Clinical trial NCT02639182
Conditions: Metastatic Renal Cell Carcinoma
Keywords: Axitinib Metastatic Renal Cell Carcinoma AGS-16C3F
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2016-05-03; Completion date: 2020-10-02
Enrollment: 133 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the progression free survival (PFS), based on investigator radiologic review, of AGS-16C3F compared to axitinib in subjects with metastatic renal cell carcinoma.

Detailed description:

Arms: arm 1: Participants received 1.8 milligram per kilogram (mg/kg) of AGS-16C3F once every three weeks by single intravenous (IV) infusion. arm 2: Participants received 2 to 10 milligram (mg) of axitinib twice daily by oral administration as defined in the product label and per local institutional guidelines.
Interventions: intervention 1: AGS-16C3F intervention 2: Axitinib
Intervention descriptions: intervention 1: Intravenous (IV) infusion intervention 2: Oral

Protocol documents:
Prot_002.pdf: 
Sponsor: APGD
ISN/Protocol AGS16C3F-15-3
- CONFIDENTIAL -
12 Aug 2020
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A Multi-center, Open Label, Randomized Phase 2 Study of 
AGS-16C3F vs. Axitinib in Metastatic Renal Cell Carcinoma 
ISN/Protocol AGS-16C3F-15-3
Version 6.0
Incorporating Substantial Amendment 5
12 August 2020
IND 113865
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History:
Version 1.0: 16 Sep 2015
Version 2.0: 22 Jan 2016 (Amendment 1)
Version 3.0: 27 May 2016 (Amendment 2)
Version 4.0: 18 Jul 2017 (Amendment 3)
Version 5.0: 09 Feb 2018 (Amendment 4)
--------------------------------------------------------------------------------------------------------------------------------------
This confidential document is the property of the Sponsor.  No unpublished information contained in this 
document may be disclosed without prior written approval of the Sponsor.  


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Table of Contents
I.
INVESTIGATOR’S SIGNATURE ····························································· 9
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················11
IV.
SYNOPSIS··························································································14
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································28
VI.
PK SAMPLING COLLECTION SCHEMA ·················································32
1
INTRODUCTION·················································································33
1.1
Background ····················································································33
Disease····················································································33
Agensys Antibody Drug Conjugate against Renal Cell Carcinoma···············33
ENPP3 Antigen Target and Expression in Cancer ··································33
1.2
Non-clinical and Clinical Data ······························································34
Antibody Drug Conjugate AGS-16C3F Non-clinical Pharmacology·············34
AGS-16C3F Non-clinical Toxicology and Pharmacokinetics ·····················35
Nonclinical Summary of mcMMAF ··················································36
1.3
Summary of Key Safety Information for Study Drugs ···································36
Investigational Drug - AGS-16C3F ···················································36
1.3.1.1
Development History and Background ·········································36
1.3.1.2
AGS-16C3F Phase 1 Study (Protocol AGS-16C3F-12-2)····················36
Comparator Drug - Axitinib (Inlyta®)·················································37
Class Effects ·············································································38
1.4
Risk-Benefit Assessment·····································································38
2
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS···································39
2.1
Study Objectives ··············································································39
Primary ···················································································39
Secondary ················································································39
2.2
Study Design and Dose Rationale···························································39
Study Design·············································································39
Number of Centers/World Regions ···················································41
Number of Subjects ·····································································41
Estimated Study Duration ······························································41
Dose Rationale···········································································41


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2.3
Endpoints·······················································································41
Primary Endpoints·······································································41
Secondary Endpoints····································································41
3
STUDY POPULATION··········································································42
3.1
Selection of Study Population ·······························································42
Prescreening··············································································42
3.2
Inclusion Criteria··············································································42
3.3
Exclusion Criteria ·············································································44
4
TREATMENT(S)··················································································46
4.1
Identification of Investigational Product(s) ················································46
Investigational Drug – AGS-16C3F···················································46
Comparator Drug – Axitinib (Inlyta®) ················································46
4.2
Packaging and Labeling ······································································47
4.3
Study Drug Handling ·········································································47
4.4
Assignment and Allocation ··································································48
5
TREATMENTS AND EVALUATION························································49
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················49
Dose/Dose Regimen and Administration Period ····································49
5.1.1.1
AGS-16C3F ········································································49
5.1.1.1.1
AGS-16C3F Infusion Related Adverse Events·····························49
5.1.1.1.2
AGS-16C3F Infusion Related Adverse Event Treatment Guidelines ···49
5.1.1.2
Axitinib ·············································································50
5.1.1.3
Treatment Hiatus···································································50
Increase or Reduction in Dose of the Study Drug(s)································51
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································51
5.1.3.1
Prophylactic Steroid Eye Drop Use (AGS-16C3F Subjects Only) ··········51
5.1.3.2
Prohibited Concomitant Medications ···········································52
5.1.3.2.1
Subjects Randomized to AGS-16C3F·······································52
5.1.3.2.2
Subjects Randomized to Axitinib ············································53
Treatment Compliance··································································54
5.1.4.1
AGS-16C3F ········································································54
5.1.4.2
Axitinib ·············································································54
5.2
Study Assessments and Procedures·························································54


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Tissue for Target Expression IHC Testing ···········································54
Prescreening Period ·····································································55
Screening Period·········································································55
Enrollment················································································56
Randomization···········································································56
Treatment Period ········································································56
5.2.6.1
Cycles 1 – 4 ········································································56
5.2.6.2
Cycles 5 and Beyond······························································57
Post-treatment Follow-Up Period (Safety Follow-Up visit)························58
5.3
Demographics and Baseline Characteristics ···············································58
Demographics············································································58
Medical History··········································································59
Diagnosis of the Target Disease, Severity, and Duration of Disease··············59
5.4
Pharmacokinetics Assessment·······························································59
5.5
Efficacy Assessment··········································································59
Evaluation of Target Lesions ··························································60
5.5.1.1
Complete Response (CR)·························································60
5.5.1.2
Partial Response (PR) ·····························································60
5.5.1.3
Stable Disease (SD) ·······························································60
5.5.1.4
Progressive Disease (PD)·························································61
Evaluation of Nontarget Lesions ······················································61
5.5.2.1
Complete Response (CR)·························································61
5.5.2.2
NonCR/NonPD ····································································61
5.5.2.3
Progressive Disease (PD)·························································61
Evaluation of Time Point Response···················································61
5.6
Safety Assessment ············································································61
Vital Signs················································································61
Adverse Events ··········································································61
5.6.2.1
Adverse Events Requiring Treatment Modifications and/or 
Discontinuation of AGS-16C3F Administration·······························62
5.6.2.1.1
Thrombocytopenia·····························································62
5.6.2.1.2
Adverse Events of Possible Hepatic Origin·································63
5.6.2.1.3
Other Adverse Events ·························································63
Laboratory Assessments································································63
5.6.3.1
Pharmacokinetic and ADA samples·············································63


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Electrocardiogram (ECG) ······························································63
Ocular Assessments·····································································64
5.6.5.1
Symptom Based Ocular AEs ·····················································64
5.6.5.2
Clinical Ocular Adverse Events (AE)···········································65
5.6.5.2.1
Treatment Guidelines for Clinical Ocular Toxicities······················66
5.6.5.2.2
Ophthalmology Findings······················································68
5.7
Adverse Events and Other Safety Aspects ·················································68
Definition of Adverse Events (AEs) ··················································68
Definition of Serious Adverse Events (SAEs) ·······································69
Criteria for Causal Relationship to the Study Drug ·································70
Criteria for Defining the Severity of an Adverse Event ····························70
5.7.4.1
Study Specific Ocular Toxicity Grading Criteria ······························70
Reporting Procedures for All Serious Adverse Events (SAEs) ····················70
Follow-up of Adverse Events··························································72
Monitoring of Common Serious Adverse Events ···································72
Procedure in Case of Pregnancy·······················································72
Emergency Procedures and Management of Overdose ·····························73
Supply of New Information Affecting the Conduct of the Study··················73
5.8
Test Drug Concentration ·····································································73
5.9
Total Amount of Blood·······································································73
6
DISCONTINUATION············································································73
6.1
Discontinuation of Individual Subject(s)···················································73
6.2
Discontinuation of the Site···································································74
6.3
Discontinuation of the Study·································································74
7
STATISTICAL METHODOLOGY ···························································74
7.1
Sample Size····················································································75
7.2
Analysis Set····················································································75
Full Analysis Set (FAS) ································································75
Per Protocol Set (PPS) ··································································75
Safety Analysis Set (SAF)······························································76
Pharmacokinetic Analysis Set (PKAS): AGS-16C3F Only························76
Pharmacodynamic Analysis Set (PDAS) ·············································76
7.3
Demographics and Other Baseline Characteristics········································76
Demographics············································································76


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Medical History··········································································76
Disease History ··········································································76
Previous and Concomitant Medications ··············································76
7.4
Analysis of Efficacy ··········································································76
Analysis of Primary Endpoint ·························································77
7.4.1.1
Primary Analysis···································································77
7.4.1.2
Secondary Analysis································································78
7.4.1.3
Subgroup Analysis·································································78
Analysis of Secondary Endpoints ·····················································79
Analysis of Exploratory Endpoints····················································80
7.5
Analysis of Safety·············································································80
Adverse Events ··········································································80
Laboratory Assessments································································80
Vital Signs················································································80
Physical Examination ···································································80
Electrocardiograms······································································80
7.6
Analysis of Pharmacokinetics ·······························································80
Concentration-Response Relationship Analysis ·····································81
7.7
Protocol Deviations and Other Analyses···················································81
7.8
Independent Data-Monitoring Committee Oversight·····································81
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········81
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················81
8.1
Procedure for Clinical Study Quality Control ·············································81
Data Collection ··········································································81
Specification of Source Documents···················································82
Clinical Study Monitoring······························································82
Direct Access to Source Data/Documents············································83
Data Management ·······································································83
Protocol Deviations ·····································································83
End of Trial in All Participating Countries···········································84
8.2
Ethics and Protection of Subject Confidentiality··········································84
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/ 
Competent Authorities (CA) ···························································84
Ethical Conduct of the Study···························································84


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Informed Consent of Subjects ·························································85
8.2.3.1
Subject Information and Consent················································85
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························85
Subject Confidentiality ·································································85
8.3
Administrative Matters ·······································································86
Arrangement for Use of Information and Publication of the Clinical Study ·····86
Documents and Records Related to the Clinical Study ·····························86
Protocol Amendment and/or Revision················································87
Insurance of Subjects and Others······················································87
Signatory Investigator for Clinical Study Report····································87
9
QUALITY ASSURANCE········································································88
10
STUDY ORGANIZATION······································································88
10.1
Independent Data-Monitoring Committee ·················································88
10.2
Other Study Organization ····································································88
11
REFERENCES ····················································································89
12
APPENDICES ·····················································································92
12.1
List of Excluded Concomitant Medications················································92
12.2
Liver Safety Monitoring and Assessment ··················································94
12.3
Common Serious Adverse Events···························································97
12.4
Blood Sample Requirements·································································98
12.5
ECOG Performance Status································································· 100
12.6
Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1 ······················ 101
13
ATTACHMENT 1:   SUBSTANTIAL AMENDMENT 5 ······························· 103
14
SPONSOR’S SIGNATURES·································································· 115


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List of Tables
Table 1
Schedule of Assessments·····································································29
Table 2
AGS-16C3F PK Sampling Time Points····················································32
Table 3
Stratification Categories for Randomization Process ·····································48
Table 4
Recommended Guidelines for Infusion Related Adverse Event·························50
Table 5
Sample Schedule for Prophylactic Steroid Eye Drop·····································52
Table 6
Prohibited Medications for Subjects Randomized to AGS-16C3F······················53
Table 7
Prohibited Medications for Subjects Randomized to Axitinib···························53
Table 8
Medications/Food to be Avoided or Used with Caution for Subjects 
Randomized to Axitinib ······································································53
Table 9
Recommended Guidelines for Thrombocytopenia········································62
Table 10
Subject Reported Symptom Based Ocular AE (i.e., per CTCAE v4.03) ···············65
Table 11
Examples of Clinical Ocular AE: Keratopathy············································66
Table 12
Visual Acuity Grading Chart ································································67
Table 13
Date of Progression or Censoring for PFS ·················································78
List of Figures
Figure 1
Flow Chart ·····················································································28


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I.
INVESTIGATOR’S SIGNATURE
Protocol AGS-16C3F-15-3
A Multi-center, Open Label, Randomized Phase 2 Study of AGS-16C3F vs. Axitinib in 
Metastatic Renal Cell Carcinoma 
Version 6.0 Incorporating Substantial Amendment 5
12 August 2020
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree 
to conduct the study as outlined in the protocol and to comply with all the terms and 
conditions set out therein. I confirm that I will conduct the study in accordance with ICH 
GCP guidelines and applicable local regulations. I will also ensure that sub-investigator(s) 
and other relevant members of my staff have access to copies of this protocol and the ICH 
GCP guidelines to enable them to work in accordance with the provisions of these 
documents.
Principal Investigator:
Signature:
Printed Name:
Date (DD Mmm YYYY)
Address:


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II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL
24h-Contact for Serious 
Adverse Events (SAEs)
See Section 5.7.5
24h Quintiles Medical Emergency Contact Center:
1-973-659-6677
1-570-819-8565
Please fax the SAE Worksheet to:
Astellas Pharma Global Development, Inc. 
Medical Safety Pharmacovigilance 
Fax number: 1-888-396-3750
Email: Safety-US@astellas.com
Clinical Research Contacts
, Medical and Development
Medical Monitor/Medical 
Expert:
PPD
PPD
PPD


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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
Abbreviations
Description of abbreviations
ADA
Anti-drug Antibody
ADC
Antibody drug conjugate
AE
Adverse event
AGS-16C3F
Antibody Drug Conjugate derived from CHO cell line
AGS-16M8F
Antibody Drug Conjugate derived from hybridoma cell line
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (GPT)
ANC
Absolute Neutrophil Count
aPTT
Activated  partial thromboplastin time
AST
Aspartate aminotransferase (GOT)
ATP
Adenosine Triphosphate
AUC
Area under the concentration-time curve
BCVA
Best corrected visual acuity
BUN
Blood urea nitrogen
C1D1
Cycle 1 Day 1
CBC
Complete blood count
ccRCC
Clear cell renal cell carcinoma
CEOI
Concentration at the end of infusion
CHO
Chinese hamster ovary
CI
Confidence interval
Cmax
Maximum concentration
CR
Complete response
CRO
Contract Research Organization
CRP
C-Reactive protein
CT
Computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
Cys-mcMMAF
Active metabolite resulting from the catabolism of AGS-16C3F
DILI
Drug-induced Liver Injury
DLT
Dose limiting toxicity
DVT
Deep Venous (Vein) Thrombosis
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
ENPP
ectonucleotide phosphodiesterases-pyrophosphatase
EOI
End of infusion
EOM
Extraocular movement
ESQ
Eye Symptom Questionnaire
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
ICF
Informed Consent form
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use


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Abbreviations
Description of abbreviations
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemical
IND
Investigational New Drug application
INR
International normalized ratio
IOP
Intraocular pressure
IRB
Institutional Review Board
IRT
Interactive response technology
IV
Intravenous
LA-CRF
Liver Abnormality Case Report form
LDH
Lactate dehydrogenase
LFT
Liver function tests
mAb
Monoclonal Antibody
MedDRA
Medical Dictionary for Regulatory Activities
MMAF
Monomethyl auristatin F
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
mTOR
Mammalian target of rapamycin
NOAEL
No Observed Adverse Effect Level
PD
Progressive Disease
PE
Pulmonary Embolism
PFS
Progression Free Survival
PK
Pharmacokinetics
PKAS
Pharmacokinetic analysis set
PPS
Per protocol set
PR
Partial response
PRN
as needed
PT
Prothrombin time
REB
Research Ethics Board
RECIST
Response Evaluation Criteria in Solid Tumors
RCC
Renal cell carcinoma
SAE
Serious adverse event
SPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SUSAR
Suspected unexpected serious adverse reaction
t 1/2
Apparent terminal elimination half-life
TBL
Total bilirubin
TEAE
Treatment Emergent Adverse Event
TK
Toxicokinetic
tmax
Time after dosing when Cmax occurs
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
uPCR
Urine protein to creatinine ratio
VA
Visual acuity
VEGF
Vascular endothelial growth factor
VHL
von Hippel-Lindau
Vss
Volume of Distribution at Steady State


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Definition of Key Study Terms
Terms
Definition of terms
Baseline 
Observed values/findings which are regarded observed starting point for 
comparison. 
Enroll
To register or enter into a clinical trial. NOTE: For this study, a subject is 
considered enrolled once they have been randomized
Intervention
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study. (e.g., health-
related quality of life, efficacy, safety, pharmacoeconomics). 
Prescreening period
Period of time after a subject signs the prescreening consent, lasting until the 
subject signs the main consent
Randomization
The process of assigning trial subjects to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias.
Screening period
Period of time before entering the treatment period, usually from the time of  
a subject signing main consent until just before the test drug or comparative 
drug is given to a subject. 
Screening
A process of active consideration of potential subjects for enrollment in a 
trial.
Screen failure
Potential subject who did not meet one or more criteria required for 
participation in a trial.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:
12 August 2020, Version 6.0
Sponsor: Astellas Pharma Global Development Inc (APGD)
Protocol Number: AGS-16C3F-15-3
Name of Study Drug:
AGS-16C3F
Phase of Development:  
2
Title of Study:  
A Multi-center, Open Label, Randomized Phase 2 Study of AGS-16C3F vs. Axitinib in Metastatic 
Renal Cell Carcinoma
Planned Study Period: 
From 2Q2016 to 3Q2020
Study Objective(s):
Primary Objective
To evaluate the Progression Free Survival (PFS), based on investigator radiologic review, of AGS-
16C3F compared to axitinib in subjects with metastatic renal cell carcinoma (RCC)
Secondary Objectives

To evaluate the following for AGS-16C3F compared against axitinib:
o
PFS per RECIST v1.1  by blinded central radiology assessment 
o
Objective Response Rate (ORR) based on the investigator’s radiographic assessment
o
Duration of Response (DOR) based on the investigator’s radiographic assessment
o
Overall Survival (OS)
o
Disease Control Rate (DCR) based on the investigator’s radiographic assessment
o
Safety

To evaluate the pharmacokinetics of AGS-16C3F

To evaluate the incidence of antidrug antibody formation to human native antibody (AGS-16C3) 
and antibody drug conjugate (AGS-16C3F)
Planned Total Number of Study Centers and Location(s):  
Approximately 30 centers
US, Canada 
Study Population:  
Subjects with metastatic RCC of any histology, who have evidence of progression on or after the last 
regimen received: 

Clear cell histology subjects must have received at least 2 prior systemic regimens, one of which 
is an anti-VEGF agent.  

Non-clear cell histology subjects must have received at least 1 prior anti-VEGF regimen and also 
screen positive by immunohistochemical (IHC) for ENPP3
Number of Subjects to be Enrolled/Randomized:  
Approximately 134 subjects in total randomized 1:1 (the number of subjects with non-clear cell 
histology is limited to 26 total).


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Study Design Overview:  
This multi-center, open-label, randomized study will enroll subjects with metastatic RCC of all 
histologies who have evidence of progression on or after the last regimen received and have also 
received at least 2 prior systemic regimens, 1 of which is an anti-VEGF agent (clear cell subjects). 
Non-clear cell RCC is a heterogeneous group of tumors typically not driven by von Hippel-Lindau 
(VHL) gene and sensitivity to anti-VEGF treatments differ from that shown in clear cell RCC. Hence, 
subjects with non-clear cell histology are only required to have progressed on or after at least one anti-
VEGF regimen.  
Subjects with non-clear cell histology must also have ENPP3 positive IHC staining at prescreening.  
Positivity is defined as an IHC H-score ≥ 15.  Non-clear cell subjects whose tissue has an IHC H-score 
of ≥ 15 will qualify to screen for the study.  
Clear cell subjects are not required to be screened for ENPP3 to qualify the study, but subjects must 
submit tissue during the study for retrospective target expression assessment by IHC. 
Subjects will be randomized at 1:1 ratio to either AGS-16C3F or axitinib.  Randomization will be 
stratified according to Eastern Cooperative Oncology Group (ECOG) Performance Status (0 or 1), the 
number of prior systemic RCC regimens (2 or > 2) and RCC histology (clear cell or non-clear cell). 
For stratification purpose:

Non-clear cell subjects who have progressed after only one prior anti-VEGF regimen will be 
regarded the same as those clear cell subjects who have progressed after 2 prior systemic RCC 
regimens. 

Non-clear cell subjects who have progressed after > 1 prior systemic RCC regimens will be 
regarded the same as those clear cell subjects who have progressed after > 2 prior systemic RCC 
regimens. 
Stratification Categories for Randomization Process (see Table 3 below)
Prior Systemic RCC Regimen 
Stratum 
Clear Cell Subjects
Non-Clear Cell Subjects
2 
2 prior systemic RCC regimens
1 prior systemic RCC regimen
> 2
> 2 prior systemic RCC regimens
> 1 prior systemic RCC regimens
The RCC histology categorization is defined as the following:

Clear cell group:
o
Clear cell
o
Clear cell component
o
Mixed clear cell

Non-clear cell group:
o
Papillary and everything else*
* everything else: chromophobe, collecting duct, renal medullary, etc., not so common but possible 
other RCC histologies
Subjects will be eligible to continue receiving treatment on study until disease progression per RECIST 
v.1.1, unacceptable toxicity, investigator’s decision, or study withdrawal.  Subjects will also be 
discontinued from treatment if a significant non-compliance occurs (e.g., those that compromise study 
objectives or subject safety), or if a subject is lost to follow-up.
All subjects will be required to have a Safety Follow-Up visit at least 28 days (+ 7 days) after the last 
dose (Refer to Section 5.2.7).  
All subjects will be followed for survival approximately every 8 weeks from the Safety Follow-Up 
visit. This will be done by telephone, until death or study closure, whichever occurs first. A standard of 
care clinic visit can be used in lieu of a telephone call, if the subject is already coming to clinic.


