORTC QLQ-C30 assesses the quality of 
life (disease and treatment-related symptoms, physical, psychological, and social 
functioning) of cancer patients using a self-reported questionnaire. The EORTC QLQ-C30 
will be assessed from baseline for Cycles 0 (if applicable) through Cycle 2, then every 2 
cycles, and 30 days after discontinuation.  
7.4 
Pharmacokinetic Assessments 
Blood samples will be obtained prior to the administration of vofatamab and within 30 (± 15) 
minutes after the completion of the administration of vofatamab on Day 1 of Cycle 0. Blood 
samples will be obtained prior to the administration of pembrolizumab and within 30 (± 15) 
minutes after the completion of the administration of vofatamab on Day 1 of Cycles 1 and 4, 
and once at the End of Treatment/ET visit. Serum samples will be analyzed for the 
quantitative determination of vofatamab. 
7.5 
Anti-therapeutic Antibody Assessments 
As may occur with any recombinant antibodies, either vofatamab or pembrolizumab may 
elicit an immune response and subjects may develop antibodies against either agent. 
Although ATAs directed against either agent are not expected to result in significant clinical 
consequence, subjects will be monitored for any potential immune response to vofatamab in 
this clinical study.  
Blood samples for ATA assessment will be obtained prior to infusion of vofatamab on Day 1 
of Cycles 0 (if applicable), 1 and 4, and once at the End of Treatment/ET visit. Serum 
samples will be analyzed for the determination of antibodies to vofatamab. 
7.6 
Biomarker Assessments 
Whole blood (PBMCs), serum, and plasma samples for biomarker analyses will be obtained 
prior to infusion of vofatamab on Day 1 of Cycles 0, 1, 3, and 5, and once at the End of 
Treatment/ET visit. 
Blood for circulating tumor DNA will be collected at the time of progression to assess 
FGFR3 status. 
The effects of vofatamab on the downstream signaling of the FGFR3 pathway, tumor sub-
type and on the immune surveillance of UCC tumors will be monitored using a range of 
techniques that may include but are not limited to gene expression profiling (such as whole 
transcriptome RNAseq), sequencing of TCRs, flow cytometry, ELISA, and 
immunohistochemistry. Analyses will be performed on biopsy samples taken pre- and 
post-vofatamab treatment (as described in Section 7.1.2), archival tissue samples (described 
in Section 7.1.3), and whole blood, serum and plasma samples, as appropriate.  

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In order to identify possible predictors or response to therapy, in addition to the techniques 
described in the preceding paragraph, samples may be analyzed for mutational burden and 
genetic alterations in genes associated with cancer including FGFR3.  
7.7 
Appropriateness of Measurements 
The efficacy and safety assessments for this study are standard, widely used, and generally 
recognized as reliable, accurate, and relevant. 

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8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE 
8.1 
Site Training and Monitoring Procedures 
Manuals with instructions for study compliance and CRF completion will be provided. Prior 
to the enrollment of subjects at the site, the Sponsor or its designated clinical and medical 
personnel will review the following items with the Investigator and clinic staff: 
• The protocol, study objectives, eligibility requirements, study procedures, registration 
and withdrawal processes 
• Current Investigator’s brochure/package insert 
• Recording and reporting AEs and SAEs 
• Enrollment goals and study timelines 
• The CRF completion process and source documentation requirements 
• Monitoring requirements 
• Institutional Review Board/Independent Ethics Committee (IRB/IEC) review and 
approval process 
• Informed consent process 
• Good Clinical Practice (GCP) guidelines and related regulatory documentation 
requirements 
• Key study team roles and responsibilities 
• Investigational product storage, accountability, labeling, dispensing and record keeping 
• Subject coding 
• Study samples/specimen collection, handling and shipping 
• Protocol compliance 
• Clinical study record keeping, document retention, and administrative requirements 
Monitoring and auditing procedures developed by the Sponsor and/or its designee will be 
implemented to ensure compliance with FDA and International Council for Harmonisation 
(ICH) GCP guidelines. The Sponsor's designated representative (the monitor) will contact the 
investigator and conduct regular visits to the study site. The monitor will be expected and 
allowed to verify the investigator's qualifications, to inspect clinical site facilities, and to 
inspect study records, including proof of IRB review, with the stipulation that subject 
confidentiality will be maintained in accordance with local and federal regulations, including 
Health Insurance Portability and Accountability Act (HIPAA) requirements. The monitor 
will also be responsible for confirming adherence to the study protocol, inspecting CRFs and 
source documents, and ensuring the integrity of the data. CRFs will be checked for accuracy, 

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completeness, and clarity and will be cross-checked for consistency with source documents, 
including laboratory test reports and other subject records. Instances of missing or 
uninterruptable data will be resolved in coordination with the investigator. 
The monitor will also investigate any questions concerning adherence to regulatory 
requirements. Any administrative concerns will be clarified and followed. The monitor will 
maintain contact with the site through frequent direct communications with the study site by 
e-mail, telephone, facsimile, and/or mail. The investigator and all other site personnel agree 
to cooperate fully with the monitor and will work in good faith with the monitor to resolve 
any and all questions raised and any and all issues identified by the monitor. 
8.2 
Data Management Procedures 
The Sponsor or its designee will provide CRF Completion Guidelines for electronic CRF 
(eCRF) data entry. Study specific data management procedures will be maintained in the data 
management plan. Queries resulting from edit checks and/or data verification procedures will 
be posted electronically in the eCRF. 
8.3 
Access to Source Data 
The investigator understands that regulatory authorities, the IRB, and/or the Sponsor or its 
designees have the right to access all CRFs, source documents, and other study 
documentation for on-site audit or inspection and will retain this right from the start of the 
study to at least 2 years after the last approval of a marketing application or for at least 
2 years after clinical development of the study drug for the indication being studied has been 
discontinued. The investigator is required to guarantee access to these documents and to 
cooperate with and support such audits and inspections. 
8.4 
Accuracy and Reliability of Data 
Steps to be taken to assure the accuracy and reliability of data include: 
• The selection of qualified investigators and appropriate study centers. 
• Review of protocol procedures with the investigators and associated personnel prior to 
the study. 
• Periodic monitoring visits by the designated monitor(s). 
 
