Clinical trial NCT01559363
Conditions: Polycystic Kidney, Autosomal Dominant
Sponsor: Kadmon, a Sanofi Company
Start date: 2012-10-11; Completion date: 2019-02-08
Enrollment: 69 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this study Phase 1b was to determine the safety, plasma pharmacokinetics, and maximum tolerated dose (MTD) of tesevatinib when administered to participants with autosomal dominant polycystic kidney disease (ADPKD).

The primary objective of this study Phase 2a was to evaluate the annualized change in glomerular filtration rate (GFR) in participants with ADPKD when treated with tesevatinib.

Detailed description:
Phase 1b:

* Primary objective was to determine the safety of tesevatinib.
* Dosing was for 28 days daily. After the 28-day treatment period, participants would, at the discretion of the investigator, continue to receive study treatment for 24 months from their first dose or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision. Participants might continue beyond 24 months at the discretion of the investigator after consultation with the medical monitor.
* All participants received active tesevatinib study drug.
* Tesevatinib is an oral once daily tablet. Tablets were 50 milligrams (mg), 100 mg and 150 mg in strength. Participants were enrolled into three sequential dosing cohort levels (50 mg, 100 mg and 150 mg.). Participants in Phase 1b had their dose increased or decreased to the maximum tolerated dose (MTD).
* Study participants had magnetic resonance imaging (MRI) of the abdomen (kidneys) at Screening and 6 months thereafter to explore effects of KD019.
* Echocardiogram was performed at Screening, Day 28, months 3 and 6 and every 6 months thereafter.

Phase 2a:

* Primary objective was to compare the annualized change in GFR in participants with ADPKD when treated with tesevatinib.
* Two alternate dosing schedules were explored to determine if they were more tolerable than daily dosing when used chronically in participants with ADPKD.
* Participants received study treatment for 24 months from their first dose or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision. Participants continued beyond 24 months at the discretion of the investigator after consultation with the sponsor.
* All participants received active tesevatinib study drug.
* Tablets were 50 mg, 100 mg, and 150 mg in strength.
* Study participants had MRI of the abdomen (kidneys) at Screening and Month 6 visit and every 6 months after to explore effects of tesevatinib.
* Echocardiogram was performed at Screening, Day 28, and Months 3 and 6 and 6 months thereafter.

Arms: arm 1: Participants received tesevatinib 50 milligrams (mg) tablet orally once daily (QD) for 28 days. After initial 28 days treatment, at the investigator's discretion, participants continued to receive tesevatinib for a total of 24 months (since treatment initiation) or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision (maximum duration: up to 36 months). arm 2: Participants received tesevatinib 100 mg tablet orally QD for 28 days. After initial 28 days treatment, at the investigator's discretion, participants continued to receive tesevatinib for a total of 24 months (since treatment initiation) or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision (maximum exposure duration: up to 36 months). arm 3: Participants received tesevatinib 150 mg tablet orally QD for 28 days. After initial 28 days treatment, at the investigator's discretion, participants continued to receive tesevatinib for a total of 24 months (since treatment initiation) or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision (maximum exposure duration: up to 36 months). arm 4: Participants received tesevatinib 150 mg tablet orally bi-weekly in alternative dosing schedules on Monday and Thursday for initial 25 days. After initial 25 days treatment, at the investigator's discretion, participants continued to receive tesevatinib for a total of 24 months (since treatment initiation) or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision (maximum exposure duration: up to 28 months). arm 5: Participants received tesevatinib 150 mg tablet orally tri-weekly in alternative dosing schedules on Monday, Wednesday and Friday for initial 26 days. After initial 26 days treatment, at the investigator's discretion, participants continued to receive tesevatinib for a total of 24 months (since treatment initiation) or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision (maximum exposure duration: up to 28 months). arm 6: Participants with autosomal dominant polycystic kidney disease (and Baseline estimated glomerular filtration rate (eGFR) greater than or equal to (\>=) 35 milliliters per minute per 1.73 square meter (mL/min/1.73 m\^2) and less than or equal to (\<=) 80 mL/min/1.73 m\^2, and height-adjusted total kidney volume (htTKV) \>=1000 mL were enrolled and received tesevatinib 50 mg tablet orally QD for initial 28 days. After initial 28 days treatment, at the investigator's discretion, participants continued to receive tesevatinib for a total of 24 months (since treatment initiation) or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision (maximum exposure duration: up to 28 months).
Interventions: intervention 1: Tesevatinib
Intervention descriptions: intervention 1: Pharmaceutical form: Tablets Route of administration: Oral