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Those subjects who discontinued the study for reasons other than objective disease progression by 
RECIST v.1.1 will continue to have disease assessments every 8 weeks (± 7 days) counting from 
C1D1. This will continue until subject has radiologically confirmed progression, initiates a new 
therapy, study closure or subject dies.
The primary endpoint is PFS based on investigator assessment utilizing RECIST v.1.1.  Secondary 
endpoints include PFS per blinded central review, and DCR, ORR, DOR (each of the 3 based on 
investigator review), OS, Safety, and PK.
The study will have an Independent Data-Monitoring Committee (IDMC).
Treatment Plan:  
Subjects randomized to AGS-16C3F will be administered at 1.8 mg/kg as a single 60-minute 
intravenous (IV) infusion once every 3 weeks.  Therapy may be interrupted and/or dose adjusted in 
case of toxicity. Dose changes must be discussed with the Medical Monitor.
These subjects must also use 1% prednisolone acetate ophthalmic suspension prophylactically 
(prophylaxis steroid drops) starting from Day (-1) of each treatment cycle (Refer to Table 5 in Section 
5.1.3.1).  Prophylaxis steroid drops will be applied to both eyes, 1 drop to each eye, 6 times daily while 
awake for the first 7 days of each cycle (starting at Day [-1]), then 4 times daily while awake for an 
additional 7 days, and then stopped.  This will be repeated in each treatment cycle.  Should the 
subsequent dose be delayed, the “no prophylaxis steroid eye drop use” period will extend.  The study 
will not provide the prophylaxis steroid drops (i.e., each site to supply); but the cost will be reimbursed.
Subjects randomized to axitinib will all have a starting dose of 5 mg, administered twice daily 
continuously, by mouth. This dose may be adjusted during the study as needed, as defined in the 
product label and local institutional guidelines, in doses ranging from 2 to 10 mg, administered twice 
daily continuously, by mouth. Axitinib dose changes may be discussed with the Medical Monitor at the 
discretion of the Investigator.
For both treatment arms, subjects will have disease assessments every 8 weeks (± 7 days) counting 
from C1D1, irrespective of any treatment hiatus.

Subject may continue therapy if the disease status is at least Stable Disease (SD) per RECIST 
v.1.1. 

If the treatment hiatus will be longer than 5 weeks, each case must be discussed with the Medical 
Monitor.
Treatment Re-challenge:
The Medical Monitor must be consulted for all AGS-16C3F toxicities that may require adjustment in 
treatment schedule and/or dose. AGS-16C3F dose modifications and/or treatment schedule 
modifications must be discussed and agreed to in writing by the Medical Monitor on a case-by-case 
basis before any adjustment is made.  
In case of a therapy hiatus longer than 5 weeks, the plan for resuming therapy must be discussed with 
the Medical Monitor.
Disease Assessment:  
A disease assessment (CT or MRI) will be performed every 8 weeks (± 7 days) counting from C1D1, 
irrespective of any treatment delays. 


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Inclusion/Exclusion Criteria:  
Inclusion:  
1.
Is at least 18 years of age
2.
Histologically confirmed diagnosis of RCC
a.
Non-clear subjects must be ENPP3 positive, defined as IHC H-score ≥15
3.
Has evidence of progression on or after the last regimen received:
a.
Clear cell subject: must have received at least 2 prior systemic regimens, one of which is 
an anti-VEGF agent.  
b.
Non-clear cell subject: must have received at least one prior anti-VEGF regimen
4.
Has measurable disease according to Response Criteria for Solid Tumors (RECIST v.1.1)
5.
Has ECOG Performance Status of 0 or 1
6.
Has archive tumor tissue from primary tumor or metastatic site (excluding bone), for which the 
source and availability have been confirmed.  
a.
If no archive tissue is available, the subject may elect to have a biopsy performed to obtain 
tissue.
7.
Has adequate organ function including:
a.
Hematopoietic function as follows:
i.
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
ii.
Platelet count ≥ 100 x 109/L
iii.
Hemoglobin ≥ 9 g/dL (transfusions are allowed)
b.
Renal Function as follows:
i.
Creatinine ≤ 1.5 x ULN, or calculated GFR > 40 mL/min (Cockcroft-Gault) if 
creatinine > 1.5 x ULN
c.
Hepatic function, as follows:
i.
Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 x ULN 
or ≤ 5 x ULN if known liver metastases
ii.
Total bilirubin ≤ 1.5 x ULN
8.
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels ≤1.5 x ULN. If 
institution does not report PT value, the INR must be ≤ ULN. 
a.
If subject is receiving Coumadin (warfarin), a stable international normalization ratio 
(INR) of 2-3 is required.
9.
No clinical symptoms of hypothyroidism
10. Urine Protein to Creatinine Ratio (uPCR) < 2.0 
a.
If uPCR ≥ 2.0 then a 24-hour urine collection can be performed to qualify.  If this is 
performed to qualify, the protein result must be < 2 g per 24 hours.
11. Female subject must either:
a.
Be of non-childbearing potential:
i.
post-menopausal (defined as at least 1 year without any menses) prior to Screening, 
or 
ii.
documented surgically sterile 
b.
Or, if of childbearing potential, 
i.
Agree not to try to become pregnant during the study and for 6 months after the final 
study drug administration
ii.
And have a negative serum pregnancy test ≤ 10 days of C1D1
iii.
And, if heterosexually active, agree to consistently use 2 forms of highly effective 
birth control* (at least one of which must be a barrier method) starting at Screening 
and throughout the study period and for 6 months after the final study drug 
administration.


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12. Female subject must agree not to breastfeed starting at Screening and throughout the study period, 
and for 6 months after the final study drug administration.
13. Female subject must not donate ova starting at Screening and throughout the study period, and for 
6 months after the final study drug administration.
14. Male subject and their female spouse/partners who are of childbearing potential must be using 
highly effective contraception* consisting of 2 forms of birth control (at least one of which must be 
a barrier method) starting at Screening and continue throughout the study period, and for 6 months 
after the final study drug administration
15. Male subject must not donate sperm starting at Screening and throughout the study period and, for 
6 months after the final study drug administration
16. Is competent to comprehend, sign, and date an independent ethics committee/institutional review 
board (IEC/IRB) approved informed consent form, as evaluated and documented by the 
investigator.
Note: *Highly effective forms of birth control include:

Consistent and correct usage of established oral contraception.

Established intrauterine device (IUD) or intrauterine system (IUS).

Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
Waivers to the inclusion criteria will NOT be allowed.
Exclusion: 
1.
Has previously been treated with axitinib, AGS-16C3F, or AGS-16M8F
2.
Has untreated brain metastasis. In the case of a solitary brain metastasis which has been resected, 
there must be evidence of a disease-free interval of at least 3 months post-surgery. For brain 
metastases treated with whole brain or stereotactic radiation therapy, brain imaging must be stable 
> 3 months. All subjects previously treated for brain metastases must be stable off corticosteroid 
therapy for at least 28 days prior to C1D1.
3.
Has uncontrolled hypertension defined as blood pressure > 150/90 on medication(s) by 2 blood 
pressure readings taken at least 1 hour apart. 
4.
Has gastrointestinal abnormalities including:
a.
inability to take oral medication;
b.
requirement for intravenous alimentation;
c.
prior surgical procedures affecting absorption including total gastric resection;
d.
active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, 
hematochezia or melena in the past 3 months without evidence of resolution documented 
by endoscopy or colonoscopy;
e.
malabsorption syndromes such as celiac disease, cystic fibrosis, inflammatory bowel 
disease, systemic sclerosis, and carcinoid syndrome
5.
Has ocular conditions such as:
a.
Active infection or corneal ulcer
b.
Monocularity
c.
Visual acuity of 20/70 or worse in both eyes
d.
History of corneal transplantation
e.
Contact lens dependent (if using contact lens, must be able to switch to glasses during the 
entire study duration)
f.
Uncontrolled glaucoma (topical medications allowed)
g.
Uncontrolled or active ocular problems (e.g., retinopathy, macular edema, active uveitis, 
wet macular degeneration) requiring surgery, laser treatment, or intravitreal injections
h.
Papilledema or other active optic nerve disorder


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6.
Has used any investigational drug (including marketed drugs not approved for this indication)  
≤ 14 days of C1D1.  No time limit applies to the use of marketed drugs approved for this 
indication provided that the subject has progressed on the treatment and all toxicities attributable 
to the drug have resolved, returned to baseline or stabilized. 
7.
Has known sensitivity to any of the ingredients of:
a.
investigational product AGS-16C3F (Refer to IB for list of ingredients) and/or, 
b.
Inlyta® (axitinib) (Refer to product package insert) and/or,
c.
1% prednisolone acetate ophthalmic suspension (Refer to Product package insert) and any 
other corticosteroids.
8.
Is currently using (i.e., within 14-days prior to first dose) drugs that are known strong CYP3A4/5 
inhibitors/inducers (See Appendix 12.1 for list of excluded drugs).
9.
Thromboembolic event (e.g., DVT and PE) ≤4 weeks of C1D1. 
a.
Subjects who had a thromboembolic event ≤4 weeks of C1D1 must be receiving  adequate 
anticoagulation treatment for at least 2 weeks before C1D1 and must continue as clinically 
indicated post first dose.
10. Has history of bleeding disorders (e.g., pulmonary hemorrhage, significant hemoptysis, 
menometrorrhagia not responding to hormonal treatment) ≤ 2 months before C1D1 
11. Has active angina or Class III or IV Congestive Heart Failure (New York Heart Association CHF 
Functional Classification System) or clinically significant cardiac disease within 6 months of 
study enrollment, including myocardial infarction, unstable angina, Grade 2 or greater peripheral 
vascular disease, congestive heart failure, or arrhythmias not controlled by medication.
12. Had major surgery ≤ 4 weeks of C1D1
13. Is pregnant (confirmed by positive serum pregnancy test) or lactating
14. Has active infection requiring treatment with systemic (intravenous or oral) anti-infectives 
(antibiotic, antifungal, or antiviral agent) ≤ 10 days of C1D1
15. Is unwilling or unable to comply with study requirements
16. Has any medical or psychiatric disorder that compromises the ability of the subject to give written 
informed consent, and/or comply with the study procedures as evidenced and documented by the 
investigator.
Waivers to the exclusion criteria will NOT be allowed




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Concomitant Medication Restrictions or Requirements:   
The investigator may prescribe any medication necessary to ensure the safety and wellbeing of the 
subject during the study. Please refer to Section 5.1.3.2.  If however, the investigator determines that 
any of the following medications are necessary to provide adequate medical support to the subject, the 
subject must be withdrawn from further study drug administration. Protocol prohibited medications 
that are needed temporarily to treat an AE is permitted at investigator’s discretion (e.g., dexamethasone 
used to treat nausea).
1.
Chemotherapy, radiotherapy, immunotherapy, monocolonal antibody therapy or other medications 
intended for antitumor activity (palliative radiation is permitted provided it does not interfere with 
subject safety and efficacy of the study drug being administered. Palliative radiation cannot be 
administered to any target lesion)
2.
Investigational products or therapy other than AGS-16C3F
3.
For subjects randomized to axitinib only: Drugs that are known strong CYP3A4/5 inducers (Refer 
to Section 5.1.3.2 and Appendix 12.1 for list of excluded drugs).  
Duration of Treatment:  
Subjects will be eligible to continue receiving treatment on study until disease progression per RECIST 
v.1.1, unacceptable toxicity, investigator’s decision, or study withdrawal.  Subjects will also be 
discontinued from treatment if a significant non-compliance occurs (e.g., those that compromise study 
objectives or subject safety), or if a subject is lost to follow-up.
Prescreening 
Subjects with RCC of non-clear cell histology must sign the prescreening ICF and be prescreened for 
ENPP3 expression prior to undergoing screening procedures for the main study.  Tumor tissue, from a 
primary or metastatic site (excluding bone), will be submitted to the Sponsor-designated CLIA certified 
laboratory for ENPP3 determination by IHC.  An IHC H-score of ≥ 15 is required for non-clear cell 
subjects to qualify for study screening.  IHC H-scores for ENPP3 eligibility will not expire for the 
duration of the study (i.e., there is no time limit from prescreen qualification to screening start).  Every 
effort will be made to report the IHC H-score to the investigator ≤ 72 hours of sample receipt at the 
Sponsor-designated CLIA certified laboratory provided that the specimens were received in good 
condition along with all required documents fully completed.
Clear cell histology subjects are not required to be screened for target expression to qualify for the 
study but must provide tissue during the study.  Consent to provide tissue is included in the main study 
informed consent form.  Clear cell histology subjects’ specimens will be batch assayed during the 
study.  The IHC H-score will be reported back to the investigator for information only when the data 
become available.
Procedures
Schedule of Assessment and Procedures by study week and days are outlined in Table 1 and
Section 5.2.


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Ocular Toxicities 
A complete eye exam will be done during screening. Subjects randomized to AGS-16C3F, will have a 
complete eye exam done after the Cycle 2 Day 1 dose but before the Cycle 3 Day 1 dose, after the
Cycle 5 Day 1 dose but before the Cycle 6 Day 1 dose, and as clinically indicated. Subjects randomized 
to axitinib will have a complete eye exam done post baseline as clinically indicated. The frequency of 
ophthalmology follow-ups outside of protocol requirement is at the discretion of the Investigator and 
ophthalmologist. 
Ocular symptoms reported by the subject during clinic visits will be graded per CTCAE v4.03 (i.e., 
symptom based assessment) and this will guide the treatment decision for that visit and the necessity 
for a follow up ophthalmology consult.
An Eye Symptom Questionnaire (ESQ) will be administered at every visit in the oncology clinic. 
Please see the Study Guide for the form and for complete instructions.
If a subject develops ocular toxicity, the following guidelines may be used:
Subject Reported Symptom Based Ocular AE (i.e., per CTCAE v4.03) (see Table 10 below)
Grade
Study Treatment Action
Ophthalmology Referral
1
Continue per dose and schedule (i.e., AGS-16C3F 
1.8 mg/kg q3w or axitinib 5 mg, twice daily)
May be done at Investigator discretion
2
May continue treatment per dose and schedule at 
Investigator discretion
Required; must occur prior to the 
subsequent cycle.
3
Hold treatment
Required; must occur prior to the 
subsequent cycle.
Clinical Ocular AEs are objective findings (e.g., keratitis, macular edema, retinal degeneration) from 
the ophthalmology evaluation. Clinical Ocular AE grading will be determined based on visual acuity 
(VA) change from screening (baseline).
The process for grading Clinical Ocular AEs is outlined in Section 5.6.5.2.
Corneal Clinical Ocular AEs 

If Clinical Ocular AE is Grade 3, Medical Monitor will be consulted for treatment decision.

If Clinical Ocular AE is Grade 4, subject will be permanently discontinued from study treatment. 
Non-corneal related clinical ocular AEs

Clinical Ocular AEs other than ocular surface disease/keratopathy in nature, irrespective of the 
grade, must be discussed with the Medical Monitor before the subsequent dose (per axitinib 
product label, patients treated with this product experienced both retinal artery and retinal 
vein occlusions. Please see product label for details).
The ophthalmology report along with the completed study provided cover form will be forwarded to 
the Investigator in a timely manner. The investigator will review the ophthalmology report to guide 
further treatment decisions.  
The redacted ophthalmology report will be forwarded to the Sponsor in a timely manner.


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Thrombocytopenia Adverse Events:
For thrombocytopenia without signs and symptoms of bleeding that the investigator considers 
clinically significant, the following AGS-16C3F dosing guidelines will be used (see Table 9 below):
Grade
Description
Action
2
Present, without signs and symptoms of 
bleeding.
The dose may be administered or held at 
investigator discretion
Persistent (i.e., lasting for ≥ 5 weeks), 
without signs and symptoms of bleeding, 
and without documented bone marrow 
suppression.
The subject may be considered for a dose reduction 
to 1.2 mg/kg. Dose reduction must be discussed with 
and approved in writing by the Medical Monitor.
Persistent (i.e., lasting for ≥ 5 weeks), 
without signs and symptoms of bleeding, 
and with documented bone marrow 
suppression.
The subject will be discussed with the Medical 
Monitor. The possible need for permanent 
discontinuation will be considered based on clinical 
benefit of treatment as well as review of overall 
patient profile (concomitant medication and medical 
history review, presence or absence of mucosal 
bleed, other AEs, etc.).
3
Present, without signs and symptoms of 
bleeding.
The dose will be held until platelet count improves 
to at least Grade 2 (≥ 50 x 109/L)
Present, without signs and symptoms of 
bleeding, and has not recovered to at least 
Grade 2 (≥ 50 x 109/L) ≤ 5 weeks. 
The subject will either be permanently discontinued 
or may be considered for a dose reduction to 1.2 
mg/kg. Dose reduction must be discussed with and 
approved in writing by the Medical Monitor.
4
Present, without signs and symptoms of 
bleeding, and platelet count is confirmed 
with a repeat lab performed ≤ 72 hours.
Subject will be permanently discontinued.
Present, without signs and symptoms of 
bleeding, and isolated (i.e., not confirmed 
with a repeat lab ≤ 72 hours after first 
assessment).
Dose will be held until platelet count improves to at 
least Grade 2 (≥ 50 x 109/L)
Present, without signs and symptoms of 
bleeding, isolated (i.e., not confirmed with 
a repeat lab ≤ 72 hours after first 
assessment), and has not recovered to at 
least Grade 2 (≥ 50 x 109/L) ≤ 5 weeks.  
The subject will either be permanently discontinued 
or may be considered for a dose reduction to 1.2 
mg/kg. Dose reduction must be discussed with and 
approved in writing by the Medical Monitor.
Beginning at Cycle 5 Day 1 and for all subsequent cycles, a bone marrow study or hematology consult, 
is strongly encouraged for all AGS-16C3F subjects whose predose platelet count is < 75 x 109/L at any 
2 timepoints.  If a hematology consult and/or bone marrow study is/are performed, the redacted 
report(s) will be timely submitted to the Sponsor.
Adverse Events of Possible Hepatic Origin 
See Appendix 12.2 for detailed information on the monitoring and assessment of liver abnormalities, if
the AE for a subject enrolled in a study and receiving study drug is accompanied by increases in liver 
function testing (LFT, e.g.: AST, ALT, bilirubin, etc.) or is suspected to be due to hepatic dysfunction. 
Subjects with AEs of hepatic origin accompanied by Liver Function Test (LFT) abnormalities should 
be carefully monitored.  


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Other Adverse Events
Subjects who experience a Grade 4 toxicity other than those related to the eye, liver, and 
thrombocytopenia, as described in Sections 5.6.5, 5.6.2.1.2, 5.6.2.1.1 will be permanently discontinued 
from AGS-16C3F treatment.  Laboratory AEs with a Grade 4 value, must be confirmed with a repeat 
analysis ≤ 72 hours before discontinuing subject from treatment.  
Formal Stopping Rules  
The subject will be discontinued from treatment if any of the following occurs:

Subject develops disease progression per RECIST v.1.1 criteria based on investigator assessment.

Subject develops clinical progression (if objective disease progression is not evaluated).

Subject develops a Grade 4 or unacceptable AE as assessed by the Investigator (Refer also to
Section 5.6.2.1.3 and Section 5.6.5.2.1)

Investigator decides that it is in the subject’s best interest to discontinue.

Subject declines further study participation (i.e., study withdrawal).

A significant protocol violation or non-compliance occurs with a subject that compromises study 
objectives or subject safety.

Subject is lost to follow-up despite reasonable efforts by the Investigator to locate the subject.

The study is terminated by the Sponsor.
The Medical Monitor must be contacted before a subject is discontinued from study treatment for 
reasons other than objective disease progression per RECIST v.1.1. 
Endpoints for Evaluation
Primary Endpoint:
To evaluate the progression-free survival (PFS) of AGS-16C3F compared against axitinib (Investigator 
radiology assessment per RECIST v.1.1).
PFS is defined as the time from the date of randomization to the earliest of documented disease 
progression as defined by RECIST v.1.1 or death from any cause.
Secondary Endpoints:
To evaluate the following for AGS-16C3F compared against axitinib:

PFS calculated based on blinded central radiology assessment per RECIST v.1.1 

Objective Response Rate (ORR); based on the investigator’s radiographic assessment
o
Objective response rate (ORR) is defined as the proportion of subjects who have a best 
overall response of complete response (CR) or partial response (PR). 

Duration of Response (DOR); based on the investigator’s radiographic assessment

Duration of objective response (DOR) is defined as the time from the date of the first response of 
CR/PR (whichever is first recorded) to the first date of documented progressive disease or death 
due to any cause. 

Overall Survival (OS)
o
Overall survival, defined as the time from the date of randomization until the date of death 
from any cause.

Disease control rate (DCR); based on the investigator’s radiographic assessment
o
Disease control rate (DCR) is defined as the proportion of subjects who have a best overall 
response of CR, PR, or at least 6 months Stable Disease (SD).

Safety
o
Incidence of AEs (including Grade 3 and 4 AEs, treatment-related AEs, SAEs (serious 
adverse events), and AEs requiring discontinuation of study drug), laboratory changes and 
vital signs


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Statistical Methods: 
The primary efficacy endpoint is progression-free survival (PFS), defined as the time from the date of 
randomization to the earliest of documented disease progression as defined by RECIST v 1.1 per 
investigator radiology review, or death from any cause. Disease assessment will continue until disease 
progression, even after the originally assigned treatment is discontinued.  
The primary analysis of investigator assessed PFS will be performed in accordance with the intention-
to-treat (ITT) principle. All subjects who undergo randomization will be included in the primary 
analysis.  Subjects will be grouped according to the treatment groups assigned by randomization.  
For the primary analysis of PFS, the difference in treatment effect between treatment groups will be 
tested using the stratified log rank test (on ECOG Performance Status and the number of prior systemic 
RCC regimens) at a one-sided 0.1 significance level. Histology will not be used as a stratification 
variable in inferential comparison because a limited number of non-clear cell subjects is expected to be 
enrolled in the study (no more than 26 non-clear cell histology).
Estimation of the hazard ratio for treatment and its corresponding one-sided 90% CI will be determined 
using a stratified Cox proportional hazards model (on ECOG Performance Status and the number of 
prior systemic RCC regimens), without any other covariate. A two-sided 95% CI will also be reported 
in the clinical study report. Homogeneity in the hazard ratios between strata will be examined by 
Wald’s test. The corresponding results without stratification will be reported as supplemental analyses. 
The adequacy of the model will be evaluated, including an assessment of the proportional hazards 
assumption (Therneau, 2000). Exploratory subgroup analyses may be conducted to assess potential 
heterogeneity of treatment effects across levels of baseline characteristics.
For the primary analysis, PFS will be right-censored for subjects who meet one or more of the 
following conditions:

Subjects with no post-baseline disease assessments unless death occurred prior to the first planned 
assessment (in which case death will be considered a PFS event)

Subjects who initiate subsequent anti-cancer therapy or intervention in the absence of documented 
progression

Subjects who die or have disease progression after missing 2 or more consecutively scheduled 
disease assessment visits

Subjects who are last known to be alive and progression-free on or before the data cut-off date
For such subjects, PFS will be right-censored based on the May 2007 FDA Guidance for Industry 
“Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics”. Sensitivity analyses will 
be performed to evaluate the robustness of the PFS results derived under the primary analysis 
(Bhattacharya, 2009; Carroll, 2007; Stone, 2011).  
Progression-free survival by blinded central radiology review and overall survival, defined as the 
number of months from the date of randomization until the date of death from any cause, will be 
evaluated as secondary endpoints. They will be analyzed using the same methodology as described for 
the primary endpoint.
Disease control rate (DCR) will be estimated for each treatment group based on the crude proportion of 
subjects who have a best overall response of CR, PR or SD. For DCR, SD with a minimum duration of 
6 months from the date of randomization is required. Objective response rate (ORR) will be estimated 
for each treatment group based on the crude proportion of subjects who have a best overall response of 
CR or PR. The inferential comparison between treatment groups for both DCR and ORR by 
investigator and central review will be made using the stratified Cochran-Mantel-Haenszel chi-square 
test at a two-sided significance level of 0.05.