CRFs will be reviewed for accuracy and completeness by the designated monitor(s) during 
monitoring visits to the study centers. Any discrepancies will be resolved with the 
Investigator or designees as appropriate. 
8.5 
Quality Assurance Procedures 
The Clinical Quality Assurance group or its designee may conduct audits at the clinical site 
or other study-related facilities and organizations during or at any time after the study. Audit 

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reports will be retained by the Sponsor’s Clinical Quality Assurance group or its designee as 
part of the written record. 
8.6 
Data Handling and Record Keeping 
8.6.1 
Data Handling 
The investigator is required to initiate and maintain, for each subject, an adequate and 
accurate case history that records all observations and other data related to the study for that 
subject. Data must be recorded on CRFs approved by the Sponsor or its designee. All 
information recorded on CRFs for this study must be consistent with the subject's source 
documentation.  
Initial data entry and any changes to the data will be made only by authorized users. An 
explanation of any data change should be recorded in the CRF. All data entered in to the CRF 
must be verifiable; therefore, CRFs will be routinely checked for accuracy, completeness, 
and clarity and will be cross-checked for consistency with source documents, including 
laboratory test reports and other subject records by the Sponsor or its designee. The 
investigator must allow direct access to all source documents. 
8.6.2 
Records Retention 
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the US or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the US or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product under study. 
The Investigator/institution should retain subject identifiers for at least 15 years after the 
completion or discontinuation of the study. Subject files and other source data must be kept 
for the maximum period of time permitted by the hospital, institution or private practice, but 
not less than 15 years. These documents should be retained for a longer period, however, if 
required by the applicable regulatory requirements or by agreement. The Sponsor must be 
notified and will assist with retention should the Investigator/institution be unable to continue 
maintenance of subject files for the full 15 years. All study records must be stored in a secure 
and safe facility. 

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9 
STATISTICAL METHODS 
Complete details of the prospective analyses and procedures for handling missing/spurious 
data handling will be provided in the Statistical Analysis Plan. 
9.1 
Sample Size Consideration 
In Phase 1b of the study, at least 6 subjects are required for the first dose level and up to 18 
subjects may be required for 3 dose levels. 
The primary efficacy endpoint for Phase 2 of the study is ORR and will be compared against 
historical ORR of pembrolizumab (21.1%) (Bellmunt J, et al., 2017).  
The total of 90 subjects in Cohort 1,2,3 and 4 will be the primary efficacy analysis set for 
Phase 2. Given the expected π=0.343 with Type I error (alpha) at 0.05 (one-sided), 90 
subjects will give a power of approximately 87.5% to reject the null hypothesis of π≤0.211. 
With the expected π=0.343, the 95% CI half width is around 0.098 for the sample size of 90 
subjects.  The sample size calculation for Phase 2 was performed for a 3-look group 
sequential design. The 𝛼-spending formula of Lan and DeMets O’Brian-Fleming stopping 
boundary was used. EAST v6.4.1 was used to derive the sample size and efficacy and 
futility boundary as well as the alpha allocation. Results are shown in Table 6. 
Table 6 Three- Look Group Sequential Sample Size, Boundary and Alpha Allocation 
 
Look # 
Information 
Fraction 
Sample 
Size  
Efficacy Boundary 
Futility Boundary 
Alpha 
N 
Proportion 
(95% CI) 
Alpha 
N 
Proportion  
(95% CI) 
1 
28/90=0.311 
28 
0.0004 
14 
0.5 
(0.307  
0.694) 
0.890 
3 
 0.107 
(0.023   
0.282) 
2 
52/90=0.578 
52 
0.010 
 18 
0.346 
(0.220   
0.491) 
0.379 
11 
 0.212 
(0.111   
0.347) 
3 
1 
90 
00.47 
26 
0.289 
(0.198   
0.394) 
 
 
 
 
Note: The total sample size has increased from 74 in protocol amendment 4 to 90 in amendment 5; therefore the 
information fractions for the 1st interim and 2nd interim analysis both changed. These changes lead to changes in 
alpha spending and subsequent changes in boundaries from protocol amendment 4.  
 
 
9.2 
Interim Analysis  
There is no interim analysis planned for Phase 1b.  

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There will be two pre-specified interim analyses during Phase 2, one has already been 
conducted on the first 28 subjects (20 WT and 8 Mut/Fus). The second planned interim will 
occur when a minimum of 52 subjects have been enrolled and have data available to 
determine ORR.  
 