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Duration of objective response (DOR) is defined as the time from the date of the first response of CR 
or PR (whichever is first recorded), and subsequently confirmed, to the first date of documented 
progressive disease or death due to any cause. Duration of response will be summarized for subjects 
who have best overall response of CR or PR.
Safety will be evaluated based on the incidence of AEs (including Grade 3 and 4 AEs, treatment-
related adverse events, serious adverse events, and AEs requiring discontinuation of study treatment), 
electrocardiogram (ECG) and laboratory changes and vital signs.  AEs will be graded using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading 
scale, version 4.03. Ocular toxicities based on ophthalmology exams reported on the Eye Exam eCRFs 
will be graded using the study specific ocular criteria and these will be separately tabulated. 
Descriptive statistics will be provided for the PK parameter estimates and subject concentration plots 
over time may be generated.  Please refer to Section 7.6
Descriptive statistics for the incidence of human native antibody (AGS-16C3) and antibody drug 
conjugate (AGS-16C3F) antibody formation will be provided by treatment group.
Sample size justification: 
For subjects with metastatic RCC who have progressed after at least 2 prior lines of therapy, a median 
PFS of 4 months is anticipated for the control agent.  It is hypothesized that AGS-16C3F will improve 
median PFS in such subjects by 2 months (i.e., 4 vs 6 months).  Under the assumption of exponential 
distribution of PFS, such an improvement corresponds to a hypothesized hazard ratio of 0.667.  If this 
hypothesized hazard ratio is true, 110 PFS events provide 80% power to achieve a one-sided p-value of 
0.1 or smaller.  Such a result will be achieved when the observed hazard ratio is 0.783 or smaller; and 
the observed difference in median PFS is 1.1 months or larger (assuming observed median PFS for the 
control arm is 4 months).  Assuming accrual of approximately 7 subjects per month for 18 months, 110 
PFS events are projected 24 months after the date the first subject is randomized.  Approximately 134 
subjects may be enrolled to accommodate for up to 10% of subjects who may become lost to follow-
up. 
Efficacy:  
PFS is defined as the time from the date of randomization to the earliest of documented disease 
progression as defined by RECIST v.1.1 or death from any cause.  Disease assessment will continue 
until disease progression, even after the originally assigned treatment is discontinued.  
PFS will be summarized descriptively using the Kaplan-Meier method with 95% confidence intervals 
calculated about the median using Greenwood’s formula. For the primary analysis of PFS, the 
difference in treatment effect between treatment groups will be tested using the stratified log rank test 
(on ECOG Performance Status and the number of prior systemic RCC regimens) at a one-sided 0.1 
significance level.
Pharmacokinetics:  
The PK data for ADC and MMAF will be analyzed using the noncompartmental method. Parameters to 
be assessed will include concentrations at the end of infusion or maximum observed concentration 
(CEOI or Cmax), concentrations at trough (Ctrough), time to maximum observed concentration (Tmax), 
partial area under the concentration time curve (AUCτ) for Cycle 1 and 4, and either terminal or 
apparent terminal half-life (t1/2) as appropriate. Additionally, clearance (CL) and volume of distribution 
at steady state (Vss) will be included as appropriate. Descriptive statistics will be provided for the PK 
parameter estimates and subject concentration plots over time may be generated. 


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Pharmacodynamics:  
N/A.  A pharmacodynamic marker has not yet been established for this target. 
Safety:  
Safety will be evaluated based on the incidence of AEs (including Grade 3 and 4 AEs, treatment-
related adverse events, serious adverse events, and AEs requiring discontinuation of study treatment), 
ECG and laboratory changes and vital signs. AEs will be graded using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale, version 4.03. Ocular 
toxicities based on ophthalmology exams reported on the Eye Exam eCRFs will be graded using the 
study specific ocular criteria and these will be separately tabulated.  
Interim Safety Review:
The study will have an Independent Data-Monitoring Committee (IDMC) overseeing the study.  The 
IDMC will conduct safety reviews at prespecified times during the study to make a recommendation 
for continuation of recruitment, protocol modification or study discontinuation for safety reasons.         
The IDMC will operate under the Study’s IDMC Charter. 








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o Disease assessments (CT and/or MRI; refer to Section 5.5) will be done every 8 weeks (± 7 days) counting from C1D1. 
p
Required only if clinically indicated. Post screening bone imaging will be done only for subjects with bone disease at screening.  The imaging method will be any imaging modality per 
local or institutional standard of care (SOC) (e.g., NaF PET, MRI Bone, Tc-99 Bone Scan, etc.)
q
Subjects randomized to AGS-16C3F must use 1% prednisolone acetate ophthalmic suspension prophylactically (prophylaxis steroid drops) starting from Day (-1) of each treatment cycle. 
Refer to Section 5.1.3.1.
r
Paraffin-embedded tumor tissue from primary or metastasis (excluding bone), for immunohistochemical studies to be conducted at a Sponsor specified CLIA certified laboratory.  This is 
required for all non-clear cell histology subjects before Screening.  Clear cell histology subjects must also provide tissue but at any point during the study. If no archive tissue is available; 
a biopsy may be performed to obtain tissue. 
s Subjects are required to have a safety follow-up visit; refer to Section 5.2.7.
t
Physical exam, laboratory assesssments, and ECOG assessment may be performed ≤ 4 days in advance of the subsequent Cycle Day 1.
u
An Eye Symptom Questionnaire (ESQ) will be administered at every visit. Only subjects randomized to AGS-16C3F will have the ESQ done on PK only days. Refer to Section 5.6.5.1




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1
INTRODUCTION
1.1
Background
Disease
Renal cell carcinoma (RCC) accounts for 2% to 3% of all malignant diseases in adults. It is 
the seventh most common cancer in men and the ninth most common in women. 
Historically, treatment has focused primarily on nephrectomy, followed by nonspecific 
immunotherapy, and sometimes radiation therapy. Nonspecific immunotherapy includes 
treatment with the cytokines interleukin-2 or interferon-2α, as either single agents or in 
combination (Belldegrun et al, 2008).  After surgical excision, 20-30% of patients will develop 
metastatic disease within 1-3 years, often in the lung (Motzer, 2011).  Median survival for 
patients with metastatic disease is approximately 13 months (Ljungberg et al, 2010). 
Since 2005, 10 agents have been approved in the United States and other world regions for 
the treatment of advanced RCC: sorafenib (Nexavar®), sunitinib (Sutent®), temsirolimus 
(Torisel®), everolimus (Affinitor®), bevacizumab (Avastin® in combination with interferon 
alpha),  pazopanib (Votrient®), axitinib (Inlyta®), cabozantinib (Cabometyx®), lenvatinib 
(Lenvima® in combination with everolimus), and nivolumab (Opdivo®). These drugs target 
specific pathways important in RCC, including angiogenesis and mTOR signaling, or act as a 
checkpoint inhibitor, allowing the immune system to fight the cancer.  Their use was shown 
mostly to affect response rate and/or duration. 
While these drugs which either block the vascular endothelial growth factor (VEGF) pathway, 
inhibit mammalian target of rapamycin (mTOR), or block the signal that prevents activated T 
cells from attacking the cancer have significantly increased both treatment options and 
improved outcomes for patients with advanced RCC, the vast majority still relapse. 
The recent advances in treatment options mainly affected patients with clear cell histology, 
while no real progress has been made in those with other histologies.
A novel mechanism of action drug to treat advanced RCC of all histologies with a different 
treatment approach is much desired.
Agensys Antibody Drug Conjugate against Renal Cell Carcinoma
AGS-16C3F, an antibody drug conjugate (ADC) developed by Agensys, is comprised of a 
chinese hamster ovary (CHO) cell line-derived antibody against ENPP3, conjugated to 
monomethyl auristatin F (MMAF), a microtubule disruptive agent.  A Phase 1 study was 
conducted to evaluate the pharmacokinetics and safety of AGS-16C3F administered 
monotherapy in metastatic RCC subjects.  This Astellas Phase 2 study is planned based on 
the results of the Phase 1 study.  Results from the Phase 1 study are pending full data 
analysis.
ENPP3 Antigen Target and Expression in Cancer
The antigen target, ENPP3 (referred to as AGS-16 ), was cloned from a patient renal 
carcinoma specimen and identified as an 875 amino acid type II single transmembrane 


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antigen that is upregulated in the majority of renal and in a subset of hepatocellular cancers.  
Sequencing of AGS-16 identified it as ENPP3 (CD203c), one of 7 members of a family of 
cell surface ectonucleotide phosphodiesterases-pyrophosphatases (PDEs), ENPP1-7 (Deissler 
et al, 1995; Jin-Hua et al, 1997, Buhring et al, 2001; Goding et al, 2003; Stefan et al, 2005). 
The physiological substrate of ENPP3 is unknown, but studies have suggested that the 
enzyme catalyzes extracellular nucleotides (e.g., ATP; Goding et al, 2003).
Immunohistochemical (IHC) and tissue cross reactivity studies have shown restricted 
expression of ENPP3 in normal tissues predominantly in a subset of cells in the kidney 
cortex.  Low levels of staining were also observed in the epithelium of the fallopian tube, a 
subset of cells within gastrointestinal tract epithelium, in uterine endometrium, parotid gland, 
and the cortex of the thymus. Flow cytometric analysis has also shown that ENPP3 is 
expressed on activated basophils and mast cells (Buhring, 1999). ENPP3 is highly expressed 
in approximately 90% renal clear cell carcinoma; 69% papillary RCC and 27% hepatocellular 
carcinoma as determined at Agensys by staining tissue microarrays with an 
immunohistochemistry antibody specific for ENPP3.
1.2
Non-clinical and Clinical Data
Antibody Drug Conjugate AGS-16C3F Non-clinical Pharmacology
AGS-16C3F is comprised of a fully human IgG2k mAb, following conjugation with the 
cytotoxic drug MMAF via a non-cleavable maleimidocaproyl (mc) linker.  MMAF is a 
synthetic analog of the naturally occurring tubulin-binding drug, dolastatin 10, that was 
modified to contain a charged C-terminal phenylalanine residue (Doronina et al, 2006, Pettit, 
1987). Conjugation takes place on cysteine residues that comprise the interchain disulfide 
bonds of the antibody to yield a product with a target drug to antibody ratio of 4.0 + 0.5.
AGS-16C3F binds specifically to ENPP3 (AGS-16) expressed on the surface of renal, 
hepatocellular and chronic myelogenous leukemia (CML) cells with high affinity (Kd = 0.54 
nM).  Following binding to cell surface ENPP3, AGS-16C3F is internalized and trafficked 
through the endocytic pathway to the lysosomes where catabolism results in release of 
cysteine adducts of mcMMAF that subsequently bind to and inhibit microtubules (Sutherland 
et al, 2006). 
The mechanism of action and catabolism of AGS-16C3F is similar to that of other mAbs 
conjugated with non-cleavable linkers (Polson et al, 2009; Oflazoglu et al, 2008; Erickson et 
al, 2006). These ADCs have the potential to yield an excellent therapeutic index due to 
increased stability of  the non-cleavable linker in circulation and impaired cellular access of 
the charged metabolic products produced intracellularly (Alley et al, 2009, Doronina et al, 
2006). The pharmacologic data collected for AGS-16C3F demonstrate that it binds with high 
affinity to both human and cynomolgus monkey ENPP3 and that it does not cross react with 
other ENPP family members. Moreover, treatment with AGS-16C3F produces potent cellular 
cytotoxicity in vitro and regression or long term growth inhibition of well-established tumors 
in vivo.


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AGS-16C3F inhibited tumor growth in 3 different ccRCC xenograft models. While AGS-
16M8F, the hybridoma cell line-derived version of the same ADC studied earlier, was shown 
to bind to basophils from human and monkey, in vitro experiments showed no histamine 
release upon incubation of human or cynomolgus monkey blood with AGS-
16M8F. Moreover, there were no signs of allergic reactions to AGS-16M8F in cynomolgus 
monkeys treated with doses up to 6 mg/kg/week for 4 weeks. Likewise, no overt kidney 
toxicities were observed.
Please refer to the confidential AGS-16C3F Investigator’s Brochure for further details.
AGS-16C3F Non-clinical Toxicology and Pharmacokinetics
A comprehensive non-clinical safety assessment package was conducted for AGS-16M8F, 
the fully human hybridoma-derived monoclonal antibody conjugated to MMAF.  A summary 
of findings from these studies can be found in the Investigator Brochure. 
Based on biological characterization and analytical testing of the CHO-derived product,
AGS-16C3F, it was shown to be similar to AGS-16M8F.  To supplement these results, a non-
clinical bridging study was conducted in primates comparing the pharmacokinetic and 
toxicology properties of AGS-16M8F and AGS-16C3F at a dose level of 6 mg/kg 
(established NOAEL dose for AGS-16M8F in the non-human primate study).  
Administration of AGS-16C3F by once-weekly intravenous (IV) infusion for 4 weeks was 
well tolerated in cynomolgus monkeys at levels of 6 mg/kg/week.  There were no differences 
noted between AGS-16M8F and AGS-16C3F for in-life toxicology parameters assessed in 
this study.
There were AGS-16C3F-related changes in a number of hematology (decreased platelets and 
increased monocytes) and clinical chemistry parameters (increased ALT, AST, LDH, ALP, 
GGT (Gamma Glutamyl Transferase), globulin, and total protein and decreased albumin and 
A:G ratio).  In general, the magnitude of these changes was similar for AGS-16M8F and 
AGS-16C3F treated male and female animals.  The changes returned to baseline following 
recovery and did not correlate with clinical signs or histopathology, and were therefore not 
considered adverse. 
Toxicokinetic data for AGS-16C3F and AGS-16M8F were considered similar based on the 
pre-specified comparability criteria.  
Microscopic findings related to AGS-16C3F at terminal sacrifice were present in the liver 
and seminal vesicle, and microscopic findings related to AGS-16M8F and AGS-16C3F were 
present in the uterus.  None of these changes were present in recovery animals.  In the liver of 
AGS-16C3F males, minimal to moderate focal to multifocal dilation of the hepatic sinusoids 
was present, and correlated with increased liver weight, but the biological significance was 
unknown since there were no clinical or clinical pathology correlates.  A mild increase in 
cellular apoptosis and mitotic figures was present in the seminal vesicle of the only sexually 
mature male dosed with AGS-16C3F.  Minimal to moderate increases in cellular apoptosis 
and/or mitotic figures were present in the uterus (endometrial glandular epithelium) of most 
females treated with AGS-16M8F or AGS-16C3F.  The increase in cellular apoptosis and 


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mitotic figures was an expected effect based on the intended activity of the drug payload 
(MMAF) to inhibit microtubule formation.   
Overall, the toxicity and TK characteristics of AGS-16M8F and AGS-16C3F when given at a 
comparable dose by IV infusion once weekly for 4 weeks to cynomolgus monkeys were 
comparable.  
Nonclinical Summary of mcMMAF
The safety of the primary metabolite of AGS-16C3F, Cys-mcMMAF, was evaluated in 
several studies described in the AGS-16C3F Investigator’s Brochure. Cys-mcMMAF was not 
found to be genotoxic in a standard battery of assays; however, no embryo-fetal toxicity data 
is currently available. MMAF is a tubulin inhibitor and has the same mechanism of action as 
monomethyl auristatin E (MMAE), which has been shown to be genotoxic and embryotoxic.
As a precautionary measure, it is recommended that males and females continue to use 
contraception for 6 months after taking the last dose of AGS-16C3F and avoid pregnancy, 
breastfeeding and donating ova/sperm.
Please refer to the confidential AGS-16C3F Investigator’s Brochure for further details.
1.3
Summary of Key Safety Information for Study Drugs
Investigational Drug - AGS-16C3F 
1.3.1.1
Development History and Background
One Phase 1 AGS-16C3F-12-2 study evaluated the safety and pharmacokinetics of 
AGS-16C3F given by IV infusion over 60 minutes every 3 weeks to subjects with metastatic 
RCC of either clear cell or papillary histology.  The study started at a bridging dose identified 
from an earlier metastatic RCC Phase 1 study in which the target antibody (AGS-16M8F)
was manufactured from a hybridoma cell line.  AGS-16M8F and AGS-16C3F demonstrated 
highly similar analytical results, comparable biological characteristics, and similar 
pharmacologic, pharmacokinetic, and toxicological profiles.  The AGS-16M8F Phase 1 study 
closed for enrollment without reaching the maximum tolerated dose (MTD) to transition the 
compound development to AGS-16C3F.  The highest dose tested in the AGS-16M8F study 
was 4.8 mg/kg, which was the starting dose for protocol AGS-16C3F-12-2.  
1.3.1.2
AGS-16C3F Phase 1 Study (Protocol AGS-16C3F-12-2)
Overall, 34 subjects were treated in protocol AGS-16C3F-12-2 in 4 dose cohorts and the dose 
that was determined to be the recommended Phase 2 dose was 1.8 mg/kg. 
The study is complete, and the safety information is as follows.    
All subjects in the study experienced at least 1 treatment emergent adverse event (TEAE), 
many of which were attributable to the underlying disease. Three (3) dose limiting toxicities
(DLT) were observed at the 4.8 and 3.6 mg/kg dose levels. Two (2) subjects at 4.8 mg/kg 
experienced a DLT of Grade 3 keratitis, and Grade 2 leukoencephalopathy and Grade 3 fall. 
One (1) subject at 3.6 mg/kg had a Grade 4 thrombocytopenia DLT.  


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The most frequently reported TEAEs across all dose levels and irrespective of severity, 
seriousness or causal attribution were: fatigue (71%), nausea (56%), dry eye (50%), vision 
blurred and decreased appetite (with individual frequency of 44% each), vomiting (38%), 
thrombocytopenia (35%), and keratitis and headache (with individual frequency of 32% 
each).  Eight (8) subjects (24%) experienced infusion related reactions.  
At the 1.8 mg/kg dose level, the most frequently reported TEAEs were: fatigue (85%), nausea 
(69%), dry eye, headache, and constipation (with individual frequency of 54% each), vision 
blurred and decreased appetite (with individual frequency of 46% each), epistaxis and 
vomiting (with individual frequency of 39% each), and dyspnea and anemia and diarrhea and 
insomnia (with individual frequency of 31% each).
Eighteen (18) subjects experienced serious adverse events (SAEs) across all doses. Of these, 
6 subjects had SAEs that were judged as at least possibly related to the investigational 
product.  One (1) of these drug related SAEs occurred in a subject treated at the 1.8 mg/kg
dose level.
Two (2) subjects at dose level 2.7 mg/kg died on study: 1 due to peritoneal hemorrhage and 1
due to cardiac arrest.  Both fatal events were judged unrelated to the investigational product.
Please refer to the confidential AGS-16C3F Investigator’s Brochure for further details.
Comparator Drug - Axitinib (Inlyta®)
Axitinib is an oral kinase inhibitor which has the chemical name N-methyl-2-[3-((E)2-pyridin-2-
yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide. Axitinib has been shown to inhibit receptor 
tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, 
and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic 
angiogenesis, tumor growth, and cancer progression. VEGF-mediated endothelial cell 
proliferation and survival were inhibited by axitinib in vitro and in mouse models. Axitinib was 
shown to inhibit tumor growth and phosphorylation of VEGFR-2 in tumor xenograft mouse 
models [Axitinib U.S. Package Insert (Pfizer Labs), Aug 2014].
Most frequent adverse reactions from a pooled dataset of 672 patients who received axitinib 
in clinical studies for the treatment of RCC were as follows: diarrhea (55%), hypertension 
(51%), fatigue (45%), decreased appetite (39%), nausea, weight decrease and dysphonia 
(33% each), hand-foot syndrome (32%), hemorrhage (26%), hypothyroidism (25%), 
vomiting (24%), proteinuria (21%),constipation and cough (20% each).  
Detailed information on the toxicity associated with axitinib can be found within the Package 
Insert, Summary of Product Characteristics (SPC) or local product information. Please note 
the prescribing warnings and precautions for use in patients with cardiac failure, 
hypertension, thyroid dysfunction, arterial and venous embolic/thrombotic events, elevation 
of hemoglobin/hematocrit, hemorrhage, gastrointestinal perforation, wound healing 
complications, posterior reversible encephalopathy syndrome, proteinuria, and liver-related 
adverse reactions/hepatic impairment.


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Class Effects
Monoclonal antibodies and ADCs are known to carry the risk of hypersensitivity and/or 
infusion related toxicity.  As a reference, infusion related reactions occurred in about 10% of 
subjects enrolled in the Phase 1 and 2 Studies of brentuximab vedotin, 15-21% of those who 
received cetuximab and about 40% of those who received trastuzumab (Hong et al, 2012, 
Younes et al, 2012, Younes et al, 2010, Schwartzberg et al, 2009,).  Mild-to-moderate 
infusion reactions may include pruritus, rash, bronchospasm, fever and chills.  More severe 
infusion related reactions might include hypotension and shock.
Hematopoietic toxicity, predominantly expressed as neutropenia, is a common complication 
of several ADCs, including vedotin- (Younes et al, 2012, Younes et al, 2010), emtansine-
(Burris et al, 2011) and ozogamicin-conjugates (Advani et al, 2010, Larson et al, 2005).  
ADCs are also reported to cause isolated thrombocytopenia as reported as a DLT by 
trastuzumab-DM1.  The pathogenesis is unknown (Krop et al, 2010).  
Neuropathy is described as a complication of most tubulin inhibitor-based ADCs (Younes et 
al, 2012, Burris et al, 2011, Younes et al, 2010, Swain et al, 2008) although it has not 
emerged so far in the ongoing Phase 1 study using AGS-16C3F.  
Monoclonal antibodies and ADCs can also be associated with the development of antibodies 
(Hughes, 2010, Lambert et al, 2005).  
Finally, corneal lesions are an emerging toxicity, reported in subjects treated with auristatin 
F- or DM4 –conjugated ADC (Coiffier et al, 2011).
1.4
Risk-Benefit Assessment
The recommended Phase 2 dose from the completed Study AGS-16C3F-12-2 was 1.8 mg/kg 
administered once every 3 weeks.  Thirteen (13) subjects were enrolled at this dose level.  
At this dose and frequency, durable anti-tumor effects (Partial Response [PR] and Stable 
Disease [SD]) were observed.  Three (3) subjects achieved durable PR (3/13, 23%), 9/13 
subjects had SD (69%), and 1/13 subject had PD (8%).  
The median treatment duration for the 13 subjects who were enrolled at 1.8 mg/kg is 17.7 
weeks (9.3-143.1 weeks).  
The compound’s primary unique toxicity is ocular toxicities. At the 1.8 mg/kg dose level, 
reversible ocular toxicities were reported from all but one subject (12/13, 92%) but only 2 
subjects (15%) experienced Grade 3 events.  No Grade 4 ocular toxicities were reported.
Another common toxicity of this compound is thrombocytopenia.  One subject (7.7%) at the 
1.8 mg/kg dose level experienced a Grade 3 thrombocytopenia.  
Refer to Section 1.3.1.2 for other frequently reported AEs from Study AGS-16C3F-12-2.


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2
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS
2.1
Study Objectives
Primary 
To evaluate the Progression Free Survival (PFS), based on investigator radiologic review, of 
AGS-16C3F compared to axitinib in subjects with metastatic RCC
Secondary 

To evaluate the following for AGS-16C3F compared against axitinib:
o
PFS per RECIST v1.1 by blinded central radiology assessment 
o
Objective Response Rate (ORR) based on the investigator’s radiographic 
assessment
o
Duration of Response (DOR) based on the investigator’s radiographic assessment
o
Overall Survival (OS)
o
Disease Control Rate (DCR) based on the investigator’s radiographic assessment
o
Safety

To evaluate the pharmacokinetics of AGS-16C3F

To evaluate the incidence of antidrug antibody formation to human native antibody 
(AGS-16C3) and antibody drug conjugate (AGS-16C3F).
2.2
Study Design and Dose Rationale
Study Design
This multi-center, open-label, randomized study will enroll subjects with metastatic RCC of 
all histologies who have evidence of progression on or after the last regimen received and 
have also received at least 2 prior systemic regimens 1 of which is an anti-VEGF agent (clear 
cell subjects). 
Non-clear cell RCC is a heterogeneous group of tumors typically not driven by von Hippel-
Lindau (VHL) gene and sensitivity to anti-VEGF treatments differ from that shown in clear 
cell RCC.  Hence, subjects with non-clear cell histology are only required to have progressed 
on or after only at least one anti-VEGF regimen.  
Subjects with non-clear cell histology must also have ENPP3 positive immunohistochemical 
(IHC) staining at prescreening.  Positivity is defined as an IHC H-score ≥ 15.  Non-clear cell
subjects whose tissue has an IHC H-score of ≥ 15 will qualify to screen for the study.  
Clear cell subjects are not required to be screened for ENPP3 to qualify for the study, but 
subjects must submit tissue during the study for retrospective target expression assessment by 
IHC. 
Subjects will be randomized at 1:1 ratio to either AGS-16C3F or axitinib.  Randomization 
will be stratified according to Eastern Cooperative Oncology Group (ECOG) Performance 


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Status (0 or 1), the number of prior systemic RCC regimens (2 or > 2), and RCC histology 
(clear cell or non-clear cell).  
For stratification purpose:

Non-clear cell subjects who have progressed after only one prior anti-VEGF regimen 
will be regarded the same as those clear cell subjects who have progressed after 2 prior 
systemic RCC regimens. 

Non-clear cell subjects who have progressed after > 1 prior systemic RCC regimens will 
be regarded the same as those clear cell subjects who have progressed after > 2 prior 
systemic RCC regimens. 
AGS-16C3F will be administered at 1.8 mg/kg as a single 60-minute IV infusion once every 
3 weeks. 
Axitinib is a commercial product and will be administered as defined in its product label.  
Axitinib will have a starting dose of 5 mg, twice daily continuously, by mouth.  Axitinib dose 
may be adjusted during the study as needed as defined in the product label and local 
institutional guidelines, in doses ranging from 2 to 10 mg, twice daily continuously, by 
mouth.
Subjects will be eligible to continue receiving treatment on study until disease progression
per RECIST v.1.1, unacceptable toxicity, investigator’s decision, or study withdrawal.  
Subjects will also be discontinued from treatment if a significant non-compliance occurs 
(e.g., those that compromise study objectives or subject safety), or if a subject is lost to 
follow-up.  The study may also be terminated by the Sponsor for any reason.  Refer to 
Section 6 for details.
Disease assessments will be performed every 8 weeks (± 7 days) counting from C1D1.  Bone 
imaging will be performed every 12 weeks (± 7 days) counting from C1D1 (only subjects 
with bone disease at screening).
Those subjects who discontinued the study for reasons other than objective disease 
progression by RECIST v.1.1 will continue to have disease assessments every 8 weeks 
(± 7 days) counting from C1D1. This will continue until subject has radiologically confirmed 
progression, initiates a new therapy, study closure or subject dies. 
The study will have an Independent Data Monitoring Committee (IDMC) overseeing the 
study.  The IDMC will conduct safety reviews at predetermined times during the study to 
make a recommendation for continuation of recruitment, protocol modification or study 
discontinuation for safety reasons.  
A separate IDMC Charter will specify the governance and conduct of the IDMC. Refer to 
Section 7.8 for IDMC composition and additional details.


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Number of Centers/World Regions
Approximately 30 sites (United States and Canada) are planned to participate in this study.  
Each site is expected to enroll at least 4 subjects in this study.  Sites that do not enroll a 
subject ≤3 months from the study initiation visit date may be terminated and replaced.
Number of Subjects
Participants in this clinical investigation shall be referred to as “subjects”. This study will 
enroll approximately 134 subjects total. Within this total (i.e., 134), the number of subjects 
with non-clear cell histology is limited to 26 total.
Estimated Study Duration
The study duration, up to the study’s primary endpoint assessment, is approximately 24 
months.
Dose Rationale
In the Phase 1 study, AGS-16C3F-12-2, 4 dose levels were tested; 4.8, 3.6, 2.7, and 1.8 
mg/kg administered via IV every 3 weeks.  The 3 higher dose levels were not tolerated in 
multiple doses.  Thirteen (13) subjects were enrolled at the 1.8 mg/kg and 5 subjects were 
dose reduced to 1.8 mg/kg from 2.7 mg/kg. The 1.8 mg/kg dose level was tolerated in 
multiple doses administered every 3 weeks and determined to be the recommended Phase 2 
dose.
Axitinib is a commercial product and will be administered as defined in its product label.  
Axitinib will be administered at a starting dose of 5 mg, twice daily continuously, by mouth.  
Axitinib dose may be adjusted during the study as needed as defined in the product label and 
local institutional guidelines, in doses ranging from 2 to 10 mg, twice daily continuously, by 
mouth.  
2.3
Endpoints 
Primary Endpoints
To evaluate the PFS of AGS-16C3F compared against axitinib (Investigator radiology 
assessment per RECIST v.1.1).
PFS is defined as the time from the date of randomization to the earliest of documented 
disease progression as defined by RECIST v.1.1 or death from any cause.
Secondary Endpoints 
To evaluate the following for AGS-16C3F compared against axitinib:

PFS calculated based on blinded central radiology assessment per RECIST v.1.1

Objective Response Rate (ORR); based on the investigator’s radiographic assessment
o
Objective response rate (ORR) is defined as the proportion of subjects who have a 
best overall response of Complete Response (CR) or Partial Response (PR). 


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
Duration of Response (DOR); based on the investigator’s radiographic assessment
o
Duration of objective response (DOR) is defined as the time from the date of the 
first response of CR/PR (whichever is first recorded) to the first date of 
documented progressive disease or death due to any cause.

Overall Survival (OS)
o
Overall survival, defined as the time from the date of randomization until the date 
of death from any cause.

Disease control rate (DCR); based on the investigator’s radiographic assessment
o
Disease control rate (DCR) is defined as the proportion of subjects who have a best 
overall response of Complete Response (CR), Partial Response (PR), or at least 
6 months Stable Disease (SD).

Safety
o
Incidence of AEs (including grade 3 and 4 AEs, treatment-related AEs, SAEs, and 
AEs requiring discontinuation of study drug), laboratory changes and vital signs.  
3
STUDY POPULATION
3.1
Selection of Study Population 
Subjects with metastatic RCC of any histology, who have evidence of progression on or after 
the last regimen received: 

Clear cell histology subjects must have received at least 2 prior systemic regimens, one 
of which is an anti-VEGF agent.  

Non-clear histology subjects must have received at least 1 prior anti-VEGF regimen and 
also screen positive by IHC for ENPP3.
Prescreening
Subjects with RCC of non-clear cell histology must sign the prescreening ICF and be 
prescreened for ENPP3 expression prior to undergoing screening procedures for the main 
study.  Refer to Section 5.2.2 for details.
Clear cell histology subjects are not required to be prescreened for target expression to 
qualify for the study but must provide tissue during the study for ENPP3 determination by 
IHC.
3.2
Inclusion Criteria
1. Is at least 18 years of age
2. Histologically confirmed diagnosis of RCC
a.
Non-clear subjects must be ENPP3 positive, defined as IHC H-score ≥15
3. Has evidence of progression on or after the last regimen received:


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a.
Clear cell subject: must have received at least 2 prior systemic regimens, one of 
which is an anti-VEGF agent.  
b. Non-clear cell subject: must have received at least one prior anti-VEGF regimen
4. Has measurable disease according to Response Criteria for Solid Tumors (RECIST v.1.1)
5. Has ECOG Performance Status of 0 or 1
6. Has archive tumor tissue from primary tumor or metastatic site (excluding bone), for 
which the source and availability have been confirmed.  
a.
If no archive tissue is available, the subject may elect to have a biopsy performed to 
obtain tissue.
7. Has adequate organ function including:
a.
Hematopoietic function as follows:
i. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
ii. Platelet count ≥ 100 x 109/L
iii. Hemoglobin ≥ 9 g/dL (transfusions are allowed)
b. Renal Function as follows:
i. Creatinine ≤ 1.5 x ULN, or calculated GFR > 40 mL/min (Cockcroft-Gault) 
if creatinine > 1.5x ULN
c.
Hepatic function, as follows:
i. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 
x ULN or ≤ 5x ULN if known liver metastases
ii. Total bilirubin ≤ 1.5 x ULN
8. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels ≤1.5 x 
ULN. If institution does not report PT value, the INR must be ≤ ULN
a.
If subject is receiving Coumadin (warfarin), a stable international normalization 
ratio (INR) of 2-3 is required.
9. No clinical symptoms of hypothyroidism
10. Urine Protein to Creatinine Ratio (uPCR) < 2.0
a.
If uPCR ≥ 2.0 then a 24-hour urine collection can be performed to qualify.  If this is 
performed to qualify, the protein result must be < 2 g per 24 hours.
11. Female subject must either:
a.
Be of non-childbearing potential:
i. post-menopausal (defined as at least 1 year without any menses) prior to 
Screening, or 
ii. documented surgically sterile 


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b. Or, if of childbearing potential, 
i. Agree not to try to become pregnant during the study and for 6 months after 
the final study drug administration
ii. And have a negative serum pregnancy test ≤10 days of C1D1
iii. And, if heterosexually active, agree to consistently use 2 forms of highly 
effective birth control* (at least one of which must be a barrier method) 
starting at Screening and throughout the study period and for 6 months after 
the final study drug administration.
12. Female subject must agree not to breastfeed starting at Screening and throughout the 
study period, and for 6 months after the final study drug administration.
13. Female subject must not donate ova starting at Screening and throughout the study 
period, and for 6 months after the final study drug administration.
14. Male subject and their female spouse/partners who are of childbearing potential must be 
using highly effective contraception* consisting of 2 forms of birth control (at least one 
of which must be a barrier method) starting at Screening and continue throughout the 
study period, and for 6 months after the final study drug administration
15. Male subject must not donate sperm starting at Screening and throughout the study period 
and, for 6 months after the final study drug administration 
16. Is competent to comprehend, sign, and date an independent ethics committee/institutional 
review board (IEC/IRB) approved informed consent form, as evaluated and documented 
by the investigator.
Note: *Highly effective forms of birth control include:

Consistent and correct usage of established oral contraception.

Established intrauterine device (IUD) or intrauterine system (IUS).Barrier 
methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
1. Has previously been treated with axitinib, AGS-16C3F, or AGS-16M8F
2. Has untreated brain metastasis. In the case of a solitary brain metastasis which has been 
resected, there must be evidence of a disease-free interval of at least 3 months post-
surgery. For brain metastases treated with whole brain or stereotactic radiation therapy, 
brain imaging must be stable > 3 months. All subjects previously treated for brain 
metastases must be stable off corticosteroid therapy for at least 28 days prior to C1D1.
3. Has uncontrolled hypertension defined as blood pressure > 150/90 on medication(s) by 2 
blood pressure readings taken at least 1 hour apart.


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4. Has gastrointestinal abnormalities including:
a.
inability to take oral medication;
b. requirement for intravenous alimentation;
c.
prior surgical procedures affecting absorption including total gastric resection;
d. active gastrointestinal bleeding, unrelated to cancer, as evidenced by 
hematemesis, hematochezia or melena in the past 3 months without evidence of 
resolution documented by endoscopy or colonoscopy;
e.
malabsorption syndromes such as celiac disease, cystic fibrosis, inflammatory 
bowel disease, systemic sclerosis, and carcinoid syndrome
5. Has ocular conditions such as:
a.
Active infection or corneal ulcer
b. Monocularity
c.
Visual acuity of 20/70 or worse in both eyes
d. History of corneal transplantation
e.
Contact lens dependent (if using contact lens, must be able to switch to glasses 
during the entire study duration)
f.
Uncontrolled glaucoma (topical medications allowed)
g. Uncontrolled or active ocular problems (e.g., retinopathy, macular edema, active 
uveitis, wet macular degeneration) requiring surgery, laser treatment, or 
intravitreal injections
h. Papilledema or other active optic nerve disorder
6. Has used any investigational drug (including marketed drugs not approved for this 
indication) ≤14 days of C1D1.  No time limit applies to the use of marketed drugs 
approved for this indication provided that the subject has progressed on the treatment and 
all toxicities attributable to the drug have resolved, returned to baseline or stabilized. 
7. Has known sensitivity to any of the ingredients of:
a.
investigational product AGS-16C3F (Refer to IB for list of ingredients) and/or, 
b. Inlyta® (axitinib) (Refer to product package insert) and/or,
c.
1% prednisolone acetate ophthalmic suspension (Refer to Product package insert) 
and any other corticosteroids.
8. Is currently using (i.e., within 14-days prior to first dose) drugs that are known strong 
CYP3A4/5 inhibitors/inducers (See Appendix 12.1 for list of excluded drugs).
9. Thromboembolic event (e.g., DVT and PE) ≤ 4 weeks of C1D1. 
a.
Subjects who had a thromboembolic event ≤ 4 weeks of C1D1 must be receiving  
adequate anticoagulation treatment for at least 2 weeks before C1D1 and must 
continue as clinically indicated post first dose. 


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10. Has history bleeding disorders (e.g., pulmonary hemorrhage, significant hemoptysis, 
menometrorrhagia not responding to hormonal treatment) ≤ 2 months before C1D1
11. Has active angina or Class III or IV Congestive Heart Failure (New York Heart 
Association CHF Functional Classification System) or clinically significant cardiac 
disease within 6 months of randomization, including myocardial infarction, unstable 
angina, Grade 2 or greater peripheral vascular disease, congestive heart failure,  or 
arrhythmias not controlled by medication.
12. Had major surgery ≤4 weeks of C1D1
13. Is pregnant (confirmed by positive serum pregnancy test) or lactating
14. Has active infection requiring treatment with systemic (intravenous or oral) anti-
infectives (antibiotic, antifungal, or antiviral agent) ≤10 days of C1D1
15. Is unwilling or unable to comply with study requirements
16. Has any medical or psychiatric disorder that compromises the ability of the subject to 
give written informed consent, and/or comply with the study procedures as supported by 
subject records and/or documented by the investigator.
Waivers to the exclusion criteria will NOT be allowed. 
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
Investigational Drug – AGS-16C3F
AGS-16C3F is a fully human monoclonal antibody conjugated to a cytotoxic agent MMAF 
targeting ENPP3 (company code name AGS-16).  Subjects randomized to AGS-16C3F will 
receive AGS-16C3F at 1.8 mg/kg via IV infusion.
AGS-16C3F will be reconstituted with sterile water for injection (USP grade) and diluted in 
pyrogen-free 
 dextrose solution (USP grade).  Depending on the total dose of AGS-16C3F 
(i.e., reconstituted volume), the investigational product may also be administered undiluted. 
If diluted, the protein concentration must be ≥ 0.3 mg/mL.
AGS-16C3F will be administered via an infusion pump.  The total prescribed dose should be 
administered over 60 minutes, including time required to flush the line. Supplies necessary 
for infusion preparation will be supplied by the site pharmacy.
Refer to the Study Pharmacy Guide for reconstitution and infusion preparation instructions.
Comparator Drug – Axitinib (Inlyta®)
Inlyta® (axitinib, manufacturer Pfizer) is an oral kinase inhibitor indicated for the treatment 
of advanced RCC after failure of one prior systemic therapy. Axitinib is a commercial 
product and will be administered as defined in its product label. The Sponsor will provide 
axitinib for the study.
CCI


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Subjects randomized to axitinib will all have a starting dose of 5 mg, twice daily 
continuously, by mouth. This dose may be adjusted during the study as needed as defined in 
the product label and local institutional guidelines, in doses ranging from 2 to 10 mg, twice 
daily continuously, by mouth.  Drug to be used without further modification.
4.2
Packaging and Labeling
Each vial of AGS-16C3F Drug Product (DP) is supplied as a single-use, sterile, preservative-
free, lyophilized product (30 mg) in 20 mL glass vials to be stored refrigerated (2-8 °C).  Six 
(6) individually labeled vials will be packaged in a labeled carton for this study.  AGS-16C3F 
will be supplied to site pharmacy in the necessary quantity as a site supply (i.e., supply is not 
subject specific). 
Axitinib will be provided to subjects for the study in its original packaging with a study label 
affixed.  Axitinib will be dispensed in a whole bottle unit to each subject. Axitinib should be 
stored at room temperature (20-25 °C).
Refer to separate Pharmacy Guide for details.
4.3
Study Drug Handling 
For this protocol, the term “study drug” refers to both AGS-16C3F and axitinib, unless 
otherwise specified.
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the Sponsor are received by the investigator and

that such deliveries are recorded,

that study drug is handled and stored according to labeled storage conditions,

that study drug has an appropriate expiry date and is only dispensed to study subjects in 
accordance with the protocol, and

that any unused study drug is destroyed per local pharmacy SOP with appropriate 
destruction documentation or returned to the Sponsor designated vendor. 
Drug inventory and accountability records for the study drugs will be kept by the 
investigator. Study drug accountability throughout the study must be documented and 
reconciled. The following guidelines are therefore pertinent:

The investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol.

The investigator will keep the study drugs in a pharmacy or other locked and secure 
storage facility under controlled storage conditions, accessible only to those authorized 
by the investigator to dispense these test drugs.

A study drug inventory will be maintained by the investigator. The inventory will 
include details of material received and a clear record of when they were dispensed and 
to which subject.


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
At the conclusion or termination of this study, the investigator agrees to conduct a final 
drug supply inventory and to record the results of this inventory on the Drug 
Accountability Record. It must be possible to reconcile delivery records with those of 
used and/or destroyed/returned medication. Any discrepancies must be accounted for 
and documented. Appropriate forms of deliveries and returns must be signed by the site 
staff delegated this responsibility.

At the end of the study or after product expiry, with Sponsor approval, the site will 
destroy unused study drugs per local pharmacy SOP with appropriate destruction 
documentation.  If local destruction is not possible, contact the Sponsor for alternate 
destruction arrangements. 
Refer to Pharmacy Guide for details.
4.4
Assignment and Allocation
Randomization will be performed via Interactive Response Technology (IRT). After the 
subject has completed screening and the eligibility worksheet process, the site staff will 
access the study’s IRT system for subject randomization ≤ 5 days before C1D1. The IRT 
system will not allow randomization to occur if it has been more than 28 days since the main 
ICF has been signed. Specific procedures for randomization through the IRT are described in 
the study’s IRT manual.
Subjects will be randomized at 1:1 ratio to either AGS-16C3F or axitinib.  Randomization 
will be stratified according to ECOG Performance Status (0 or 1), the number of prior 
systemic RCC regimens (2 or > 2) and RCC histology (clear cell or non-clear cell).  
The RCC histology categorization is defined as the following:

Clear cell group:
o
Clear cell
o
Clear cell component
o
Mixed clear cell

Non-clear cell group:
o
Papillary and everything else*
* everything else: chromophobe, collecting duct, renal medullary, etc., not so common but 
possible other RCC histologies
Table 3
Stratification Categories for Randomization Process
Prior Systemic RCC Regimen 
Stratum 
Clear Cell Subjects
Non-Clear Cell Subjects
2 
2 prior systemic RCC regimens
1 prior systemic RCC regimen
> 2
> 2 prior systemic RCC regimens
> 1 prior systemic RCC regimens
Subject must start study treatment ≤5 days of randomization.


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5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug(s) and Other 
Medication(s)
Dose/Dose Regimen and Administration Period
5.1.1.1
AGS-16C3F
The dose of AGS-16C3F will be calculated based on the subject’s actual body weight in 
kilograms obtained predose C1D1 (baseline weight).  The same dose will be used throughout 
the study unless the subject’s baseline weight changes by ≥ 10%. The dose of AGS-16C3F 
will then be administered based on the weight change and this will become the new baseline 
weight.
The effects of overdose of this product are not known.
Each subject will receive AGS-16C3F every 3 weeks at 1.8 mg/kg through an IV infusion.
The 21-day dosing cycle time will reset at each dosing date (i.e., determine the next dosing 
date from the current actual dosing date). If for logistical reasons (e.g., public holidays, clinic 
scheduling, etc.) the next dose cannot be given 21 days from the last dose, a -2 day and a +7 
day dosing window is allowed. This window is intended to accommodate occasional 
scheduling conflicts and is not intended for routine use.  The Medical Monitor must be 
consulted for any dose delays that are due to toxicity and for dose intervals that exceed 5 
weeks.  Refer to Sections 5.1.2 and 5.1.1.3.
5.1.1.1.1
AGS-16C3F Infusion Related Adverse Events
Of the 34 subjects in the Phase 1 study (AGS-16C3F-12-2), 7/34 (20.6%) experienced an 
infusion related reaction; all were mild in severity (Grade 1/2). At the 1.8 mg/kg dose, 3/13 
(23.1%) reported an infusion related reaction; 2 were Grade 1 and 1 was Grade 2. All 
infusion related reactions were effectively managed with medication and no subject 
discontinued study due to infusion reaction.
The antibody moiety of this ADC is fully human and immune problems (e.g., anaphylactoid 
reactions) with ADCs of such type are rare.
5.1.1.1.2
AGS-16C3F Infusion Related Adverse Event Treatment Guidelines
The initial infusion should be administered, without premedication and the total prescribed
dose should be administered over 60 minutes, including flush of the line. After completion
of the infusion, subjects should be observed for signs of toxicity as necessary and 
appropriate.  It is recommended that each subject be observed for 1 hour after the first 
infusion. Observation time for subsequent infusions should be determined at Investigator 
discretion.
The following guidelines are recommended courses of action that the investigator should 
consider in an event of an infusion related reaction with AGS-16C3F administration.
Investigator may, in addition, follow his/her own institutional or local infusion reaction 
management guidelines:


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Table 4
Recommended Guidelines for Infusion Related Adverse Event 
Grade/ Severity
Description
Action
Grade 1 or 2
Mild fever, rash, pruritus, urticaria 
and wheezing; the subject is 
hemodynamically stable with no 
clinically significant changes in 
vital signs (i.e., temperature, pulse 
or heart rate, respiratory rate, or 
blood pressure)
May be treated with acetaminophen, 
diphenhydramine hydrochloride, H2 blocker (e.g., 
ranitidine) and/or steroids (e.g., methylprednisolone) 
as clinically appropriate.
The investigator may complete the remaining 
infusion with watchful monitoring at 50% decreased 
infusion rate.
Grade > 2
Anaphylaxis or anaphylactoid 
signs or symptoms; the subject has 
clinically significant changes in 
vital signs (i.e., temperature, pulse 
or heart rate, blood pressure or 
respiratory rate)
May be treated with steroids and/or epinephrine in 
addition to diphenhydramine, H2 blocker or 
acetaminophen as clinically indicated.
Terminate AGS-16C3F infusion in subjects 
experiencing severe infusion reactions with severe 
hemodynamic instability or respiratory distress. 
Subject should be discontinued from further 
treatment.
A subject who experienced an infusion related reaction should be provided similar 
prophylactic treatment in subsequent infusions. Infusion rate should be determined based on 
severity of prior infusion reaction(s) and how the subject tolerated the remainder of the 
infusion (i.e., after medical management of event).  
Recurrent Grade 2 and 3 infusion reactions, in spite of optimum medical management, must 
be discussed with the Medical Monitor. Study treatment discontinuation should be considered 
for recurrent Grade 3 events.
5.1.1.2 Axitinib
Axitinib will have a starting dose of 5 mg, administered twice daily continuously, by mouth.   
Refer to product label for details. Axitinib subjects will return to clinic every 21 days for 
clinical assessment and additional axitinib dispensing.  If for logistical reasons (e.g., public 
holidays, clinic scheduling, etc.) the next clinic visit cannot occur 21 days from the last visit, 
a -2 day and a + 7 day visit window is allowed. This window is intended to accommodate 
occasional scheduling conflicts and is not intended for routine use.  The Medical Monitor 
must be consulted for any study visit delays that are due to toxicity and for treatment hiatus 
that exceeds 5 weeks.  Refer to Section 5.1.1.3.
5.1.1.3 Treatment Hiatus
For both treatment arms, subjects will have disease assessments every 8 weeks (± 7 days) 
counting from C1D1, irrespective of any treatment hiatus.