All tumor assessment scans used in the interim analysis will be assessed by investigator for 
response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). 
Analysis will then be conducted using RECIST 1.1 and iRECIST. The first interim analysis 
has been performed for 28 subjects (20 in the WT cohort and 8 in the Mut/Fus cohort).  
The second interim analysis will be performed for 52 subjects.  If the number of responders 
is below or equal to the futility boundary (N = 11), the study may stop for futility. If the 
number of responders is above or equal to efficacy boundary (N = 18), the study may stop for 
efficacy.  
The primary efficacy analysis will be performed when approximately 90 subjects (including 
expansion) in Phase 2 have been followed with sufficient duration to evaluate the primary 
efficacy endpoint, at the discretion of the sponsor. The number and proportion of responders 
along with DOR (duration of response) will be reported. The final analysis will be when OS 
endpoint has been met or 3 years after the last subject enrolled, at the discretion of the 
sponsor. 
Additional informal interim analyses may be performed for presentation at scientific 
meetings. 
If the study is not stopped during the interim analyses, the primary analysis will be conducted 
with 90 subjects. If the number of responders is above or equal to 26, the null hypothesis of 
π≤0.211 shall be rejected.  
9.3 
Analysis Populations 
Safety Population: For both Phase 1b and Phase 2, the safety population will consist of all 
subjects that receive at least one dose of study drug. All subjects receiving a dose of study 
drug will be included in all safety summaries. 
Full Analysis Set (FAS) Population: The efficacy analysis for Phase 2 will be performed on 
the FAS population, which is defined as all subjects who were enrolled in the study, 
regardless of whether they received a dose of study drug. 
For Phase 2, all efficacy analyses will be presented by overall and by subgroups of FGFR3 
status at enrollment.  For Cohort 3, subgroup analysis by luminal subtypes may also be 
performed. 
9.4 
Planned Analyses 
9.4.1 
Safety Monitoring Rule 
The study will be monitored by the program safety steering as per the charter.  

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9.4.2 
Primary Biomarker Analysis 
For primary analysis, descriptive statistics will be used to summarize FGFR3 receptor 
expression and expressions of markers of FGFR3 pathway. Details of analyses will be 
provided in a statistical analysis plan.  
9.4.3 
Subject Disposition 
The disposition of subjects will be tabulated for all subjects in Phase 1b and Phase 2 
(including Phase 2 expansion). Subjects who received at least one dose of study treatment 
and the reasons for discontinuation of treatment or withdrawal from the study will be 
tabulated.  
9.4.4 
Demographic and Baseline Characteristics 
For Phase 1b and Phase 2 (including Phase 2 expansion), demographics (i.e., age, sex, race, 
ethnicity), baseline characteristics (i.e., ECOG, BMI) and disease history (i.e., cancer stage at 
time of diagnosis and enrollment, prior anti-cancer therapy) will be summarized 
descriptively.  
9.4.5 
Medical History and Physical Examination 
For Phase 1b and Phase 2 (including Phase 2 expansion), medical history will be coded with 
MedDRA and will be presented by system organ class and preferred term.  
Descriptive summary statistics for physical examination and their changes from baseline will 
be presented by visit. Clinically significant abnormalities on physical examination noted at 
baseline will be presented as preexisting conditions. New clinically significant abnormalities 
on study will be presented as AEs. 
9.4.6 
Study Drug Administration 
For Phase 1b and Phase 2 (including Phase 2 expansion), the total number of vofatamab and 
pembrolizumab doses administered and dose modifications, including dose delays, dose 
omissions, and reasons, will be summarized.  
9.4.7 
Safety Analyses 
Safety will be assessed through summaries of AEs, changes in laboratory test results, ECGs, 
and changes in vital signs. All subjects who receive any amount of vofatamab or 
pembrolizumab will be included in the safety analysis. 
The safety data will be presented in individual subject listings and summary tables.  
For both Phase 1b and Phase 2 (including Phase 2 expansion), all safety endpoints will be 
summarized in the safety population. 

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9.4.7.1 
Adverse Events 
Subject incidence of all AEs occurring on or after first dose will be summarized by Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class (SOC), MedDRA 
preferred term (PT), and NCI CTCAE v4.0 toxicity grade. Each subject will be counted only 
once within an SOC or a PT by using the AEs with the highest severity (per CTCAE v4.0) 
within each category.  
Subjects who experienced at least one treatment-emergent AE, treatment-related AE, serious 
AE (SAE), AE with toxicity grade 3 and above, AE leading to treatment discontinuation, and 
AE leading to death will be summarized by incidence rate. 
Number of treatment interruptions or cessations due to an adverse event will be summarized. 
9.4.7.2 
Laboratory Tests 
Descriptive summary statistics for selected chemistry, hematology, and coagulation 
laboratory test results and their changes from baseline will be presented by visit. 
Shift tables will be generated for selected laboratory parameters showing the worst post-
baseline toxicity grade per NCI CTCAE v4.0 by baseline categories.  
9.4.7.3 
Vital Signs 
Descriptive summary statistics for vital signs (including temperature, respiratory rate, blood 
pressure, heart rate, and weight) and their changes from baseline will be presented by visit. 
9.4.7.4 
12-Lead Electrocardiogram  
Descriptive summary statistics for the 12-lead ECG and their changes from baseline will be 
presented by visit. Clinically significant changes may be summarized.  
9.4.7.5 
ECOG Performance Status 
Descriptive summary statistics for Eastern Cooperative Oncology Group (ECOG) 
Performance Score and changes from baseline will be presented by visit. A shift table of 
ECOG may be generated.  
9.4.7.6 
Prior and Concomitant Medications and Therapies  
The World Health Organization (WHO) Drug Dictionary will be used to classify concomitant 
medications by anatomical therapeutic class (ATC) and preferred term. Concomitant 
medications include medications that stop at any time after first dose of study treatment or 
remain ongoing at the end of the entire treatment period. Prior medications include 
medications that started before the first dose.  