Subject may stay on study if the disease status is at least Stable Disease (SD) per 
RECIST v.1.1. 

If the treatment hiatus will be longer than 5 weeks, each case must be discussed with the 
Medical Monitor.


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Increase or Reduction in Dose of the Study Drug(s)
The Medical Monitor must be consulted for all AGS-16C3F toxicities that may require 
adjustment in treatment schedule and/or dose. AGS-16C3F dose modifications and/or 
treatment schedule modifications must be discussed and agreed to in writing by the Medical 
Monitor on a case-by-case basis before any adjustment is made.  
Axitinib dose may be adjusted during the study as needed as defined in the product label and 
local institutional guidelines, in doses ranging from 2 to 10 mg, twice daily continuously, by 
mouth.  
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy)
All medications and concomitant treatments administered from date of ICF signature through 
the last formal follow-up observational period must be recorded in the eDC system. 
5.1.3.1
Prophylactic Steroid Eye Drop Use (AGS-16C3F Subjects Only)
Subjects randomized to AGS-16C3F must use 1% prednisolone acetate ophthalmic 
suspension prophylactically (prophylaxis steroid drops) starting from Day (-1) of each 
treatment cycle.  Prophylaxis steroid drops will be applied to both eyes, 1 drop to each eye, 
6 times daily while awake for the first 7 days of each cycle (starting at Day [-1]), then 4 times 
daily while awake for an additional 7 days, and then stopped.  This will be repeated in each 
treatment cycle.  Refer to Table 5 below. 
Should the subsequent dose be delayed, the “no prophylaxis steroid eye drop use” period will 
extend.  The study will not provide the prophylaxis steroid drops (i.e., each site to supply); 
but the cost will be reimbursed.




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Table 6
Prohibited Medications for Subjects Randomized to AGS-16C3F
Prohibited Medication
Reason to Exclude
1
Chemotherapy, radiotherapy, immunotherapy, monocolonal 
antibody therapy or other medications intended for antitumor 
activity1
Likely affect efficacy, safety or 
pharmacokinetics of AGS-
16C3F
2
Investigational products or therapy other than AGS-16C3F 
1 Palliative radiation is permitted provided it does not interfere with subject safety and efficacy of the study drug 
being administered. Palliative radiation cannot be administered to any target lesion. Medications used to treat 
bone metastases (e.g., zoledronic acid, denosumab, etc.) are allowed provided they are not initiated at the same 
time as Cycle 1 Day 1.
5.1.3.2.2
Subjects Randomized to Axitinib
The following medications are likely to influence evaluation of the safety, pharmacokinetics 
or efficacy of axitinib. If the investigator determines that any of the following medications 
are necessary to provide adequate medical support, the subject must be withdrawn from 
further study drug administration:
Table 7
Prohibited Medications for Subjects Randomized to Axitinib
Prohibited Medication
Reason to Exclude
1
Chemotherapy, radiotherapy, immunotherapy, monocolonal 
antibody therapy or other medications intended for antitumor 
activity other than axitinib1
Likely affect efficacy, safety or 
pharmacokinetics of AGS-
16C3F
2
Investigational products or therapy
3
Strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, 
phenytoin, carbamazepine, rifabutin, rifapentin, 
phenobarbital, and St. John’s wort)2
Axitinib is a substrate of 
CYP3A4/5
1 Palliative radiation is permitted provided it does not interfere with subject safety and efficacy of the study drug being 
administered. Palliative radiation cannot be administered to any target lesion. Medications used to treat bone metastases 
(e.g., zoledronic acid, denosumab, etc.) are allowed provided they are not initiated at the same time as Cycle 1 Day 1.
2 The drugs defined as CYP Substrates with Narrow Therapeutic Range by FDA’s guidance - Guidance for Industry Drug 
Interaction Studies - Study Design, Data analysis, and Implications for Dosing and Labeling): 
http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf)
The use of the following medications and foods should be avoided or used with caution and 
closely monitored:
Table 8
Medications/Food to be Avoided or Used with Caution for Subjects 
Randomized to Axitinib
Medications/Food to be Avoided or Used with Caution1
Reason to be Cautious
1
Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, 
etravirine, modafinil, and nafcillin)2
Axitinib is a substrate of 
CYP3A4/5
2
Strong CYP3A4/5 inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, erythromycin, atazanavir, indinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, and telithromycin); Grapefruit 
or grapefruit juice2
1 Please refer to the product label for additional guidance
2 The drugs defined as CYP Substrates with Narrow Therapeutic Range by FDA’s guidance - Guidance for Industry Drug 
Interaction Studies - Study Design, Data analysis, and Implications for Dosing and Labeling): 
http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf)


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Treatment Compliance
5.1.4.1
AGS-16C3F
For the purpose of this study, an overdose will be defined as any dose exceeding the 
prescribed dose by greater than 20%. In the event of an overdose, refer to Section 5.7.9.
Compliance for prophylaxis steroid eye drop use will be qualitatively assessed at each visit 
through the study coordinator/nurse administered ESQ.
5.1.4.2
Axitinib
Study subjects are expected to adhere to the investigator’s prescribing instructions. The 
investigator will ensure that subjects are following the prescribing instructions throughout the 
study.   This will be assessed by accounting for the total number of tablets dispensed and 
returned at each visit and documenting it in the subject’s medical records.If the subject is not 
adequately following the prescribing instructions, the investigator will counsel the subject 
and ensure steps are taken for improvement. 
Subjects randomized to the axitinib arm must bring their axitinib bottles (including empty 
bottles), to each clinic visit.
In the event of an overdose, refer to Section 5.7.9.
5.2
Study Assessments and Procedures
Tissue for Target Expression IHC Testing
All subjects are required to submit tumor tissue for target expression assessment by IHC in 
the study.  At least 5 tumor tissue sections (4 microns thick) or a tumor block must be 
provided for the assay.  If no archive tissue is available, the subject may elect to have a 
biopsy performed to obtain tissue.  
Non-Clear Cell Subjects
Tumor tissue, from primary or metastatic site (excluding bone), will be submitted to the 
Sponsor-designated CLIA certified laboratory for ENPP3 determination by IHC.  An IHC 
H-score of ≥ 15 is required for non-clear cell subjects to qualify for study screening.  IHC 
H-scores for ENPP3 eligibility will not expire for the duration of the study (i.e., there is no 
time limit from prescreen qualification to screening start).
Every effort will be made to report the IHC H-score to the investigator ≤72 hours of sample 
receipt at the Sponsor-designated CLIA certified laboratory provided that the specimens were 
received in good condition along with all required documents fully completed.  Refer to 
Study Guide for details.
Clear Cell Subjects
Clear cell histology subjects are not required to be screened for target expression to qualify 
for the study, however, the source and availability of archive tissue must be confirmed to 
meet study eligibility criteria (Inclusion #6).  Tissue should be submitted for IHC testing 
< 3 months from main study consent form signature date.  Consent to provide tissue is 


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included in the main study informed consent form.  Clear cell histology subjects’ specimens 
will be batch assayed during the study.  The IHC H-score will be reported back to the 
investigator for information only when the data become available.
Prescreening Period
Prescreening of target expression testing is only required for non-clear cell subjects.  Refer to 
details in Section 5.2.1.  Non-clear cell subjects must sign a prescreening informed consent 
form to obtain and submit tissue for the study and be prescreened for ENPP3 expression prior 
to undergoing screening procedures for the main study.  Only those with an IHC H-score 
≥ 15 qualify to proceed with screening. A copy of all signed and dated informed consent 
forms must be given to the subject before any study specific procedure is performed.  
Screening Period
All subjects with RCC of clear cell histology and subjects with RCC of non-clear cell 
histology who have received an IHC H-score of ≥ 15 are eligible for screening.
All subjects who are eligible to screen will sign the main study ICF ≤ 28 days of C1D1. A 
copy of all signed and dated informed consent forms must be given to the subject before any 
study specific procedure is performed. Subjects may undergo study screening procedures 
prior to giving informed consent provided they are considered standard of care. 
The following screening procedures must be performed ≤28 days of the C1D1 date, unless 
otherwise noted.

Medical history, including previous renal cancer therapies; refer to Section 5.3.2

Physical Examination including vital signs (blood pressure, heart rate, and respiration 
rate) and weight

ECOG Performance Status score; refer to Appendix 12.5

Hematology, chemistry, CRP, and PT/aPTT evaluations (≤10 days of the C1D1; refer to 
Section 5.6.3)

Thyroid Function Tests; refer to Section 5.6.3

uPCR

Serum pregnancy test (women of childbearing potential; ≤ 10 days of the C1D1)

Electrocardiogram (ECG) (in triplicate, approximately 3-5 minutes in between ECGs); 
≤10 days of the C1D1; refer to Section 5.6.4

Disease assessment; refer to Section 5.5
o
CT scan of the chest, abdomen, and pelvis (Magnetic Resonance Imaging (MRI) is 
acceptable to assess disease extent if used throughout the study).
o
Imaging of the brain (e.g., MRI or CT), if clinically indicated
o
Bone imaging, if clinically indicated. The imaging method will be any imaging 
modality per local or institutional standard of care (SOC) (e.g., NaF PET, MRI 
Bone, Tc-99 Bone Scan, etc.)


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
Complete eye exam for all subjects; refer to Section 5.6.5

Complete ESQ for both Cancer Treatment History and Screening sections; refer to 
Section 5.6.5.1

Randomization; refer to Section 5.2.5 for additional details

Tumor Tissue; refer to Section 5.2.1

Complete and submit an eligibility worksheet for review. Please see the Study Guide for 
the form and for complete instructions
Subjects who do not meet the eligibility criteria may be re-screened at the discretion of the 
Investigator. 
Enrollment
In this study, subjects are considered enrolled once randomized.
Randomization
See Section 4.4 and the separate relevant study manuals for details. Randomization will occur 
after screening has been completed and must be done ≤5 days of C1D1. Randomized 
subjects will not be replaced, whether or not, the subject receives study treatment.
Treatment Period
On C1D1, all procedures, other than post-infusion specific procedures, must be performed 
BEFORE first dose of study drug is administered and meet all inclusion and exclusion 
criteria. 
During the treatment period, subjects who have a standard of care tumor biopsy or surgery, 
will have the opportunity to submit part of the sample for ENPP3 analysis. The subject will 
indicate their choice in the informed consent form.
5.2.6.1
Cycles 1 – 4
All predose procedures below may be performed ≤ 4 days in advance of the actual dosing 
day, with the exception of the following which must be done on the dosing day:

Vital signs

ECG (C1D1 Only)

Predose PK sample collection for AGS-16C3F subjects on Cycles 2-4.  Predose PK 
sample for Cycles 2-4 must be collected anytime before AGS-16C3F drug 
administration on the day of infusion.

Physical exam and body weight

Vital signs; refer to Section 5.6.1: 
o
For AGS-16C3F Subjects: On the days of study drug administration, vital 
signs will be taken predose, and approximately 30 minutes after 
administration of study drug 


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o
For axitinib Subjects: Vital signs will be taken once at each clinic visit

ECG (C1D1 only); refer to Section 5.6.4: 
o
For AGS-16C3F Subjects: It will be done predose (anytime predose on actual 
dosing day) and 2 hours after the end of infusion, when the total prescribed 
dose has been administered (e.g., 2 h after the end of infusion), both in 
triplicate (approximately 3-5 minutes in between ECGs).  Ensure that the 
subject is in the same position for every reading
o
For axitinib Subjects: ECG will be taken in triplicate (approximately 3-5 
minutes in between ECGs) predose (anytime predose on actual dosing day). 
Ensure that the subject is in the same position for every reading

ECOG Performance Status; refer to Appendix 12.5

Hematology, chemistry, CRP, and PT/aPTT; refer to Section 5.6.3. 

Thyroid Function Test, every odd cycle (e.g., Cycle 1, Cycle 3, etc.); refer to Section 
5.6.3

uPCR, every odd cycle (e.g., Cycle 1, Cycle 3, etc.); refer to Section 5.6.3

Complete eye exam for AGS-16C3F subjects only will be done after the Cycle 2 Day 
1 dose but before the Cycle 3 Day 1 dose, and as clinically indicated; refer to Section 
5.6.5

Complete ESQ at every scheduled and unscheduled visit; refer to Section 5.6.5.1

PK and ADA blood samples will be collected for AGS-16C3F subjects only; refer to 
Table 1 and Table 2

Disease assessment; refer to Section 5.5
5.2.6.2 Cycles 5 and Beyond
Procedures below will be done starting at Cycle 5 and every 3 weeks thereafter, unless 
otherwise specified. All predose procedures below may be performed ≤ 4 days in advance of 
the actual dosing day, with the exception of the following which must be done on the dosing 
day:
a. Vital signs

Physical exam and body weight

Vital signs; refer to Section 5.6.1: 
o
For AGS-16C3F Subjects: On the days of study drug administration, vital 
signs will be taken predose,  and approximately 30 minutes after 
administration of study drug 
o
For axitinib Subjects: Vital signs will be taken once at each clinic visit

ECOG Performance Status; refer to Appendix 12.5

Hematology, chemistry, CRP, and PT/aPTT; refer to Section 5.6.3


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
Thyroid Function Test, every odd cycle (e.g., Cycle 5, Cycle 7, etc.); refer to Section 
5.6.3

uPCR, every odd cycle (e.g., Cycle 5, Cycle 7, etc.); refer to Section 5.6.3

Complete eye exam for AGS-16C3F subjects only will be done after the Cycle 5 Day 
1 dose but before the Cycle 6 Day 1 dose, and as clinically indicated; refer to Section 
5.6.5

Complete ESQ at every scheduled and unscheduled visit; refer to Section 5.6.5.1

PK and ADA blood samples will be collected for AGS-16C3F subjects only; refer to 
Table 1 and Table 2

Disease assessment; refer to Section 5.5
Post-treatment Follow-Up Period (Safety Follow-Up visit)
All subjects will be required to have a Safety Follow-Up visit at least 28 days (+ 7 days) after 
the last dose. Every effort should be made to have this visit occur within the specified 
timeframe. If this visit cannot be performed within the specified timeframe (e.g., subject 
initiating new treatment, subject admitted to hospice), this visit should be scheduled as close 
as possible to the specified timeframe. To ensure subject’s wellbeing and safety, a Safety 
Follow-Up visit performed outside of the window is strongly preferred over no Safety 
Follow-Up Visit.
Procedures below will be done during the Safety Follow-Up Visit, unless otherwise specified.

Physical exam and body weight

Vital signs; refer to Section 5.6.1

ECG in triplicate (approximately 3-5 minutes in between ECGs). Ensure that the 
subject is in the same position for every reading; refer to Section 5.6.4

ECOG Performance Status; refer to Appendix 12.5

Hematology, chemistry, CRP, Thyroid Function Test, PT/aPTT, and uPCR; refer to 
Section 5.6.3.

Complete eye exam as clinically indicated; refer to Section 5.6.5

Complete ESQ; refer to Section 5.6.5.1

PK and ADA blood samples will be collected for AGS-16C3F subjects only, as 
specified in Table 1 and Table 2.
5.3
Demographics and Baseline Characteristics
Demographics
Age at first dose, gender, sex, race, ethnicity, height, and body weight will be collected 
during the Screening visit for this study.


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Medical History
Medical history will be recorded for all medical conditions within the past 5 years from the 
date of randomization. Please use the following list as a minimum guideline for what should 
be collected and entered into the eDC system.

Record all cancer diagnoses.

Record all diseases and/or diagnoses requiring cytotoxic treatment (e.g., including non-
oncology treatments such as arthritis treated with methotrexate).

Record all diseases and/or diagnoses of major organs (e.g., myocardial infarction, 
hepatitis).

Record all non-renal cell cancer history.
Diagnosis of the Target Disease, Severity, and Duration of Disease 
A complete medical history of the target disease will be recorded at Screening. This will 
include:

RCC diagnosis (date and method of diagnosis, including dates of diagnostic procedures)

TNM classification and disease stage at screening

Metastasis diagnosis date

Dates and type of previous therapy for RCC

Other disease specific information as designated in the eCRF
5.4
Pharmacokinetics Assessment
The PK data for ADC and MMAF will be analyzed using noncompartmental method. 
Parameters to be assessed will include concentrations at the end of infusion or maximum 
observed concentration (CEOI or Cmax), concentrations at trough (Ctrough), time to maximum 
observed concentration (Tmax), partial area under the concentration time curve (AUCτ) for 
Cycle 1 and 4, and either terminal or apparent terminal half-life (t1/2) as appropriate. 
Additionally, clearance (CL) and volume of distribution at steady state (Vss) will be included 
as appropriate. Descriptive statistics will be provided for the PK parameter estimates and 
subject concentration plots over time may be generated. Additional model-based analyses 
may be performed and reported separately.
5.5
Efficacy Assessment
Response and progression will be evaluated in this study using RECIST v.1.1, refer to 
Appendix 12.6.  Investigator’s radiographic disease assessment will be used for treatment 
decisions.
Disease assessments will be performed every 8 weeks (± 7 days) counting from C1D1.  Bone 
imaging will be performed every 12 weeks (± 7 days) counting from C1D1 (only subjects 
with bone disease at screening).
Those subjects who discontinued the study for reasons other than objective disease 
progression by RECIST v.1.1 will continue to have disease assessments every 8 weeks (± 7 


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days) counting from C1D1. This will continue until subject has radiologically confirmed 
progression, initiates a new therapy, study closure or subject dies.
Scans will be read on site.
CT scan with contrast (chest, abdomen, and pelvis) is the preferred modality for tumor 
assessment. MRI is acceptable if local standard practice, or CT scans are contraindicated in a 
subject (e.g., subject is allergic to contrast media). All other RECIST-approved scanning 
methods such as x-ray are optional. PET-CT scans must use contrast. The modality chosen 
for the subject must be used throughout the study. 
Additional instructions for imaging assessments can be found in the study guide. The
assessment will include tumor measurements for target lesions, nontarget lesions, and any 
new lesions. An overall assessment will be characterized for a given time point evaluation. At 
the end of study for that subject, the best overall response to the study regimen will be 
characterized. To ensure comparability, the screening and subsequent assessment of response 
should be performed using identical techniques. The same individual should assess images 
for any 1 subject for the duration of the study if possible. 
For subjects with known treated stable brain metastases at study entry, it is recommended that 
repeat imaging also include the brain and the same methods used to detect brain lesions at 
baseline are to be used to follow the lesions throughout the study. 
Per RECIST v1.1, lesions that cannot be accurately measured such as bone lesions and 
previously radiated lesions should not be selected as measurable lesions.   
Confirmation scans for CR or PR should be done at the next scheduled assessment. The site 
of disease progression as well as target or nontarget lesion should be documented in the 
eCRF. Additional imaging may be performed at any time to confirm suspected progression of 
disease.  
Evaluation of Target Lesions
5.5.1.1
Complete Response (CR)
CR is defined as disappearance of all target and nontarget lesions. Any pathological lymph 
nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from 
baseline measurement.
5.5.1.2
Partial Response (PR)
PR is defined as at least a 30% decrease in the sum of diameters (longest for nonnodal 
lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum 
of diameters.
5.5.1.3
Stable Disease (SD)
SD is defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify 
for progressive disease taking as reference the smallest sum of diameters while on study drug.


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5.5.1.4
Progressive Disease (PD)
PD is defined as at least a 20% increase in the sum of diameters (longest for nonnodal 
lesions, short axis for nodal lesions) of the target lesions taking as reference the smallest sum 
on study (this includes the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. The appearance of 1 or more new lesions is also considered progression.
Evaluation of Nontarget Lesions
To achieve unequivocal progression on the basis of nontarget lesions, there must be an 
overall level of substantial worsening in nontarget disease such that, even in presence of SD 
or PR of target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest increase in the size of 1 or more nontarget lesions is 
usually not sufficient to qualify for unequivocal progression.
5.5.2.1
Complete Response (CR)
For CR of nontarget lesions, subjects must have disappearance of all nontarget lesions and all 
lymph nodes must be nonpathological in size (< 10 mm short axis).
5.5.2.2
NonCR/NonPD
NonCR/NonPD of nontarget lesions is defined as persistence of 1 or more nontarget lesions.
5.5.2.3
Progressive Disease (PD)
PD of nontarget lesions is defined as unequivocal progression of existing nontarget lesions or 
the appearance of 1 or more new lesions.
Evaluation of Time Point Response
The overall response status at each time point for subjects with measurable disease at 
baseline will be reported according to Table 1 in Appendix 12.6.
5.6
Safety Assessment
Vital Signs
Measurements consisting of blood pressure, heart rate, respiration rate, and temperature will 
be collected throughout this trial. Vital signs will be collected according to the schedule 
displayed in Table 1.

For subjects randomized to AGS-16C3F, on the days of study drug administration, vital 
signs will be taken predose, and approximately 30 minutes after administration of study 
drug 

For subjects randomized to axitinib, vital signs will be taken once at each clinic visit
Adverse Events
See Section 5.7 for information regarding AE collection and data handling. 