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The frequency counts and percentages of subjects taking a prior or a concomitant medication 
will be tabulated by ATC and PT. Although a subject may have taken two or more 
medications, the subject is counted only once within an ATC classification.  
9.5 
Efficacy Analysis 
Efficacy analysis will only be performed in the FAS population.  
9.5.1 
Primary Efficacy Endpoint 
The primary efficacy outcome measure will be ORR, defined as the percentage of subjects 
who have baseline measurable disease and who achieve a best response of either CR or PR as 
assessed by the investigator using RECIST 1.1 criteria. All the responses will be confirmed 
according to RECIST 1.1. The end of Cycle 1 radiographic assessment will not be used to 
determine progression per RECIST 1.1. Progression per RECIST 1.1 will be determined 
using radiographic assessments taken at end of Cycle 3 onward. 
The ORR will be summarized descriptively by percentage and its 95% CI.  
The comparison of ORR with historical ORR of pembrolizumab (21.1%) (Bellmunt J, et al., 
2017) will be performed using one-sample binomial test in interim analyses as well as the 
primary analysis.  
A sensitivity analysis will also be performed on the efficacy evaluable (EE) population. 
Sensitivity analysis for ORR assessed by iRECIST will also be performed. 
9.5.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are PFS, OS, DOR, Disease Control Rate (DCR), and 
Patient-Reported Outcome (PRO). 
• PFS is defined as the time from first study drug administration to first occurrence of 
disease progression (per RECIST 1.1) or death, whichever occurs first. If a subject does 
not experience PD or death, PFS will be censored at the day of the last adequate tumor 
assessment.  
• OS is defined as the time from first study drug administration to death from any cause. 
For subjects who are alive at the time of analysis data cutoff, OS will be censored at the 
last date the subject was known to be alive. Survival time for subjects with no 
post-baseline survival information will be censored on the date of first study drug 
administration. 
• DOR is defined as from the first occurrence of a documented, objective response until the 
time of disease progression or death from any cause. This will be calculated only for 
responders. In the absence of confirmation of death or progressive disease, duration of 
response will be censored at the last adequate disease assessment date. 

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• DCR is defined as the percentage of subjects who achieve either CR or PR or SD, as 
assessed by the investigator per RECIST 1.1.  
• DCR (90) is defined as 90 days from the time of first study drug administration.  
• DCR (180) is defined as the absence of disease progression and/or death in 180 days 
from the time of first study drug administration.  
 
Distribution of the time-to-event endpoints (OS, PFS, DOR) will be summarized 
descriptively and plotted as Kaplan-Meier curves. Median time and its 95% confidence 
intervals will be presented.  
The categorical response (DCR) will be summarized as percentage with 95% confidence 
intervals. 
Descriptive summary statistics for PRO EORTC QLQ-C30 questionnaires and changes from 
baseline will be presented by visit.  
Time to Deterioration (TTD), defined as more than 10 points decreases from baseline in 
QLQ-C30 questionnaires, will be summarized descriptively.  
9.6 
Exploratory Endpoints 
PK and biomarker endpoints will be summarized.   
9.6.1 
Pharmacokinetic Analyses 
Vofatamab Ctrough levels will be summarized over time throughout the study and will be 
compared to predicted exposure-based levels from data observed in previous studies with 
vofatamab. The vofatamab Ctrough levels will also be compared to historical data to ensure 
that the co- administration of pembrolizumab has no impact on vofatamab pharmacokinetics. 
9.6.2 
Immunogenicity Analyses 
The incidence of ATAs to vofatamab will be summarized. The possible effects of ATA on 
pharmacokinetics, efficacy and safety may be explored.  

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10 
ETHICAL AND REGULATORY CONSIDERATIONS 
This study will be conducted in accordance with the Protocol; ICH Guidance E6 (R1); 
FDA CFR [21 CFR Parts 50, 56, 312]); Declaration of Helsinki World Medical Association 
Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, 
as it may be amended; applicable data protection laws and regulations; and all laws, rules and 
regulations applicable to the study or the study drug in jurisdictions in which the Investigator 
conducts the study. 
10.1 
Informed Consent 
Appropriate forms for documenting written informed consent will be provided by the 
investigator, and reviewed and approved by the Sponsor or its designee before submission to 
the IRB/IEC. The Sponsor or its designee must receive a copy of the IRB’s approval of the 
Informed Consent Form (ICF) before the shipment of Investigational Product to the study 
site. 
It is the investigator's responsibility to obtain signed written informed consent from each 
potential study subject prior to the conduct of any study procedures. This written informed 
consent will be obtained after the methods, objectives, requirements, and potential risks of 
the study have been fully explained to each potential subject. The investigator must explain 
to each subject that the subject is completely free to refuse to enter the study or to withdraw 
from it at any time. 
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of 
Human Subjects,” the HIPAA regulations, and all other applicable regulatory requirements. 
Subjects will be given a copy of the signed ICF and will be provided any new information 
during the course of the study that might affect their continued participation in the study. 
The investigator or a qualified designee will be available to answer each subject's questions 
throughout the study, and all of the subject's questions must be answered to the subject's 
satisfaction. If the protocol is amended and the ICF is revised, each subject will be required 
to provide written informed consent again using the revised ICF. 
Receipt of written informed consent will be documented in each potential subject’s CRF. 
The signed ICF will remain in each subject's study file and must be available to the study 
monitor(s) at all times. 
10.2 
Confidentiality of Personal Subject Information 
The investigator must ensure that each subject’s anonymity is maintained as described below. 
On the CRFs or other documents submitted to the Sponsor, subjects must be identified by no 
more than their initials, date of birth, and a subject number. Signed ICFs and other 
documents should be kept in strict confidence by the investigator in compliance with 
applicable regulations and ICH GCP Guidelines. As described in Section 8.3, the investigator 
and institution must permit authorized representatives of the Sponsor, of regulatory agencies, 
and the IRB direct access to review the subject’s original medical records for verification of 
study-related procedures and data. Direct access includes examining, analyzing, verifying, 

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and reproducing any records and reports that are needed for the evaluation of the study. 
The investigator is obligated to inform the subject in the ICF that the above named 
representatives may review study-related records from subjects. 
10.3 
Biospecimens  
Clinical samples donated by subjects in the study (blood, urine, tissue, etc.) comprise study 
results of the Sponsor and will be collected and processed in accordance with this protocol 
and delivered to the Sponsor or Sponsor’s designee, as instructed by the Sponsor. Clinical 
samples shall not be retained or used by the Investigator or institution except as expressly 
permitted by the Sponsor in writing. The ICF will contain information on the treatment of 
subject personal information relating to clinical samples including, if applicable, the labeling 
of clinical samples  
10.4 
Ethical Conduct of the Study 
This protocol is written in accordance with the principles established by the 18th World 
Medical Assembly General Assembly (Helsinki, 1964) and subsequent amendments and 
clarifications adopted by the General Assemblies. The investigator will make every effort 
that the study described in this protocol is conducted in full conformance with those 
principles, current FDA regulations, ICH GCP guidelines, and local ethical and regulatory 
requirements. Should a conflict arise, the investigator will follow whichever law or guideline 
affords the greater protection to the individual subject. The investigator will also make sure 
he or she is thoroughly familiar with the appropriate administration and potential risks of 
administration of the Investigational Product, as described in this protocol and the 
Investigator's Brochure, prior to the initiation of the study. 
10.5 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
This protocol, any protocol amendments, the associated informed consent forms, and the 
informed consent procedures must be submitted to the IRB/IEC for review and must be 
approved before the enrollment of any subject into the study. Investigational Product may not 
be shipped to the investigator until the Sponsor or its designee has received a copy of the 
letter or certificate of approval from the IRB for the protocol and any protocol amendments, 
as applicable. 
All subject recruitment and/or advertising information must be submitted to the IRB/IEC and 
the Sponsor or its designee for review and approval prior to implementation. IRB/IEC 
approval of any protocol amendments must be received before any of the changes outlined in 
the amendments are put into effect, except when the amendment has been enacted to protect 
subject safety. In such cases, the chair of the IRB/IEC should be notified immediately and the 
amendment forwarded to the IRB/IEC for review and approval. 
10.6 
Regulatory Requirements 
This study will be submitted to the local regulatory authority for approval or notification 
whichever is applicable. The study will only be undertaken in compliance with the local 
regulatory requirements. 

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In accordance with Directive 2001/20/EC, the Sponsor will notify the relevant (European) 
regulatory authority(ies) and IRBs/ECs within 90 days of the end of the study. If the study 
terminates early, the Sponsor will notify the relevant (European) regulatory authority(ies) and 
IRBs/ECs within 15 days and will provide the reasons for early termination. 
Safety updates for vofatamab will be prepared by the Sponsor as required, for submission to 
the relevant regulatory authority(ies). 
10.7 
Investigators and Administrative Structure 
Each investigator must provide the Sponsor and/or its designee a completed and signed Form 
FDA 1572 and a Financial Disclosure Form. All sub-investigators must be listed on Form 
FDA 1572 and Financial Disclosure Forms must be completed for all sub-investigators listed 
on Form FDA 1572. 
The Sponsor and/or its designee will be responsible for managing and monitoring the clinical 
study to ensure compliance with FDA and ICH GCP guidelines. A trained designated 
representative (the monitor) will conduct regular visits to the clinical site, to perform SDV. 
The monitor will verify the investigator's ongoing qualifications, to inspect clinical site 
facilities, and to inspect study records, including proof of IRB review, with the stipulation 
that subject confidentiality will be maintained in accordance with local and federal 
regulations, including HIPAA requirements.  
10.8 
Protocol Amendments and Study Termination 
Any changes to the study, which arise after approval of the protocol, must be documented as 
protocol amendments. Protocol amendments that are deemed substantial (e.g. affecting the 
safety of the subject, the scope of the study and/or the scientific quality) will be submitted to 
regulatory authorities and/or to the IEC/IRB as appropriate. For substantial amendment, the 
changes will become effective only after approval by the Sponsor, the responsible 
Investigator, IEC/IRB and competent authorities. All other amendments (i.e. non-substantial 
or administrative amendments) will be documented in the Trial Master File (TMF). 
The Investigator may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to study subjects without prior IRB/IEC approval/favorable opinion. 
As soon as possible, the implemented deviation or change, the reasons for it, and, if 
appropriate, the proposed protocol amendment(s) should be submitted to the following: 
• IRB/IEC for review and approval/favorable opinion 
• Sponsor for agreement  
• Regulatory authority(ies), if required 
 

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10.9 
Clinical Study Report 
At the conclusion of the study (but within 1 year after study closure), when the data are 
analyzed, the Sponsor will prepare an integrated Clinical Study Report in compliance with 
ICH E3. A draft copy of the report will be available for review by the coordinating 
investigator. The final version will be signed by the Sponsor and the coordinating 
investigator. 
At the conclusion of the study (but within 1 year after study closure), when the data are 
analyzed, the Sponsor will also post the study results on the European database referred 
(EudraCT) per Article 11(1) of Directive 2001/20/EC. 
10.10 
Disclosure of Source Data and Documents 
Subject medical information obtained by this study is confidential and may only be disclosed 
to third parties as permitted by the Informed Consent Form (or separate authorization to use 
and disclose personal health information) signed by the subject or unless permitted or 
required by law. 
Medical information may be given to a subject’s personal physician or other appropriate 
medical personnel responsible for the subject’s welfare for treatment purposes. 
Source data/documents generated by this study must be available for inspection upon request 
by representatives of the FDA and other regulatory agencies, national and local health 
authorities, Sponsor monitors/representatives and collaborators, and the IRB for each study 
site, if appropriate. 
10.11 
Publication Policy 
The investigator shall not prepare and/or submit any manuscripts or slide shows based on the 
Sponsor data for publication or oral presentation prior to the publication of the primary 
manuscript of the study. The Sponsor shall acknowledge the investigator’s contribution to the 
study in any Sponsor publications regarding the study. 
The Sponsor shall comply with the requirements for publication of study results and 
determination of authorship in accordance with standard editorial and ethical practice and 
with the International Committee of Medical Journal Editors (ICMJE) requirements. 