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5.6.2.1 Adverse Events Requiring Treatment Modifications and/or Discontinuation of 
AGS-16C3F Administration
5.6.2.1.1
Thrombocytopenia
For thrombocytopenia without signs and symptoms of bleeding that the investigator 
considers clinically significant, the following AGS-16C3F dosing guidelines will be used.
Table 9
Recommended Guidelines for Thrombocytopenia
Grade
Description
Action
2
Present, without signs and symptoms of 
bleeding.
The dose may be administered or held at 
investigator discretion.
Persistent (i.e., lasting for ≥ 5 weeks), 
without signs and symptoms of bleeding, 
and without documented bone marrow 
suppression.
The subject may be considered for a dose 
reduction to 1.2 mg/kg. Dose reduction 
must be discussed with and approved in 
writing by the Medical Monitor.
Persistent (i.e., lasting for ≥ 5 weeks), 
without signs and symptoms of bleeding, 
and with documented bone marrow 
suppression.
The subject will be discussed with the 
Medical Monitor. The possible need for 
permanent discontinuation will be 
considered based on clinical benefit of 
treatment as well as review of overall 
patient profile (concomitant medication 
and medical history review, presence or 
absence of mucosal bleed, other AEs, etc.).
3
Present, without signs and symptoms of 
bleeding.
The dose will be held until platelet count 
improves to at least Grade 2 
(≥ 50 x 109/L).
Present, without signs and symptoms of 
bleeding, and has not recovered to at least 
Grade 2 (≥ 50 x 109/L) ≤ 5 weeks. 
The subject will either be permanently 
discontinued or may be considered for a 
dose reduction to 1.2 mg/kg. Dose 
reduction must be discussed with and 
approved in writing by the Medical 
Monitor.
4
Present, without signs and symptoms of 
bleeding, and platelet count is confirmed 
with a repeat lab performed ≤ 72 hours.
Subject will be permanently discontinued.
Present, without signs and symptoms of 
bleeding, and isolated (i.e., not confirmed 
with a repeat lab ≤ 72 hours after first 
assessment).
Dose will be held until platelet count 
improves to at least Grade 2 
(≥ 50 x 109/L)
Present, without signs and symptoms of 
bleeding, and isolated (i.e., not confirmed 
with a repeat lab ≤ 72 hours after first 
assessment), and has not recovered to at 
least Grade 2 (≥ 50 x 109/L) ≤ 5 weeks.  
The subject will either be permanently 
discontinued or may be considered for a 
dose reduction to 1.2 mg/kg. Dose 
reduction must be discussed with and 
approved in writing by the Medical 
Monitor.
Beginning at Cycle 5 Day 1 and for all subsequent cycles, a bone marrow study or 
hematology consult, is strongly encouraged for all AGS-16C3F subjects whose predose 
platelet count is < 75 x 109/L at any 2 timepoints.  If a hematology consult and/or bone 


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marrow study is/are performed, the redacted report(s) will be timely submitted to the 
Sponsor.
5.6.2.1.2
Adverse Events of Possible Hepatic Origin 
See Appendix 12.2 for detailed information on the monitoring and assessment of liver 
abnormalities, if the AE for a subject enrolled in a study and receiving study drug is 
accompanied by increases in liver function testing (LFT, e.g.: AST, ALT, bilirubin, etc.) or is 
suspected to be due to hepatic dysfunction. 
Subjects with AEs of hepatic origin accompanied by Liver Function Test (LFT) 
abnormalities should be carefully monitored.  
5.6.2.1.3
Other Adverse Events
Subjects who experience a Grade 4 toxicity other than those related to the eye, liver, and 
thrombocytopenia, as described in Sections 5.6.5, 5.6.2.1.2, 5.6.2.1.1 will be permanently 
discontinued from AGS-16C3F treatment.  Laboratory AEs with a Grade 4 value, must be 
confirmed with a repeat analysis ≤ 72 hours before discontinuing subject from treatment.  
See Sections 5.7.1 and 6.1 for additional guidance.
Laboratory Assessments
Below is a table of the safety laboratory tests that will be performed locally during the 
conduct of the study. See Table 1 for study visit collection dates. 
Chemistry 
Coagulation
Urine
Hematology
Sodium 
BUN
PT/aPTT
uPCR
CBC including 
platelet number and 
differential
Potassium 
Creatinine
Chloride 
Uric Acid
Bicarbonate 
Total bilirubin
Thyroid Function
Total protein
Direct bilirubin
TSH
Albumin
Alkaline phosphatase
Free T4
Calcium
LDH
Magnesium
AST (SGOT)
Phosphorus
ALT (SGPT)
Glucose
CRP
5.6.3.1
Pharmacokinetic and ADA samples
Subjects randomized to AGS-16C3F, will have blood samples drawn for PK and ADA 
formation assessments. Refer to Table 1 and Table 2. 
Electrocardiogram (ECG) 
ECGs will be done in triplicate for all timepoints, approximately 3-5 minutes between each 
assessment. Ensure that the subject is in the same position for every reading.
ECGs will be collected at Screening, C1D1, and at the Safety Follow-Up visits.


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For subjects randomized to AGS-16C3F, on C1D1, the ECGs will be taken predose (anytime 
predose on actual dosing day) and again 2 hours after the end of infusion, when the total 
prescribed dose has been administered (e.g., 2 h after the end of infusion).
For subjects randomized to axitinib, on C1D1, the ECGs will be taken predose (anytime 
predose on actual dosing day) only.
Ocular Assessments
A complete eye exam will be done during screening. Subjects randomized to AGS-16C3F,
will have a complete eye exam done after the Cycle 2 Day 1 dose but before the Cycle 3 Day 
1 dose, after the Cycle 5 Day 1 dose but before the Cycle 6 Day 1 dose, and as clinically 
indicated. Subjects randomized to axitinib, will have a complete eye exam done post baseline 
as clinically indicated. The frequency of ophthalmology follow-ups outside of protocol 
requirement is at the discretion of the Investigator and ophthalmologist.
The ophthalmologist will complete a study provided cover form, capturing all pertinent 
information, and submit it along with the ophthalmology report to the investigator.  Please 
see the Study Guide for the form and for complete instructions.
At the screening (baseline) ophthalmology visit, the complete eye exam will consist of Visual 
Acuity with Snellen Chart, best corrected visual acuity (BCVA), intraocular pressure (IOP), 
extraocular movement (EOM), pupils, external exam, slit lamp exam, and dilated 
fundoscopic exam.
For post baseline ophthalmology visits, the complete eye exam will be the same as the 
baseline visit, but the dilated fundoscopic exam may be deferred if not clinically indicated 
(i.e., if there is no change in vision or if the vision change can be explained as a non-retinal 
event). If deferred, an undilated fundoscopic exam is still required as part of the full eye 
exam.
The Schirmer’s test (with and without anesthetic) is optional if subject has dry eyes at 
screening (baseline).
5.6.5.1
Symptom Based Ocular AEs
Ocular symptoms reported by the subject during clinic visits will be graded per CTCAE 
v4.03 (i.e., symptom based assessment) and this will guide the treatment decision for that 
visit and the necessity for a follow up ophthalmology consult.  
An Eye Symptom Questionnaire (ESQ) will be administered at every visit in the oncology 
clinic. Please see the Study Guide for the form and for complete instructions. During 
screening, the ESQ will be completed for both Cancer Treatment History and Screening 
sections.
The ocular symptom AEs must be collected in the eDC system. 


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If a subject reports ocular symptoms, the following guidelines may be used:
Table 10
Subject Reported Symptom Based Ocular AE (i.e., per CTCAE v4.03)
Grade
Study Treatment Action
Ophthalmology Referral
1
Continue per dose and schedule 
(i.e., AGS-16C3F 1.8 mg/kg q3w or 
axitinib 5 mg, twice daily)
May be done at Investigator discretion
2
May continue treatment per dose and 
schedule at Investigator discretion
Required; must occur prior to the subsequent 
cycle.
3
Hold treatment
Required; must occur prior to the subsequent 
cycle.
5.6.5.2 Clinical Ocular Adverse Events (AE)
Clinical Ocular AEs are objective findings (e.g., keratitis, macular edema, retinal 
degeneration) from the ophthalmology evaluation. 
Clinical Ocular AE grading will be determined based on visual acuity (VA) change from 
screening (baseline).
This will be done as follows:
Step 1.
Determine baseline VA for each eye. Subject should have the VA measured 
with or without glasses depending on the subject’s requirement for daily use 
for distance vision. Use Table 12 and identify the row of the baseline vision 
for each eye.
Step 2.
Subsequent eye exam VA (obtained under same conditions as screening 
[baseline]), determine if a change in vision is present. If so, use the row in 
Table 12 identified in Step 1, to locate the current VA and determine the 
number of line-of-vision-change from baseline for each eye; this is expressed 
as the number in parenthesis. Also note the grade of the VA for each eye.  
Step 3.
Between the two eyes, determine the eye with greater line-of-vision-change 
from baseline (delta).  The Clinical Ocular AE grade for the subject is the 
grade of the worse (delta) eye. See examples 1 and 2 in Table 11. In the event 
both eyes have the same delta, then the Clinical Ocular AE grade comes from 
the eye with the worse new vision. See example 3 in Table 11.


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Table 11
Examples of Clinical Ocular AE: Keratopathy
Example 1
Baseline (CC)
New VA 
(CC)
Lines VA 
Change
VA 
Grade
Clinical Ocular 
AE Grade
OD
20/20
20/50
(4)
3
Grade 3
OS
20/40
20/70
(3)
2
Example 2
Baseline (SC)
New VA 
(SC)
Lines VA 
Change
VA 
Grade
Clinical Ocular
AE Grade
OD
20/60
20/125
(4)
3
Grade 3
OS
20/100
20/200
(2)
4
Example 3
Baseline (CC)
New VA 
(CC)
Lines VA 
Change
VA 
Grade
Clinical Ocular AE 
Grade
OD
20/30
20/80
(5)
3
Grade 4
OS
20/60
20/200
(5)
4
5.6.5.2.1
Treatment Guidelines for Clinical Ocular Toxicities
Corneal Clinical Ocular AEs 
If Clinical Ocular AE is Grade 3, Medical Monitor will be consulted for treatment 
decision.
If Clinical Ocular AE is Grade 4, subject will be permanently discontinued from study 
treatment.  
Non-corneal Related Clinical Ocular AEs
Clinical Ocular AEs other than ocular surface disease/keratopathy in nature, irrespective
of the grade, must be discussed with the Medical Monitor before the subsequent 
dose (per axitinib product label, patients treated with this product experienced both 
retinal artery and retinal vein occlusions. Please see product label for details).
If the subject develops a need or is recommended to have cataract surgery while on 
treatment in the study, discuss each case with the Medical Monitor.  


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Table 12
Visual Acuity Grading Chart
Baseline vision
(with or without 
correction, based on 
patient’s daily 
functional distance 
vision)
Grade 1*
(no change in 
vision from 
baseline)
Grade 2
(delta vision change 
= Number of line 
change in vision 
from baseline)
Grade 3
(delta vision 
change = Number 
of line change in 
vision from 
baseline)
Grade 4
(delta vision change = 
Number of line 
change in vision from 
baseline)
20/20
20/20
20/25 (1)
20/30 (2)
20/40 (3)
20/50 (4)
20/60 (5)
20/70 (6)
20/80 (7)
20/100 (8)
20/125 (9)
20/200 (10) or 
worse
20/25
20/25
20/30 (1)
20/40 (2)
20/50 (3)
20/60 (4)
20/70 (5)
20/80 (6)
20/100 (7)
20/125 (8)
20/200 (9) or 
worse
20/30
20/30
20/40 (1)
20/50 (2)
20/60 (3)
20/70 (4)
20/80 (5)
20/100 (6)
20/125 (7)
20/200 (8) or 
worse
20/40
20/40
20/50 (1)
20/60 (2)
20/70 (3)
20/80 (4)
20/100 (5)
20/125 (6)
20/200 (7) or 
worse
20/50
20/50
20/60 (1)
20/70 (2)
20/80 (3)
20/100 (4)
20/125 (5)
20/200 (6) or 
worse
20/60
20/60
20/70 (1)
20/80 (2)
20/100 (3)
20/125 (4)
20/200 (5) or 
worse
20/70
20/70
20/80 (1)
20/100 (2)
20/125 (3)
N/A
20/200 (4) or 
worse
20/80
20/80
20/100 (1)
20/125 (2)
N/A
20/200 (3) or 
worse
20/100
20/100
20/125 (1)
N/A
20/200 (2) or 
worse
20/125
20/125
N/A
N/A
20/200 (1) or 
worse
20/200
20/200
N/A
N/A
Worse than 20/200
*Grade 1 is the same as screening (baseline) from a VA perspective. The Grade 1 Clinical Ocular AE will be an 
event when the AE is present (e.g., keratopathy) but there is no change in VA from baseline and the subject has little 
to no symptoms.  If the AE is not treated aside from using artificial tears, then it would be considered Grade 1.


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5.6.5.2.2
Ophthalmology Findings
The ophthalmology report along with the completed study provided cover form will be 
forwarded to the Investigator in a timely manner. The investigator will review the 
ophthalmology report to guide further treatment decisions.  The ophthalmologist and/or 
Medical Monitor will be consulted as indicated in Section 5.6.5.2.1.  
The redacted ophthalmology report will also be forwarded to the Sponsor in a timely manner.
5.7
Adverse Events and Other Safety Aspects
Definition of Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
This definition is broadened in this study to include any such occurrence (e.g., sign, 
symptom, or diagnosis) or worsening of pre-existing medical condition.  Worsening indicates 
that the pre-existing medical condition has increased in severity, frequency, or duration of the 
condition or an association with significantly worse outcomes. 
Interventions for pretreatment conditions (e.g., elective cosmetic surgery) or medical 
procedures that were planned before study enrollment are not considered AEs.
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE.  In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are followed 
and the information is appropriately recorded in the eCRF accordingly.  
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets one of the 
following criteria:
Induces clinical signs or symptoms
Requires active intervention
Requires interruption or discontinuation of study medication
The abnormality or investigational value is clinically significant in the opinion of the 
investigator.
Disease progression should not be reported as an AE.  Rather signs and symptoms associated 
with disease progression should be reported.
All AEs occurring after the first dose of investigational product observed by the investigator 
or reported by the subject (whether or not attributed to investigational product), will be 
reported in the eCRF.  AEs will continue to be reported in the eCRF until 28 days post last 
dose, or at the subject’s Safety Follow-Up visit, whichever occurs later. SAEs and medically 
significant AEs considered related to the investigational product by the investigator or the 


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Sponsor will be followed until resolved or considered stable.  If a treatment-related adverse 
event is not resolved but is considered stable at the safety follow-up visit, this must be 
documented in the source documents.  
The following attributes must be assigned by the investigator:  description; dates of onset and 
resolution; severity; assessment of relatedness to investigational product, action taken, 
serious status and criteria.
It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient 
severity to require the subject’s removal from treatment. However, the Medical Monitor will 
be consulted prior to the subject being discontinued from study for safety reasons.    
Definition of Serious Adverse Events (SAEs)
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it results 
in any of the following outcomes: 
Results in death
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
Results in congenital anomaly, or birth defect
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 
Other medically important events
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 
definition above. These events, including those that may result in disability/incapacity, 
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.
Safety events of interest on the medicinal products administered to the subject as part of the 
study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:
Overdose of the medicinal product(s)
Suspected abuse/misuse of the medicinal product(s)
Inadvertent or accidental exposure to the medicinal product(s)


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Medication error involving the medicinal product(s) (with or without subject exposure to the 
Sponsor medicinal product, e.g., name confusion)
Criteria for Causal Relationship to the Study Drug
AEs that fall under either "Possible" or "Probable" should be defined as "AEs whose 
relationship to the study drugs could not be ruled out".
Causal relationship 
to the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a 
temporal  relationship to drug administration which makes a causal 
relationship improbable, and/or in  which other drugs, chemicals or 
underlying disease provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or 
unclear.
Probable
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to be 
attributed to concurrent disease or  other drugs or chemicals, and 
which follows a clinically reasonable response on re- administration 
(rechallenge) or withdrawal (dechallenge).
Criteria for Defining the Severity of an Adverse Event
All AEs, including abnormal clinical laboratory values, will be graded using the National 
Cancer Institute (NCI)-Common Terminology Criteria for Adverse Event (CTCAE) 
guidelines (Version 4.03). 
5.7.4.1
Study Specific Ocular Toxicity Grading Criteria
Refer to Section 5.6.5.
Reporting Procedures for All Serious Adverse Events (SAEs)
All SAEs occurring after the first dose of investigational product observed by the investigator 
or reported by the subject (whether or not attributed to investigational product), will be 
reported to the sponsor.  SAEs considered related to the investigational product by the 
investigator or the Sponsor will be followed until resolved or considered stable.  
All SAEs that occur up to the last formal follow-up observational period, must be reported 
≤1 working day of discovery or notification of the event.  
In the case of a SAE, the investigator must contact the sponsor by fax or email immediately 
(within 24 hours of awareness).
The investigator must complete and submit a SAE worksheet containing all information that 
is required by local and/or regional regulations to the sponsor by email or fax immediately 
(within 24 hours of awareness).


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For contact details, see [Section II Contact Details of Key Sponsor's Personnel]. Fax or email 
the SAE Worksheet to:
Astellas Pharma Global Development, Inc.
Pharmacovigilance
Fax number 1-888-396-3750
Alternate North America Fax number 1-847-317-1241
Email: safety-us@astellas.com
The investigator should notify the IRB/IEC/REB of SAEs occurring at the site and other AE
reports received from Sponsor, in accordance with local requirements and procedures.
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor/Expert or his/her designee (see Section II Contact Details of Key 
Sponsor’s Personnel). 
The SAE form should be completed with all available information but at the very bare
minimum the following information is required for a case to be valid:
Identifiable subject (Subject number)
Identifiable reporter (e.g., investigator)
A description of the SAE, and
Suspect drug
In addition to the above 4 critical information to establish a valid case, the following 
information is needed to assess the regulatory reporting requirement and Sponsor’s causal 
attribution:
Causality
Event description
Event onset date
Study drug treatment dates
Post initial SAE report submission, the investigator will promptly submit any relevant 
information that becomes available (e.g., information that impacts causality, changes event 
outcome, changes event severity). 
The Sponsor or Sponsor's designee will submit, as necessary, expedited safety reports (i.e., 
SUSAR [Suspected Unexpected Serious Adverse Reaction report]) to the pertinent regulatory 
agencies in the appropriate format according to International Conference on Harmonization 
(ICH) guidelines and applicable country-specific legal requirements, and will inform the 
investigators of such regulatory reports. Investigators must submit safety reports as required 
by their Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
Documentation of the submission to and receipt by the IRB/IEC must be retained by the site.
The Sponsor will notify all investigators of all expedited safety reports from all ongoing 
clinical studies with AGS-16C3F.
You may contact the Sponsor's Medical Monitor or IRB/IEC, depending on the nature 
of issue, for any questions related to subject safety, welfare, and/or rights.


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Follow-up of Adverse Events
SAEs and medically significant AEs considered related to the investigational product by the 
investigator or the Sponsor will be followed until resolved or considered stable.  
If a treatment-related adverse event is not resolved but is considered stable at the safety 
follow-up visit, this must be documented in the source documents.  
Please refer to Appendix 12.2 for detailed instructions on Drug Induced Liver Injury (DILI).
Monitoring of Common Serious Adverse Events
Common serious adverse events are SAEs commonly anticipated to occur in the study 
population independent of drug exposure. SAEs classified as “common” are provided in 
Appendix 12.3 for your reference. The list does NOT change your reporting obligations or 
prevent the need to report an AE meeting the definition of an SAE as detailed above. The 
purpose of this list is to alert you that some events reported as SAEs may not require 
expedited reporting to the regulatory authorities based on the classification of “common 
SAEs” as specified in Appendix 12.3. The Sponsor will monitor these events throughout the 
course of the study for any change in frequency. Any changes to this list will be 
communicated to the participating investigational sites. Investigators must report individual 
occurrences of these events as stated in Section 5.7.5.
Procedure in Case of Pregnancy
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or ≤6 months from the discontinuation of dosing, the investigator should report the 
information to the Sponsor as if it is an SAE. The expected date of delivery or expected date 
of the end of the pregnancy, last menstruation, estimated conception date, pregnancy result 
and neonatal data etc., should be included in this information.
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs (spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 
miscarried fetus]), the investigator should respond in accordance with the report procedure 
for SAEs. Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below.
"Spontaneous abortion" includes miscarriage, abortion and missed abortion
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth


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Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination
Emergency Procedures and Management of Overdose
The effects of overdose of this product are not known.
In the event of suspected AGS-16C3F overdose, the subject should be observed closely for 
signs of toxicity and as necessary and appropriate, receive supportive care. The Medical 
Monitor must be immediately notified of an overdose or a suspected overdose.
In the event of suspected overdose for axitinib, refer to the approved Package Insert, SPC, or 
local product information supplied by the manufacturer for the agent. 
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study, the 
Sponsor will inform all investigators involved in the clinical study as well as the regulatory 
authorities. Investigators should inform the IRB/IEC of such information when needed. 
5.8
Test Drug Concentration
Blood samples for the determination of serum AGS-16C3F concentrations will be collected 
according to Table 2:  
Cycle 1, Day 1: predose (before the AGS-16C3F infusion), end of infusion (EOI), 4 
hours, and Days 2 (24 hours), 4 (72 hours), and 15 (336 hours) post infusion 
Cycle 2, Day 22: predose (before the AGS-16C3F infusion)
Cycle 3, Day 43: predose (before the AGS-16C3F infusion)
Cycle 4, Day 64: predose (before the AGS-16C3F infusion), end of infusion (EOI), 4 
hours, and Days 65 (24 hours), 67 (72 hours), and 78 (336 hours) post infusion
Cycle 6, Day 106: predose (before the AGS-16C3F infusion)
Blood sampling, processing, storage and shipment instructions will be provided in the Lab 
Manual. Samples will be shipped to and analyzed by a Sponsor designated analytical 
laboratory. Please refer to the Lab Manual for more detailed information.
5.9
Total Amount of Blood
The approximate amount of blood to be collected from each subject at each time point is for 
all laboratory assessments is included in Appendix 12.4.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently discontinued prematurely for any reason.  
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 


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investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it.
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant. 
The subject will be discontinued from treatment if any of the following occurs:
Subject develops objective disease progression per RECIST v.1.1 criteria based on 
investigator assessment.
Subject develops clinical progression (if objective disease progression is not evaluated).
Subject develops a Grade 4 or unacceptable AE as assessed by the Investigator (Refer 
also to Section 5.6.2.1.3 and Section 5.6.5.2.1)
Investigator decides that it is in the subject’s best interest to discontinue.
Subject declines further study participation (i.e., study withdrawal).
A significant protocol deviation or non-compliance occurs with a subject that 
compromises study objectives or subject safety.
Subject is lost to follow-up despite reasonable efforts by the Investigator to locate the 
subject.
The study is terminated by the Sponsor.
The Medical Monitor must be contacted before a subject is discontinued from study treatment 
for reasons other than objective disease progression per RECIST v.1.1.
6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor.
6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of Astellas. A 
Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized before 
the database soft lock at the latest. Any changes from the analyses planned in SAP will be 
justified in the Clinical Study Report (CSR).


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Prior to Database Lock, a Final Review of Data and TLFs Meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 
documented.  A meeting to determine analysis set classifications may also be held prior to 
database lock.
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints.
7.1
Sample Size
For subjects with metastatic RCC that has progressed after at least 2 prior lines of therapy, a 
median PFS of 4 months is anticipated for the control agent.  It is hypothesized that AGS-
16C3F will improve median PFS in such subjects by 2 months (i.e., 4 vs 6 months).  Under 
the assumption of exponential distribution of PFS, such an improvement corresponds to a 
hypothesized hazard ratio of 0.667.  If this hypothesized hazard ratio is true, 110 PFS events 
provide 80% power to achieve a one-sided p-value of 0.1 or smaller.  Such a result will be 
achieved when the observed hazard ratio is 0.783 or smaller; and the observed difference in 
median PFS is 1.1 months or larger if the observed median for the control arm is 4 months.  
Assuming accrual of approximately 7 subjects per month for 18 months, 110 PFS events are 
projected 24 months after the date the first subject is randomized.  Approximately 134 
subjects may be enrolled to accommodate for up to 10% of subjects who may become lost to-
follow-up.
7.2
Analysis Set
Detailed criteria for analysis sets will be defined in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock. 
Full Analysis Set (FAS)
The full analysis set (FAS) will consist of all subjects who are randomized in accordance 
with the intention-to-treat (ITT) principle. This will be the primary analysis set for efficacy 
analyses. The subjects will be grouped for purposes of the analysis according to the treatment 
assigned by the randomization, regardless of whether the subject receives the correct drug 
assignment.
Per Protocol Set (PPS)
The per protocol set (PPS) will consist of the subset of the FAS who do not meet criteria for 
PPS exclusion. These criteria are to capture relevant non-adherence to the protocol and will 
be defined in the SAP. The sensitivity analysis for the primary and key secondary efficacy 
endpoints will be performed on PPS. Selected demographic and baseline characteristics may 
also be summarized for the PPS.


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Safety Analysis Set (SAF)
The safety analysis set (SAF) will consist of all subjects who receive at least one dose of 
study drug (AGS-16C3F or axitinib), with treatment assignments designated according to 
actually study treatment received. The SAF will be used for summaries of all safety variables.
Pharmacokinetic Analysis Set (PKAS): AGS-16C3F Only
The pharmacokinetic analysis set (PKAS) consists of the study population for which 
sufficient serum concentration data is available to facilitate derivation of at least one PK 
parameter and for whom the time of dosing on the day of sampling is known. Additional 
subjects may be excluded from the PKAS at the discretion of the pharmacokineticist. Any 
formal definitions for exclusion of subjects or time-points from the PKAS will be 
documented in the Classification Specifications and determined in the Classification Meeting. 
Pharmacodynamic Analysis Set (PDAS)
A pharmacodynamic marker has not yet been established for this target.
7.3
Demographics and Other Baseline Characteristics 
Demographics
Detailed information on subject demographics and other baseline characteristics will be 
reported. All baseline summary tables will be generated by treatment group for the FAS, PPS 
and SAF. If the analysis sets are identical the tables will only be presented only once in the 
CSR. 
Medical History
A detailed medical history for each subject will be obtained during screening period and will 
be summarized by treatment group for the FAS, PPS and SAF. 
Disease History
Data collected on RCC diagnosis, metastasis, histology, and additional relevant biological 
information will be summarized by treatment group for the FAS, PPS and SAF. Each 
subject’s complete cancer history will be listed. 
Previous and Concomitant Medications
The frequency of prior and concomitant medications categorized by preferred term (PT) will 
be summarized by treatment group for FAS, PPS and SAF. Medications will be coded using 
the WHO drug dictionary. Medications will be counted by the number of subjects who took 
each medication. The number and percentage of subjects who received prior therapies and the 
type of therapy will also be summarized by treatment group. 
7.4
Analysis of Efficacy 
Efficacy analyses will be conducted on the FAS and PPS. The FAS will be considered as 
primary and the PPS will be used as secondary to assess the robustness of the results from the 
statistical analyses based on the FAS.


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The PFS, DRC, ORR, DOR, and OS will be summarized using descriptive statistics. The 
survival curve and median for time-to-event variables will be estimated using the Kaplan-
Meier method and will be reported along with the corresponding 95% confidence interval 
(CI) calculated using Greenwood’s formula. 
For the inference comparison of the primary and secondary efficacy endpoints between the 
treatment groups, 2 stratification factors will be included: ECOG Performance Status (0 or 1) 
and the number of prior systemic RCC regimens (2 or > 2 for clear cell; 1 or > 1 for non-clear 
cell). Clear cell subjects with 2 prior lines of systemic treatment and non-clear cell subject 
with 1 prior line of systemic treatment will be grouped to the same stratum under the 
assumption that they have similar prognosis. Similarly, clear cell subjects with 3 or more 
prior lines of treatment and non-clear cell subjects with 2 or more prior lines of treatment will 
be allocated to the same stratum. Histology will not be used as a stratification variable in 
inferential comparison because a limited number of non-clear cell subjects is expected to be 
enrolled in the study (no more than 26 non-clear cell histology).
Analysis of Primary Endpoint 
7.4.1.1
Primary Analysis
The primary efficacy endpoint is progression-free survival (PFS), defined as the time from 
the date of randomization to the earliest of documented disease progression as defined by 
RECIST v 1.1 per investigator radiology review, or death from any cause. Disease 
assessment will continue until disease progression, even after the originally assigned 
treatment is discontinued.  
The primary analysis of investigator assessed PFS will be performed in accordance with the 
ITT principle in the FAS. All subjects who undergo randomization will be included in the 
primary analysis and grouped according to the treatment groups assigned by randomization.  
For the primary analysis of PFS, the difference in treatment effect between treatment groups 
will be tested using the stratified log rank test (on ECOG Performance Status and the number 
of prior systemic RCC regimens) at a one-sided 0.1 significance level.
Estimation of the hazard ratio for treatment and its corresponding one-sided 90% CI will be 
determined using a stratified Cox proportional hazards model (on ECOG Performance Status
and the number of prior systemic RCC regimens), without any other covariate. A two-sided 
95% CI will also be reported in the clinical study report. Homogeneity in the hazard ratios 
between strata will be examined by Wald’s test. The corresponding results without 
stratification will be reported as supplemental analyses. The adequacy of the model will be 
evaluated, including an assessment of the proportional hazards assumption (Therneau, 2000).
For the primary analysis, PFS will be right-censored for subjects who meet one or more of 
the following conditions:

Subjects with no post-baseline disease assessments unless death occurred prior to the 
first planned assessment (in which case death will be considered a PFS event)


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
Subjects who initiate subsequent anti-cancer therapy or intervention in the absence of 
documented progression

Subjects who die or have disease progression after missing 2 or more consecutively 
scheduled disease assessment visits

Subjects who are last known to be alive and progression-free on or before the data cut-
off date
For such subjects, PFS will be right-censored according to the conventions described in 
Table 13. These conventions are based on the May 2007 FDA Guidance for Industry 
“Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics”.
Table 13
Date of Progression or Censoring for PFS
Situation
Date of Progression or Censoring
Outcome
Death or disease progression between 
planned disease assessments
Date of death or first disease assessment 
showing disease progression, whichever 
occurs first
Progressed
Death before first planned disease 
assessment
Date of death
Progressed
No post-baseline disease assessments
Date of randomization
Censored
Non-protocol anti-cancer treatment started 
before death or without documentation of 
disease progression beforehand
Date of last disease assessment prior to start 
of non-protocol anti-cancer treatment
Censored
Death or disease progression after missing 
2 or more consecutively scheduled disease 
assessments
Date of last disease assessment visit without 
documentation of disease progression that is 
before the missed visit
Censored
Alive and without documentation of 
disease progression
Date of last disease assessment
Censored
7.4.1.2 Secondary Analysis
Sensitivity analyses will be performed to evaluate the robustness of the PFS results derived 
under the primary analysis (Bhattacharya 2009, Carroll 2007, Stone 2011).  Such sensitivity 
analyses will assess potential sources of bias due to 1) differences between the planned and 
actual schedule of disease assessments, 2) censoring for subsequent anti-cancer therapy, 
3) symptomatic or non-radiological disease progression, and 4) missed disease assessments 
due to reasons such as protocol deviations, consent withdrawal, and subjects lost to follow-
up. The corresponding PFS results without stratification will be reported as supplemental 
analyses. 
The same analyses of the primary PFS will be conducted using the PPS.
7.4.1.3 Subgroup Analysis
Exploratory subgroup analyses may be conducted to assess potential heterogeneity of 
treatment effects across levels of baseline characteristics such as age, gender, ECOG 


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Performance Status, the number of prior systemic RCC regimens and histology. Analyses 
will be performed for the FAS and PPS.
Analysis of Secondary Endpoints
Progression-free survival by blinded central radiology review and overall survival, defined as 
the time from the date of randomization until the date of death from any cause, will be 
evaluated as secondary endpoints. They will be analyzed using the same methodology as 
described for the primary endpoint in Section 7.4.1 as appropriate.
Best overall response will be tabulated for each treatment group using the crude portion of 
subjects whose best response during the course of protocol treatment is Complete Response 
(CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD) and non-
evaluable (NE). Tumor response will be determined using RECIST v 1.1. The primary 
analysis of the secondary tumor response endpoints will be based on investigator’s 
assessments; the secondary sensitivity analyses of these endpoints will be performed based
on the assessments by blinded central review. A best response CR or PR must be confirmed 
no less than 28 days after the criteria for response after first met. Disease control rate (DCR) 
will be estimated for each treatment group based on the crude proportion of subjects who 
have a best overall response of CR, PR or SD. For DCR, SD with a minimum duration of 6
months from the date of randomization is required. Objective response rate (ORR) will be 
estimated for each treatment group based on the crude proportion of subjects who have a best 
overall response of CR or PR. The method of Clopper and Pearson will be used to calculate 
two-sided 95% CIs for DCR and ORR, by treatment group, both overall and within 
stratification strata.
The inferential comparison between treatment groups for both DCR and ORR will be made 
using the stratified Cochran-Mantel-Haenszel chi-square test at a two-sided significance level 
of 0.05. An estimate of the relative risk (RR) of not experiencing OR with axitinib arm as the 
reference level will be provided as a measure of relative treatment effect. The RR and two-
sided 95% CI will be estimated using stratified Mantel-Haenszel method. Homogeneity in 
ECOG Performance Status by number of prior treatments strata will be examined at a 
significance level of 0.05 by two-sided Breslow-Day test. Similarly, the RR of not 
experiencing DC will be estimated with its two-sided 95% CI. 
Duration of objective response (DOR) is defined as the time from the date of the first 
response of CR or PR (whichever is first recorded), and subsequently confirmed, to the first 
date of documented progressive disease or death due to any cause. The DOR will be 
summarized descriptively using the 25th, 50th and 75th percentile (and 95% CI) of the Kaplan-
Meier curve for subjects who have best overall response of confirmed CR or PR, by 
treatment group, both overall and within randomization strata. The DOR will be censored 
using the same censoring rules, whenever applicable, as PFS.
Each of the secondary endpoints described above will be performed for the FAS and PPS. 
For the purpose of hypothesis generation, subgroup may be performed for selected baseline 
characteristics.


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Analysis of Exploratory Endpoints 
Not Applicable.
7.5
Analysis of Safety
Adverse Events
Safety will be evaluated based on the incidence of AEs (including Grade 3 and 4 AEs, 
treatment-related adverse events, serious adverse events, and AEs requiring discontinuation 
of study drug), laboratory changes and vital signs. AEs will be coded to system organ class 
(SOC) and preferred term (PT) using Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary and will be graded according to the National Cancer Institute (NCI) 
Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03. Ocular toxicities 
based on ophthalmology exams reported on the Eye Exam eCRFs will be graded using the 
study specific ocular criteria and these will be separately tabulated. The number and 
percentage of AEs, SAEs, AEs leading to discontinuation, and AEs related to study drug will 
be summarized by SOC, PT and treatment group. The number and percentage of AEs by 
severity will also be summarized. All summaries of AEs will include only treatment-
emergent events unless otherwise stated. Listings of AEs, SAEs, deaths, and events leading 
to discontinuation of study treatment will be presented.
Laboratory Assessments
Laboratory data will be summarized by shift tables (baseline toxicity grade versus worst 
postbaseline severity grade of toxicity) and Grade 3 and 4 values, by treatment group. 
Laboratory results will also be displayed in listings.
Vital Signs
Descriptive statistics will be used to summarize vital sign results for each scheduled time 
point and changes from baseline by treatment group. Vital signs data will be displayed in 
listings.
Physical Examination
Physical examination will be listed by treatment group.
Electrocardiograms
The 12-lead ECG results will be summarized by treatment group and scheduled time point.
7.6
Analysis of Pharmacokinetics
The PK data for ADC and MMAF will be analyzed using the noncompartmental method. 
Parameters to be assessed will include concentrations at the end of infusion or maximum 
observed concentration (CEOI or Cmax), concentrations at trough (Ctrough), time to maximum 
observed concentration (Tmax), partial area under the concentration time curve (AUCτ) for 
Cycle 1 and 4, and either terminal or apparent terminal half-life (t1/2) as appropriate. 
Additionally, clearance (CL) and volume of distribution at steady state (Vss) will be included 
as appropriate. Descriptive statistics will be provided for the PK parameter estimates and 


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subject concentration plots over time may be generated. Additional model-based analyses 
may be performed and reported separately.
Descriptive statistics for the incidence of human native antibody (AGS-16C3) and antibody 
drug conjugate (AGS-16C3F) antibody formation will be provided by treatment group.
Concentration-Response Relationship Analysis
Pharmacokinetic dose proportionality and concentration-response relationship will be 
assessed.
7.7
Protocol Deviations and Other Analyses 
Protocol deviations, as defined in Section 8.1.6, will be summarized for all randomized 
subjects by treatment group and total as well as by site. A data listing will be provided by site 
and subject.   
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment. 
7.8
Independent Data-Monitoring Committee Oversight
The study will have an Independent Data-Monitoring Committee (IDMC) overseeing the 
study. The committee is comprised of an oncologist (
, MD), a 
biostatistician (
, Ph.D), and an ophthalmologist (
, MD). The IDMC will 
conduct safety reviews at prespecified times during the study to make a recommendation for 
continuation of recruitment, protocol modification or study discontinuation for safety 
reasons.  
The full procedures for IDMC safety review will be described in a separate IDMC charter.
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Imputation methods for missing data, if applicable, and the definitions for windows to be 
used for analyses by visit will be outlined in the SAP.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
Data Collection
The investigator will enter data collected using an Electronic Data Capture (eDC) system. 
Medidata RAVE will be utilized for this study. In the interest of collecting data in the most 
PPD
PPD
PPD


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efficient manner, the investigator should record data (including laboratory values) in the 
eCRF within 14 days after the data become available.
The investigator is responsible to ensure that all data in the eCRFs and queries are accurate 
and complete and that all entries are verifiable with source documents. These documents 
must be appropriately maintained by the site.
The monitor must verify the data in the eCRFs with source documents and confirm that there 
are no inconsistencies between them.
Specific guidance on which forms should be completed by the investigator can be found in 
the data entry guidelines.
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.  
The following information should be included in the source medical records:

Demographic data (age, sex, race, ethnicity, height and body weight); refer to Section 
5.3.1

Inclusion and exclusion criteria details

Participation in study and original signed and dated informed consent forms 

Visit dates

Medical history; refer to Section 5.3.2

Physical examination details

Key efficacy and safety data, (as specified in the protocol)

AEs and concomitant medication 

Eye symptom questionnaire

Results of relevant examinations (e.g., ECG charts, X-ray films etc.)

Laboratory printouts

Dispensing and return of study drug details

Reason for premature discontinuation (if applicable)

Randomization number (if applicable)

Any data not specifically listed above, that is generated during the subject’s participation 
in this study.
Clinical Study Monitoring
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The Sponsor is responsible for assigning 


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study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures.  
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
(refer to Section 8.1.2) when they are requested by the Sponsor monitors and auditors, the 
IRB/IEC, or regulatory authorities. The confidentiality of the subject's identities shall be well 
protected consistent with local and national regulations when the source documents are 
subject to direct access.
Data Management
Data Management will be coordinated by the Sponsor in accordance with the standard 
operating procedures (SOPs) for data management. All study specific processes and 
definitions will be documented by Data Management. eCRF completion will be described in 
the eCRF instructions. Coding of medical terms and medications will be performed using 
MedDRA and World Health Organization (WHO) Drug Dictionary respectively.
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.  
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who: 

Did not sign the appropriate informed consent form

Entered into the study even though they did not satisfy entry criteria. 

Developed withdrawal criteria during the study and not withdrawn

Received wrong treatment or incorrect dose. 

Received excluded concomitant treatment.

Experienced SAE(s) not reported as defined in the protocol
If a deviation impacts the safety of a subject, the investigator must contact the Sponsor 
immediately.
The Sponsor will follow up with the investigator, as applicable, to assess the deviation and 
the possible impact to the safety and/or efficacy of the subject to determine subject 
continuation in the study. 


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The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
Sponsor.
NOTE:  Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable. 
End of Trial in All Participating Countries
The end of trial in all participating countries is defined as the Last Subject’s Last Visit.
8.2
Ethics and Protection of Subject Confidentiality 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/
Competent Authorities (CA)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the Investigator’s Brochure, the informed consent form and all other forms of subject 
information related to the study (e.g., advertisements used to recruit subjects) and any other 
necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the ethical, 
scientific and medical appropriateness of the study before it is conducted.  IEC/IRB approval 
of the protocol, informed consent form and subject information and/or advertising, as 
relevant, will be obtained prior to the authorization of drug shipment to a study site.
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site.  The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to 
both responsible Ethics Committees and Regulatory Agencies, as required. During the 
conduct of the study, the investigator should promptly provide written reports (e.g., ICH 
Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB 
of any changes that affect the conduct of the study and/or increase the risk to subjects. 
Written documentation of the submission to the IEC/IRB should also be provided to Sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at required or appropriate intervals. The investigator shall 
make an accurate and adequate final report to the IEC/IRB within 90 days after the close-out 
visit or termination of the study.
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 


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Informed Consent of Subjects
8.2.3.1
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study.  Prior 
to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed and dated by the subject or his/her guardian or  
legal representative, the person who administered the informed consent and any other 
signatories according to local requirements. A copy of the signed informed consent form will 
be given to the subject and the original will be placed in the subject’s medical record. An 
entry must also be made in the subject’s dated source documents to confirm that informed 
consent was obtained prior to any study-related procedures and that the subject received a 
signed copy.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor, auditor, regulatory authorities, and other applicable individuals 
upon request.
8.2.3.2
Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information

The investigator or his/her representative will immediately inform the subject verbally
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study. 
The communication must be documented in the subject’s medical records and must 
document whether the subject is willing to remain in the study or not.

The investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The investigator 
must re-consent subjects with the updated ICF even if relevant information was provided 
orally. The investigator or his/her representative who obtained the written informed 
consent and the subject should sign and date the informed consent form. A copy of the 
signed informed consent form will be given to the subject and the original will be placed 
in the subject’s medical record. An entry must be made in the subject’s records 
documenting the re-consent process.
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.


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The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 
Sponsor. However, the Sponsor requires the investigator to permit the Sponsor, Sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The Sponsor will ensure that the use and disclosure of protected health information (PHI) 
obtained during a research study complies with the federal and/or regional legislation related 
to the privacy and protection of personal information (i.e. Health Insurance Portability and 
Accountability Act [HIPAA]). 
8.3
Administrative Matters
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the Sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator may use this information for the purpose 
of the study only. It is understood by the investigator that the Sponsor will use the 
information obtained during the clinical study in connection with the development of the drug 
and therefore may disclose it as required to other clinical investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 
investigator understands that he/she has an obligation to provide the Sponsor with all data 
obtained during the study.
Publication of the study results is discussed in the Clinical Study Agreement.
Documents and Records Related to the Clinical Study
In order to start the study, the investigator and/or study site is required to provide the 
following documentation to the Sponsor: 

Financial disclosure in compliance with federal regulation 21CFR Part 54

Signed and dated FDA form 1572

Signed Investigator's Statement in this protocol 

Current Curricula Vitae of all investigators

Local regulatory authority notification or approval to conduct study (if applicable)

Written IRB approval of the protocol, protocol amendments (if applicable), informed 
consent forms, and materials provided to subjects including a membership list or FWA 
information (COPY)

Fully executed study contract

Laboratory certification 

Dated laboratory normal reference ranges

Current subject/investigator indemnity insurance (if applicable)
The investigator will archive all study data (e.g., Subject Identification Code List, source 
data, eCRFs, and Investigator's File) and relevant correspondence.  These documents are to 


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be kept on file for the appropriate term determined by local regulation (for US sites, 2 years 
after approval of the NDA/BLA or discontinuation of the IND). The Sponsor will notify all 
sites when these events occur.
The investigator agrees to obtain the Sponsor's agreement prior to disposal, moving, or 
transferring of any study-related records. The Sponsor will archive and retain all documents 
pertaining to the study according to local regulations.
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. 
Protocol Amendment and/or Revision
Any substantial changes to the study that arise after approval of the protocol must be 
documented as  protocol amendment. Non-substantial changes (administrative changes) to 
the protocol will be documented in a protocol administrative letter and these changes will be 
incorporated into the protocol at the next protocol amendment opportunity. 
All protocol amendments must be submitted and approved by the IRB/IEC and Competent 
Authority approval or notification may be required. The changes will become effective only 
after the approval of the Sponsor, the investigator, the IRB/IEC and regulatory authorities (if 
applicable). Amendments to this protocol must be signed by the Sponsor and the investigator. 
Written verification of IRB/IEC approval will be obtained before any amendment is 
implemented. Modifications to the protocol that are administrative in nature do not require 
IRB/IEC approval, but will be submitted to the IRB/IEC for their information, if required by 
local regulations.
If there are changes to the Informed Consent Form, written verification of IRB/IEC approval 
must be forwarded to the Sponsor.  An approved copy of the new Informed Consent Form 
must also be submitted to the Sponsor.
Insurance of Subjects and Others 
The Sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's File. 
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the Coordinating Investigator(s) or the Principal Investigator(s). The 
representative for the Coordinating Investigator (s) or the Principal Investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for
Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the 
participating investigators by the Sponsor prior to database lock.


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9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, eCRFs, and source documents. Direct access to these documents will be required 
by the auditors.
10
STUDY ORGANIZATION
10.1
Independent Data-Monitoring Committee  
The study will have an Independent Data-Monitoring Committee (IDMC) overseeing the 
study.  The IDMC will conduct safety reviews at prespecified times during the study to make 
a recommendation for continuation of recruitment, protocol modification or study 
discontinuation for safety reasons.  
The IDMC will operate under the Study’s IDMC Charter.
10.2
Other Study Organization
Not applicable.