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11 
REFERENCES 
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Care Compared With Best Supportive Care Alone After a Platinum-Containing Regimen in 
Patients With Advanced Transitional Cell Carcinoma of the Urothelial Tract. J Clin Oncol. 
2009;27(27):4454-61. 
Bellmunt J, de Wit R, Vaugh DJ, et al. Pembrolizumab as Second-Line Therapy for 
Advanced Urothelial Carcinoma. N Engl J Med 2017; 376:1015-26. 
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of 
urothelial bladder carcinoma. Nature. 2014;507(7492):315-22.  
Carneiro V, Chin JL, Izawa JI, et al. Emerging therapeutic targets in bladder cancer. Cancer 
Treat Review 2014;70-78. 
Choi W, Czerniak B, Ochoa A, et al. Intrinsic basal and luminal subtypes of muscle-invasive 
bladder cancer. Nat Rev Urol. 2014;11(7):400-10. 
Costantini C and Millard F. Update on Chemotherapy in the Treatment of Urothelial 
Carcinoma. The Scientific World Journal. 2011;11:1981–94. 
Eble JNSG, Epstein JI, Sesterhenn IA. World Health Organization: Classification of 
Tumours, Pathology, and Genetics of Tumours of the Urinary System and Male Genital 
Organs, IARC Press, Lyon, France, 2004. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). EJC. 2009;45(2):228-47. 
Gómez-Román JJ, Saenz P, Cuevas González J, et al. Fibroblast growth factor receptor 3 is 
overexpressed in urinary tract carcinomas and modulates the neoplastic cell growth. Clin 
Cancer Res. 2005;11(2Pt1):459-65. 
Gust KM, McConkey DJ, Awrey S, et al. Fibroblast Growth Factor Receptor 3 is a Rational 
Therapeutic Target in Bladder Cancer. Mol Cancer Ther. 2013;12(7):1245–4. 
Jemal A, Bray F, Center MM, et al. Global Center Statistics. CA Cancer J Clin. 
2011;61(2):69-90.  
Lamont FR, Tomlinson DC, Cooper PA, et al. Small molecule FGF receptor inhibitors block 
FGFR-dependent urothelial carcinoma growth in vitro and in vivo. Br J Cancer. 
2011;104(1):75-82. 
Martínez-Torrecuadrada J, Cifuentes G, López-Serra Pet al. Targeting the extracellular 
domain of fibroblast growth factor receptor 3 with human single-chain Fv antibodies inhibits 
bladder carcinoma cell line proliferation. Clin Cancer Res. 2005;11(17):6280-90. 

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McConkey D, Choi W, Shen Y, et al: A Prognostic Gene Expression Signature in the 
Molecular Classification of Chemotherapy-naive Urothelial Cancer is Predictive of Clinical 
Outcomes from Neoadjuvant Chemotherapy: A Phase 2 Trial of Dose-dense Methotrexate, 
Vinblastine, Doxorubicin, and Cisplatin with Bevacizumab in Urothelial Cancer. Eur Urol. 
2016;69:855-862. 
Nassar AH,  Lundgren K, Kim J, et al: Sequential Response to FGFR3 Inhibition With 
Subsequent Exceptional Response to Atezolizumab in a Patient With FGFR3-
TACC3 Fusion–Positive Metastatic Urothelial Carcinoma. JCO Precision 
Oncology 2018 :2, 1-6  
 
Oken MM, Creech RH, Tormey DC, et al: Toxicity And Response Criteria Of The Eastern 
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Qing J, Du X, Chen Y, et al. Antibody-based targeting of FGFR3 in bladder carcinoma and 
t(4; 14)-positive multiple myeloma in mice. J Clin Invest. 2009;119(5):1216-29. 
Robertson AG, Kim J, Al-Ahmadie H, et al: Comprehensive Molecular Characterization of 
Muscle-Invasive Bladder Cancer. Cell. 2017 Oct 19;171(3):540-56. 
Rosenberg J, Hoffman-Censits, J, Powles, T, et al. Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following treatment with 
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Siefker-Radtke AO, Millikan RE, Tu S-M, et al. Phase III trial of fluorouracil, interferon 
alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in 
metastatic or unresectable urothelial cancer. J Clin Oncol. 2002;20:1361-7. 
Simon R. Optimal two-stage designs for Phase II clinical trials. Control Clin Trials. 
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Protocol no. 30924. J Clin Oncol. 2001;19(10):2638-46. 
Sweis RF, Spranger S, Gajewski T., Molecular drivers of the non-T cell-inflamed tumor 
microenvironment in urothelial bladder cancer. Cancer Immunol Res. 2016;4(7):563-8. 
Thall P, Simon R, Estey E. Bayesian sequential monitoring designs for single-arm clinical 
trials with multiple outcomes. Statistics in Medicine. 1995;14(4):357-379. 
Tomlinson DC, Baldo O, Harnden P, et al. FGFR3 protein expression and its relationship to 
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Tomlinson DC, Hurst CD, Knowles MA. Knockdown by shRNA identifies S249C mutant 
FGFR3 as a potential therapeutic target in bladder cancer. Oncogene. 2007b;26(40):5889-99. 
UK MHRA. Recommendations related to contraception and pregnancy testing in clinical 
trials. Advisory non-binding guidance supported by national competent authorities 
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Vallot C, Stransky N, Bernard-Pierrot I, et al. A novel epigenetic phenotype associated with 
the most aggressive pathway of bladder tumor progression. J Natl Cancer Inst. 
2011;103(1):47-60. 
von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus 
methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder 
cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin 
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2005;5:713-25. 
http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-
042151.pdf 
 

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12 
SIGNATURE PAGE 
Protocol Title: 
A Multi-Center, Open-Label Phase 1b/2 Study of a 
Novel FGFR3 Inhibitor (B-701) Combined with 
Pembrolizumab in Subjects with Locally Advanced or 
Metastatic Urothelial Carcinoma who have Progressed 
Following Platinum-based Chemotherapy 
Protocol Number: 
B-701-U22 (FIERCE-22) 
Date of Amendment 5 (USA) 
July 01, 2019 
Date of Amendment 4.2  
Date of Amendment 4.1 
Date of Amendment 4: 
Date of Amendment 3.1 
Date of Amendment 3:  
June 20, 2019  
June 07, 2018 
May 16, 2018 
March 14, 2018 
January 05, 2018 
Date of Amendment 2: 
July 11, 2017 
Date of Amendment 1: 
December 16, 2016 
Date of Original Protocol  
October 3, 2016 
By signing below, I agree to the conditions relating to this study as set out in this protocol 
(Study B-701-U22 Protocol Amendment 5 (USA), dated July 01, 2019). I agree to conduct 
this clinical study according to the International Conference of Harmonisation Guideline on 
Good Clinical Practice (ICH GCP E6). I fully understand that any changes instituted by me 
without previous discussion with the Sponsor or their designated representative constitute a 
violation of the protocol. I agree to adhere to the protocol in all circumstances other than 
where necessary to protect the well-being of the subject. I will ensure that the study products 
supplied by Rainier will be used only for administration to subjects included in this study 
protocol and for no other purpose. 
 
 
 
Investigator Signature 
 
Date 
 
Print Name 
 
 
 
 

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Accepted by the Sponsor 
As the Sponsor representative, I confirm the Sponsor will comply with all obligations as 
detailed in all applicable regulations and guidelines. I will ensure that the Investigator is 
informed of all relevant information that becomes available during the conduct of this study.  
 
 
 
 
Steve Abella M.D. 
Chief Medical Officer  
Date 

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

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APPENDIX 2 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
VERSION 1.1 (RECIST 1.1)  
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
version 1.1 (Eisenhauer 2009) are presented below, with slight modifications and the addition 
of explanatory text as needed for clarity. 
Measurability of Tumor at Baseline 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable 
as described below. 
a. Measurable Tumor Lesions 
Tumor Lesions. Tumor 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 as 
follows: 
• 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm) 
• 10 mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as non-measurable) 
20 mm by chest X-ray. 
Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and follow-up, only the 
short axis will be measured and followed. See also notes below on “Baseline Documentation 
of Target and Non-Target Lesions” for information on lymph node measurement. 
b. Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis ≥ 10 but < 15 mm), as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, and abdominal mass/abdominal organomegaly identified by physical 
examination that is not measurable by reproducible imaging techniques. 
c. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 

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• Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions. However, these techniques can 
be used to confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT or 
MRI can be considered 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 definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions. 
Lesions with Prior Local Treatment: 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.  
Target Lesions: Specifications by Methods of Measurements 
a. 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. 
b. Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during the study. Imaging-based evaluation 
should always be the preferred option. 
Clinical Lesions. Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules). For the 
case of skin lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is suggested. 
Chest X-Ray. Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 

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lesions. However, lesions on a chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
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. When CT scans have 
slice thicknesses greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable. If prior to enrollment it is known that a 
subject is unable to undergo CT scans with intravenous (IV) contrast because of allergy or 
renal insufficiency, the decision as to whether a non-contrast CT or MRI (without IV 
contrast) will be used to evaluate the subject at baseline and during the study should be 
guided by the tumor type under investigation and the anatomic location of the disease. For 
subjects who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be 
performed should also be based on the tumor type and the anatomic location of the disease 
and should be optimized to allow for comparison with 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 subject 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.  
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology. The utilization of these 
techniques for objective tumor evaluation cannot generally be advised. 
Tumor Response Evaluation 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. 
Measurable disease is defined by the presence of at least one measurable lesion, as detailed 
above. 
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 maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline. 
This means that, for instances in which subjects have only one or two organ sites involved, a 
maximum of two lesions (one site) and four lesions (two sites), respectively, will be 
recorded. Other lesions (albeit measurable) in those organs will be recorded as non-
measurable lesions (even if the size is > 10 mm by CT scan). 

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Target lesions should be selected based on their size (lesions with the longest diameter) and 
be representative of all involved organs, but in addition, should lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement, in which circumstance, the next largest 
lesion that can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor. As noted above, pathological nodes that 
are defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥ 15 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 tumor. Nodal size is normally reported as two dimensions 
in the plane in which the image is obtained (for CT, this is almost always the axial plane; for 
MRI, the plane of acquisition may be axial, sagittal, or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node that 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. All other pathological nodes 
(those with short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes 
that have a short axis of < 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 of 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 of diameters will be used as a reference to further characterize any 
objective tumor 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 required and these lesions should be followed as “present,” “absent,” or in rare cases 
“unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the same organ as a 
single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”). 
Response Criteria 
a.  Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for 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. 