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11
REFERENCES 
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Activity of Inotuzumab Ozogamicin, a Novel Immunoconjugate for the Treatment of B-Cell 
Non-Hodgkin’s Lymphoma:Results of a Phase I Study J Clin Oncol. 2010;28:2085-2093.
Alley, S.C., Zhang, X., Okeley, N.M., Anderson, M., Law, C-L., Senter, P.D. and D.R. Benjamin. 
The pharmacologic basis for antibody-auristatin conjugate activity. J. Pharmacol. Exp.Therap. 
2009;330:932- 938.
American Cancer Society. Cancer Facts and Figures 2012.
Belldegrun AS, Klatte T, Shuch B et al. Cancer-specific survival outcomes among patients treated 
during the cytokine era of kidney cancer (1989–2005): A benchmark for emerging targeted 
cancer therapies. Cancer. 2008;113:2457–2463.
Bhattacharya S, Fyfe G, Gray RJ, Sargent DJ:  Role of sensitivity analyses in assessing progression-
free survival in late-stage oncology trials. J Clin Oncol. 2009;27:5958-5964.
Buhring HJ, Simmons PJ et al. The monoclonal antibody 97A6 defines a novel surface antigen 
expressed on human basophils and their multipotent and unipotent progenitors. Blood. 
1999;94(7):2343-56.
Buhring HJ, Seifferet M et al. The basophil activation marker defined by antibody 97A6 is identical to 
the ectonucleotide pyrophosphatase/phosphodiesterase 3.  Blood. 2001;97(10):3303-5.
Burris HA, Rugo HS, Vukelja SJ, et al. Phase II Study of the Antibody Drug Conjugate Trastuzumab-
DM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) –Positive 
Breast Cancer After Prior HER2-Directed Therapy. J Clin Oncol. 2011;29:398-405.
Carroll KJ:  Analysis of progression-free survival in oncology trials:  Some common statistical issues. 
Pharm Stat. 2007 ; 6:99-113.
Coiffier B, Ribrag V, Dupuis J et al. Phase 1-2 Study of the Anti-CD19 Maytansinoid 
Immunoconjugate SAR3419 Administered Weekly to Patients with Relapsed/Refractory B-Cell 
Non-Hodgkins Lymphoma, ASCO Proceeding 2011.
Deissler H, Lottspeich F, Rajewsky MF.  Affinity purification and cDNA cloning of rat neural 
differentiation and tumor cell surface antigen gp130RB13-6 reveals relationship to human and 
murine PC-1.  J Biol Chem. 1995;270(17):9849-55.
Doronina, S.O., Mendelsohn, B.A., Bovee, T.D., Cerveny, C.G., Alley, S.C., Meyer, D.L., Oflazoglu, 
E., Toki, B.E., Sanderson, R.J., Zabinski, R.F., Wahl, A.F. and Peter D. Senter. Enhanced 
activity of Monomethylauristatin F through Monoclonal Antibody Delivery: Effects of Linker 
Technology on Efficacy and Toxicity. Bioconjugate Chem. 2006;17:114-124.
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumors: revised
RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
Ellenberg SS, Eisenberger MA.  An efficient design for phase III studies of combination 
chemotherapies.  Cancer Treatment Reports. 1985;69:1147–1154.


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Erickson, H.K., Park, P.U., Widdison, W.C., Kovtun, Y.V., Garrett, L.M., Hofman, K., Lutz, R.J., 
Goldmacher, V.S. and W.A. Blattner. Antibody-maytansinoid conjugates are activated in 
targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. 
Cancer Res. 2006;66: 4426-4433.
Goding JW, Grobben B et al.  Physiological and pathophysiological functions of the ecto-nucleotide 
pyrophosphatase/phosphodiesterase family.  Biochim Biophys Acta. 2003;1638(1):1-19.
Hong DI,  Bankova L, , Cahill KN, Kyin T, Castells MC. Allergy to monoclonal antibodies: 
desensitization methods for cutting-edge therapies Expert Rev. Clin. Immunol. 2012;8:43-54
Hughes B. Antibody-drug conjugated: poised to deliver? Nature Rev. 2010;9:665-667.
Jin-Hua P, Gooding JW et al.  Molecular cloning and chromosomal localization of PD-Iβ (PDNP3), a 
new member of the human phosphodiesterase I genes.  Genomics. 1997;45(2):412-5.
Krop, IE, BeeramM, Modi S, et al Phase I Study of Trastuzumab-DM1, an HER2 Antibody-Drug 
Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer. J 
Clin Oncol. 2010;28:2698-2704.
Lambert JM. Drug-conjugated antibodies for the treatment of cancer. Curr Opinion Pharmacol. 
2005;5:543-549.
Larson RA, Sievers EL, Stadtmauer EA et al. Final Report of the Efficacy and Safety of Gemtuzumab
Ozogamicin (Mylotarg) in Patients withCD33-Positive Acute Myeloid Leukemia in First 
Recurrence. Cancer. 2005;104:1442-52.
Ljungberg B,  Cowan NC, Hanbury DC,et al. EAU Guidelines on Renal Cell Carcinoma: The 2010 
Update. Eur Urol. 2010;58:398-406.
Motzer RJ. New Perspectives on the Treatment of Metastatic Renal Cell Carcinoma: An Introduction 
and Historical Overview. Oncologist. 2011;16(suppl 2):1-3.
Oflazoglu, E., Stone, I.J., Gordon, K., Wood, C.G., Repasky, E.A., Grewal, I.S., Law, C-L. and H. P. 
Gerber. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to 
the tubulin inhibitor auristatin via an uncleavable linker. Clin. Cancer Res. 2008;14:6171-6180.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFaddden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J CLin Oncol. 1982;5:649-
55.
Pettit G.R. The Isolation and Structure of a Remarkable Marine Animal Antineoplastic Constituent: 
Dolastatin 10. J. Am. Chem. Soc. 1987;109:6883-6885.
Polson AG, Calemine-Fenaux J, Cahn P, Chang W, Christensen E, Clark S, et al. Antibody-drug 
conjugates for the treatment of Non-Hodgkin’s lymphoma: Target and linker-drug selection. 
Cancer Res. 2009;69:2358-2364.
Schwartzberg LS, Stepanski EJ, Walker MS, Mathias S, Houts AC, Fortner BV. Implications of IV 
monoclonal antibody infusion reaction for the patient, caregiver, and practice: results of a 
multicenter study Support Care Cancer. 2009;17:91-9810.


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Stefan C, Jansen S, Bollen, M.  NPP-type ectophosphodiesterases: unity in diversity. Trends Biochem 
Sci. 2005;30(10):542-50.
Stone AM, Bushnell W, Denne J, Sargent DJ, Amit O, Chen C, Bailey-Iacona R, Helterbrand J, 
Williams G:  Research outcomes and recommendations for the assessment of progression in 
cancer trials from a PhRMA working group.  Eur J Cancer. 2011;47:1763-1771.
Sutherland MS, Sanderson RJ, Gordon KA, Andreyka J, Cerveny CG, Yu C, et al. Lysosomal 
trafficking  and cysteine protease metabolism confer target-specific cytotoxicity by peptide-
linked anti-CD30-auristatin conjugates. J. Biol. Chem. 2006;281: 10540-10547.
Swain SM, Arezzo JC. Neuropathy Associated with Microtubule Inhibitors: Diagnosis, Incidence, and 
Management . Clin Adv Hematol Oncol. 2008; 6:455-467.
Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 
2006;Apr;15(4):241-3.
Therneau T., Grambsch P.  2000.  Modeling Survival Data: Extending the Cox Model.  Springer, 
New York.
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of Cancer Drugs and Biologics.  May 2007.
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Clinical Trials. 1987;8:20-28.
Younes A, Bartlett NL, M.D., Leonard JP et al. Brentuximab Vedotin (SGN-35) for Relapsed CD30-
Positive Lymphomas. N Engl J Med. 2010;363:1812-1821.
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Company Reports:
Package Insert, Axitinib, Pfizer, 2014 (available at 
http://labeling.pfizer.com/ShowLabeling.aspx?id=759).
AGS-16C3F Investigator’s Brochure, on file at Astellas. 


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12
APPENDICES
12.1
List of Excluded Concomitant Medications
The investigator may prescribe any medication necessary to ensure the safety and wellbeing 
of the subject during the study.  Please refer to Section 5.1.3.2 for additional information. 
The following medications are likely to influence evaluation of the safety, pharmacokinetics 
or efficacy of AGS-16C3F or axitinib, and will be strictly prohibited.  If the investigator 
determines that any of the following medications are necessary to provide adequate medical 
support, the subject must be withdrawn from further study drug administration. If the use of 
prohibited medications is necessary to treat an AE and the use is temporary (e.g., 
dexamethasone used for nausea), this is permitted.   
AGS-16C3F

Chemotherapy, radiotherapy, immunotherapy 
or other medications intended for antitumor 
activity
o
Palliative radiation is permitted 
provided it does not interfere with 
subject safety and efficacy of the 
study drug being administered. 
Palliative radiation cannot be 
administered to any target lesion. 
Medications used to treat bone 
metastases (e.g., zoledronic acid, 
denosumab, etc.) are allowed 
provided they are not initiated at the 
same time as Cycle 1 Day 1.

Investigational products or therapy other than 
AGS-16C3F 
Axitinib

Chemotherapy, radiotherapy, immunotherapy 
or other medications intended for antitumor 
activity
o
Palliative radiation is permitted 
provided it does not interfere with 
subject safety and efficacy of the 
study drug being administered. 
Palliative radiation cannot be 
administered to any target lesion. 
Medications used to treat bone 
metastases (e.g., zoledronic acid, 
denosumab, etc.) are allowed 
provided they are not initiated at the 
same time as Cycle 1 Day 1.

Investigational products or therapy 

Strong CYP3A4/5 inducers1
1 The drugs defined as CYP Substrates with Narrow Therapeutic Range by FDA’s guidance - Guidance for Industry Drug 
Interaction Studies - Study Design, Data analysis, and Implications for Dosing and Labeling): 
http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf)
Examples for excluded inhibitors, inducers and substrates for enzymes and transporters are 
provided below. Subjects must have discontinued treatment with any of the following for at 
least 2 weeks prior to the first dose of study drug.  This is not intended to be a comprehensive 
list. There could also be additional new drugs and marketed drugs that could be identified as 
inhibitors/inducers with continued research.  Investigators will consult individual drug labels 
to determine liability of the drugs. 


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Strong CYP3A Inhibitors
boceprevir
clarithromycin
conivaptan
grapefruit juice
indinavir
itraconazole
ketoconazole
lopinavir/ritonavir
mibefradil
nefazodone 
nelfinavir 
posaconazole
ritonavir
saquinavir
telaprevir
telithromycin
voriconazole
CYP3A4/5 Inducers 
rifampin 
dexamethasone
phenytoin
carbamazepine
rifabutin
rifapentin
phenobarbital
St. John's wort
Additional information for inhibitors/inducers/substrates of enzymes/transporters can be 
found in FDA’s guidance (Guidance for Industry Drug Interaction Studies - Study Design, 
Data analysis, and Implications for Dosing and Labeling)1 and from the Division of Clinical 
Pharmacology of Indiana University2. 
1. http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf
2. http://medicine.iupui.edu/clinpharm/ddis/main-table/


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12.2
Liver Safety Monitoring and Assessment 
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN (to > 5 × ULN in subjects with liver metastases), 
or bilirubin > 2 × ULN, should undergo detailed testing for liver enzymes (including at least 
ALT, AST, ALP, and TBL). Testing should be repeated within 48-72 hours of notification of 
the test results. For studies for which a central laboratory is used, alerts will be generated by the 
central lab regarding moderate and severe liver abnormality to inform the investigator, study 
monitor and study team. Subjects should be asked if they have any symptoms suggestive of 
hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3 x ULN (in subjects without 
liver metastases), > 5 x ULN (in 
subjects with liver metastases)
or
> 2 x ULN
Severe*
> 3 x ULN
and
> 2 x ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks (in the absence of liver metasteses)
●
ALT or AST > 3 × ULN and INR > 1.5 (If INR testing is applicable/evaluated).
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia ( > 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring and 
follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. The site should complete the Liver Abnormality eCRF (LA-
CRF) or appropriate document. Subjects with confirmed abnormal liver function testing should 
be followed as described below.
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Severe hepatic liver function abnormalities as defined above , in the absence of another 
etiology may be considered an important medical event and may be reported as a Serious 


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Adverse Event (SAE). The Sponsor should be contacted and informed of all subjects for whom 
severe hepatic liver function abnormalities possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases. 
Symptoms and new onset-diseases should be recorded as ‘adverse events’ on the AE 
page of eCRF. Illnesses and conditions such as hypotensive events, and 
decompensated cardiac disease that may lead to secondary liver abnormalities should 
be noted. Non-alcoholic steatohepatitis (NASH) is seen in obese 
hyperlipoproteinemic, and/or diabetic subjects and may be associated with 
fluctuating aminotransferase levels. The investigator should ensure that the medical 
history form captures any illness that pre-dates study enrollment that may be relevant 
in assessing hepatic function.    
●
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page of the eCRF. Information on alcohol, other substance use, and diet 
should be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history, other testing may be appropriate including: 
o
acute viral hepatitis (A,B, C, D, E or other infectious agents). 
o
ultrasound or other imaging to assess biliary tract disease
o
other laboratory tests including INR, direct bilirubin
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFT’s, such as viral hepatitis, pre-existing or 
acute liver disease, presence of liver metastases, or exposure to other agents associated with 
liver injury, the subject may be discontinued from the study. The investigator may determine 
that it is not in the subject’s best interest to continue study enrollment. Discontinuation of 
treatment should be considered if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metasteses
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated)
●
ALT or AST > 5 × ULN and (TBL > 2 × ULN in subjects with liver metasteses)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia ( > 5%). 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued.


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*Hy’s Law Definition-Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10–50% mortality 
(or transplant).” The 2 “requirements” for Hy’s Law are: (1) Evidence that a drug can cause 
hepatocellular-type injury, generally shown by an increase in transaminase elevations higher 
3 times the upper limit of normal (“2 x ULN elevations are too common in treated and 
untreated subjects to be discriminating”). (2) Cases of increased bilirubin (at least 2 x ULN) 
with concurrent transaminase elevations at least 3 x ULN and no evidence of intra- or extra-
hepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome. 
Reference
Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
April;15(Suppl 4):241-3.
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009.


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12.3
Common Serious Adverse Events
The following is a list of SAEs that the Sponsor considers to be associated with the disease 
state being studied.  The list does NOT change your reporting obligations, or prevent the need 
to report an AE meeting the definition of an SAE as detailed in Section 5.7.2. The purpose of 
this list is to alert you that some events reported as SAEs may not require expedited reporting 
to the regulatory authorities based on the classification of “common serious adverse events”. 
You are required to follow the requirements detailed in Section 5.7.5.  
Signs/symptoms commonly reported in metastatic RCC subjects often associated to disease 
progression are:

Pain

Weight loss (weight loss not considered cachexia by investigators is excluded)

Anemia

Hypercalcemia

Proteinuria
For expedited reporting of suspected unexpected serious adverse reactions (SUSARs), single 
occurrences of the above events may be excluded from expedited reporting to regulatory 
authorities. If aggregate analysis of these events indicates they occur more frequently with 
study drug, an expedited safety report may be submitted to the regulatory authority.  






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12.5
ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light house work, office work)
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair
5
Dead
Reproduced from: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFaddden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J CLin Oncol. 1982;5:649-55.


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12.6
Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1


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Reproduced from: Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.


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13
ATTACHMENT 1:   SUBSTANTIAL AMENDMENT 5
I.  The purpose of this amendment is:
Substantial Changes
1.
Remove the Disease Assessment and Survival Assessment after the Safety 
Follow-up Visit
DESCRIPTION OF CHANGE:
“Disease Assessment” and “Survival” are removed from the study design and Flow Chart 
(Figure 1). These assessments will no longer be conducted after the Safety Follow-up visit.
RATIONALE:
Disease Assessment and Survival data will no longer be collected and analyzed.
2.
Update the Schedule of Assessments (Table 1) and AGS-16C3F Pharmacokinetic
Sampling Time Points (Table 2)
DESCRIPTION OF CHANGE:
The Schedule of Assessments is updated as follows:

Pharmacokinetics (AGS16C3F) is removed at the Safety Follow-up.

Anti-AGS16C3F samples are removed at the Safety Follow-up.
The AGS-16C3F Pharmacokinetic Sampling Time Points is updated as follows:

Q12W (every 12 weeks) and footnote § are removed.

Safety Follow-up is removed.
These assessments and time points are also removed from the study design and Sections 
5.2.6.2, 5.2.7 and 5.8. 
RATIONALE:
These samples are longer collected and analyzed.
3.
Delete the Post Safety Follow-Up Visit
DESCRIPTION OF CHANGE:
The Post-Safety Follow-Up visit (Section 5.2.8) is removed.
RATIONALE:
The data will no longer be analyzed.
4.
Update Reading of Scans
DESCRIPTION OF CHANGE:


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The requirement that scans be submitted in digital format for blinded independent central 
review is deleted. Scans will be read on site only.
RATIONALE:
The data will no longer be analyzed by a blinded independent central reviewer.
Nonsubstantial Changes
1.
Update Key Sponsor Personnel
DESCRIPTION OF CHANGE: 
Contact details for the 24-hour contact for serious adverse events (SAEs), clinical research 
contacts and medical monitor/medical expert are revised. Section 5.7.5, Reporting Procedures 
for All Serious Adverse Events is updated with revised 24-hour contact information for 
SAEs.
RATIONALE:
Contact details of sponsor personnel are updated based on changes to study personnel.
2.
Update Planned Study Period
DESCRIPTION OF CHANGE: 
The end date of the planned study period is changed to 3Q2020.
RATIONALE:
This change is made to allow more time in which to complete the study.
3.
Update References
DESCRIPTION OF CHANGE: 
Deleted Ellenberg et al, 1985 and Wieand et al 1987 references from the Reference list.
RATIONALE:
The references are deleted, because they are not cited in the protocol.
4.
Minor Administrative-type Changes
DESCRIPTION OF CHANGE: 
Include minor administrative-type changes (e.g., typos, format, numbering and consistency 
throughout the protocol), update the format of the Protocol History and Investigator’s 
Signature section for consistency with the GPF 9.0 template, and updated the style of 
references to conform with the Astellas Style Guide.












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IV. Synopsis, Study Design Overview and 2 Study Objective(s), Design and Endpoints
2.2.1 Study Design
DELETED:
All subjects will be followed for survival approximately every 8 weeks from the Safety 
Follow Up visit. This will be done by telephone, until death or study closure, whichever 
occurs first. A standard of care clinic visit can be used in lieu of a telephone call, if the 
subject is already coming to clinic.
5 Treatments and Evaluation
5.2.6.2 Cycles 5 and Beyond
WAS:
a.
Vital Signs
b. Predose PK predose PK sample collection for AGS-16C3F subjects on Cycles 6 and 
every 12 weeks thereafter.  Predose PK sample for Cycles 6 and every 12 weeks 
thereafter must be collected anytime before AGS-16C3F drug administration on the 
day of infusion.
IS AMENDED TO:
a.
Vital Signs
b. Predose PK predose PK sample collection for AGS-16C3F subjects on Cycles 6 and 
every 12 weeks thereafter.  Predose PK sample for Cycles 6 and every 12 weeks 
thereafter must be collected anytime before AGS 16C3F drug administration on the 
day of infusion.
5 Treatments and Evaluation
5.2.8 Post Safety Follow-Up Visit
DELETED:
5.2.8 Post Safety Follow Up Visit
All subjects will be followed for survival approximately every 8 weeks from the Safety 
Follow Up visit. This will be done by telephone, until death or study closure, whichever 
occurs first.  A standard of care clinic visit can be used in lieu of a telephone call, if the 
subject is already coming to clinic.
Those subjects who discontinued the study for reasons other than objective disease 
progression by RECIST v.1.1 will continue to have disease assessments every 8 weeks (± 7 
days) counting from C1D1. This will continue until subject has radiologically confirmed 
progression, initiates a new therapy, study closure or subject dies. 
Any subjects who had a positive immunogenicity result will continue to have 
immunogenicity samples collected for testing every 12 weeks until it returns to negative or 
baseline value.


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5 Treatments and Evaluation
5.5 Efficacy Assessment
WAS:
Scans will be read on site and also submitted in digital format for blinded independent central 
review.  Details of scan submission to independent central radiology vendor will be provided 
in a separate manual.
IS AMENDED TO:
Scans will be read on site. and also submitted in digital format for blinded independent 
central review.  Details of scan submission to independent central radiology vendor will be 
provided in a separate manual.
5 Treatments and Evaluation
5.8 Test Drug Concentration
DELETED:
Q12W (starting at Cycle 6): predose (before the AGS 16C3F infusion)
Safety Follow Up visit
IIB. Nonsubstantial Changes
Title Page
WAS:
Version 1.0: 16 Sep 2015
Version 2.0: 22 Jan 2016 (Amendment 1)
Version 3.0: 27 May 2016 (Amendment 2)
Version 4.0: 18 Jul 2017 (Amendment 3)
IS AMENDED TO:
Version 1.0: 16 Sep 2015
Version 2.0: 22 Jan 2016 (Substantial Amendment 1)
Version 3.0: 27 May 2016 (Substantial Amendment 2)
Version 4.0: 18 Jul 2017 (Substantial Amendment 3)
Version 5.0: 09 Feb 2018 (Substantial Amendment 4)
I. Investigator’s Signature
WAS:
Protocol AGS-16C3F-15-3, A Multi-center, Open Label, Randomized Phase 2 Study of 






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Fax number 1-888-396-3750
Alternate North America Fax number 1-847-317-1241
Email: safety-us@astellas.com
IS AMENDED TO:
For contact details, see [Section II Contact Details of Key Sponsor's Personnel]. Fax or email 
the SAE Worksheet to:
Astellas Pharma Global Development, Inc.
Medical Safety Pharmacovigilance
Fax number 1-888-396-3750
Alternate North America Fax number 1 847 317 1241
Email: Ssafety-USus@astellas.com
11 References
5.8 Test Drug Concentration
DELETED:
Ellenberg SS, Eisenberger MA.  An efficient design for phase III studies of combination 
chemotherapies.  Cancer Treatment Reports. 1985;69:1147 1154.
Wieand S, Therneau T.  A two stage design for randomized trials with binary outcomes.  Controlled 
Clinical Trials. 1987;8:20 28.


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14
SPONSOR’S SIGNATURES
Astellas Signatories
(Electronic signatures are attached at the end of the document.)
Medical Science,
Development
Data Science,
Development
PPD
PPD
PPD
PPD

SAP_000.pdf: 
A Multi-Center, Open Label, Randomized Phase 2 Study of 
AGS-16C3F vs. Axitinib in Metastatic Renal Cell Carcinoma
ISN/Protocol AGS-16C3F-15-3
ClinicalTrials.gov Identifier: NCT02639182
Date of SAP v2: 10 Jun 2019
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062