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• Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of diameters 
• Progressive disease (PD): at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. 
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 on study 
b. 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 (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to < 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 CR criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. 
Target Lesions that Become Too Small to Measure. During the study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or 
lymph nodes that 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 
CRF as follows: 
• 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 and below measurable limit (BML) should be 
ticked. (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 default value of 5 mm should be assigned in this 
circumstance as well and BML should also be ticked.) 
 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm, and in that case, BML should not be ticked. 
Lesions that Split or Coalesce on Treatment. When non-nodal lesions fragment, the 
longest diameters 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 

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would aid in obtaining maximal diameter measurements of each individual 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 maximum longest diameter for the coalesced lesion. 
c. Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor 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. 
• CR: disappearance of all non-target lesions and (if applicable) normalization of tumor 
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 lesions and/or (if applicable) 
maintenance of tumor marker level above the normal limits 
• PD: unequivocal progression of existing non-target lesions. The appearance of one or 
more new lesions is also considered progression. 
d. Special Notes on Assessment of Progression of Non-Target Disease  
When the Subject 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 
substantial worsening in non-target disease in a magnitude that, even in the presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest increase in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. The designation of 
overall progression solely based on change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare. 
When the Subject Has Only Non-Measurable Disease. This circumstance arises in some 
Phase III studies when it is not a criterion of study entry to have measurable disease. The 
same general concepts apply here as noted above; however, in this instance, there is no 
measurable disease assessment to factor into the interpretation 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-measurable), a useful test that can be 
applied when assessing subjects 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 be required to declare PD for measurable disease, that 
is, an increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion). Examples include an 
increase in a pleural effusion from “trace” to “large” or an increase in lymphangitic disease 
from localized to widespread or may be described in protocols as “sufficient to require a 
change in therapy.” If unequivocal progression is seen, the subject should be considered to 
have had overall PD at that point. While it would be ideal to have objective criteria apply to 

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non-measurable disease, the very nature of that disease makes it impossible to do so; 
therefore, the increase must be substantial. 
e. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, that is, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (for example, some 
“new” bone lesions may be simply healing or flare of preexisting lesions). This is particularly 
important when the subject’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 during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
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 confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 
Evaluation of Response 
a. Time Point Response (Overall Response) 
It is assumed that at each protocol-specified time point, a response assessment occurs. 
Table 6 provides a summary of the overall response status calculation at each time point for 
subjects who have measurable disease at baseline. When subjects have non-measurable 
(therefore non-target) disease only, Table 7 is to be used. 
Table 6 
Time Point Response: Subjects with Target Disease (With or Without 
Non-Target Lesions) 
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; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease. 

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Table 7 
Time Point Response: Subjects with Non-Target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a 
“Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable disease is 
increasingly used as an endpoint for assessment of efficacy in some studies; thus, assigning “stable disease” 
when no lesions can be measured is not advised. 
 
b. Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable at that time point. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered not evaluable 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 subject had a baseline sum of 50 mm with three measured 
lesions, and during the study, only two lesions were assessed but those gave a sum of 80 mm, 
the subject will have achieved PD status, regardless of the contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done or the 
scan could not be assessed because of poor image quality or obstructed view, the response for 
target lesions should be “unable to assess” since the subject is not evaluable. Similarly, if one 
or more non-target lesions are not assessed, the response for non-target lesions should be 
“unable to assess” except where there is clear progression. Overall response would be 
“unable to assess,” if either the target response or the non-target response is “unable to 
assess” except where this is clear evidence of progression, as this equates with the case being 
not evaluable at that time point. 
c. Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject is known. 
Best response determination in studies where confirmation of complete or partial response IS 
NOT required: Best response in these trials is defined as the best response across all time 
points (for example, a subject who has SD at first assessment, PR at second 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 otherwise the best time point response, the patient’s 
best response depends on the subsequent assessments. For example, a subject 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 subject lost to follow-up after the first SD assessment would be 
considered unevaluable at a subsequent time point as specified in the protocol (generally 

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4 weeks later). In this circumstance, the best overall response can be interpreted as in 
Table 8. 
Table 8 
Best Overall Response when Confirmation of CR and PR Required 
Overall Response 
First Time Point 
Overall Response 
Subsequent Time 
Point 
Best Overall Response 
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; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease. 
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. 
 
d. Special Notes of 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 
measurement 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 subjects with CR may not have a total sum of “zero” on the CRF. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response; it is a reason for stopping study therapy. The objective response status of 
such subjects is to be determined by evaluation of target and non-target disease. 

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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. 
In studies for which subjects with advanced disease are eligible (i.e., primary disease still or 
partially present), the primary tumor should also be captured as a target or non-target lesion, 
as appropriate. This is to avoid an incorrect assessment of CR if the primary tumor is still 
present but not evaluated as a target or non-target lesion. 

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APPENDIX 3 
ANAPHYLAXIS PRECAUTIONS AND PROCEDURES 
The following equipment is needed in the event of a suspected anaphylactic reaction during 
study drug infusion: 
• Tourniquet 
• Oxygen 
• Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance with 
standard practice as needed 
• Antihistamines 
• Corticosteroids 
• Intravenous infusion solutions, tubing, catheters, and tape. 
 
The following are the procedures to follow in the event of a suspected anaphylactic reaction 
during study drug infusion: 
1. Stop the study drug infusion. 
2. Apply a tourniquet proximal to the injection site to slow systemic absorption of 
study drug. Do not obstruct arterial flow in the limb. 
3. Maintain an adequate airway. 
4. Administer antihistamines, epinephrine, or other medications, as required by subject 
status and directed by the physician in charge. 
5. Continue to observe the subject and document observations. 
 

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APPENDIX 4 
INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
The following methods of contraception can achieve a failure rate of less than 1% per year 
when used consistently and correctly, and are considered highly effective birth control 
methods: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation1 
o oral 
o intravaginal 
o transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1 
o oral 
o injectable 
o implantable2 
• Intrauterine device (IUD)2 
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2 
• Vasectomized partner2,3 
• Sexual abstinence4 
Source:  CTFG 2014.