Protocol documents:
Prot_000.pdf: 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Kadmon Corporation 
and any unauthorized use or disclosure of such information without the prior written authorization of 
Kadmon Corporation is expressly prohibited. 
CLINICAL STUDY PROTOCOL 
A Phase 1b/2a, Safety, Pharmacokinetic and Dose-Escalation Study of 
KD019 in Subjects with Autosomal Dominant Polycystic Kidney Disease 
Protocol Number: 
KD019-101 
Study Drug: 
Tesevatinib (formerly named KD019) 
Sponsor: 
Kadmon Corporation, LLC 
450 East 29th Street
New York, NY  10016 
Medical Monitor: 
 
Date of Protocol: 
Original, 26 October 2011 
Amendment 1: 
02 December 2011 
Amendment 2:  20 January 2012 
Amendment 3:  05 March 2012 
Amendment 4:  17 April 2012 
Amendment 5: 
25 October 2012 
Amendment 6: 
15 August 2013 
Amendment 7: 
06 February 2014 
Amendment 8: 
19 May 2014 
Amendment 9: 
30 May 2014 
Amendment 10:  10 November 2014 
Amendment 11:  17 June 2015 
Amendment 12:  31 March 2016 
Amendment 13:  06 October 2016 
NCT01559363


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1 
PROCEDURES IN CASE OF EMERGENCY 
Serious Adverse Events  
All serious adverse events (SAE)* occurring in subjects while on-study or within 30 days of 
receiving study drug regardless of relationship, must be promptly reported (within 24 hours) by 
telephone, email, or telefax to the sponsor (or designee).   
Emergency Contact Information  
 
SAE AND SUSAR CRITERIA 
* A serious adverse event (SAE) is any untoward medical occurrence that at any dose results in any of the following outcomes, regardless of 
relationship to study drug (see Section 13.3.1 Serious Adverse Events for additional information): 
 
Death 
 
Life-threatening adverse drug event 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant disability/ incapacity 
 
A congenital anomaly/birth defect 
 
An important medical event that may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
Some serious events will not be reported as SAEs, including: 
 
Disease progression 
 
Death due to disease progression occurring more than 30 days after the last dose of study drugs 
 
Medical or surgical procedures when the condition that leads to the procedure is an adverse event 
 
Pre-existing diseases, or conditions or laboratory abnormalities present or detected prior to the screening visit, that do not worsen 
 
Situations for which an untoward medical occurrence has not occurred (eg, hospitalization for elective surgery, social and/or 
convenience admissions) 
**  A suspected unexpected serious adverse reaction (SUSAR) is any untoward and unintended response to an investigational product related to 
any dose administered, of which the nature or severity, is not consistent with the applicable product information (see also Section 11.3 of this 
document; Suspected Unexpected Serious Adverse Reactions).  All suspected adverse reactions related to an investigational medicinal product 
that occur in the concerned trial and that are both unexpected and serious are subject to expedited reporting. 
For SAE/SUSAR reporting: 
For any other questions or to  
contact the medical monitor: 
INC Research 
Fax:  1 (877) 464-7787 
 
In the event of an issue with the  fax line, 
forward the SAESUSAR via email to:  
 
INCDrugSafety@INCResearch.com. 




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3 
INVESTIGATOR SIGNATURE 
 
I have read this protocol, including all appendices, and I agree to conduct the study in 
compliance with all applicable regulations (including 21 CFR Part 312).  I will also make a 
reasonable effort to complete the study within the time designated.  I will provide all study 
personnel under my supervision copies of the protocol and access to all information provided by 
Kadmon Corporation, LLC.  I will discuss this material with them to ensure that they are fully 
informed about the drug and the study. 
I am aware that, prior to the commencement of this study, the Institutional Review Board must 
approve this protocol and the informed consent document associated with the clinical facility 
where the study will be conducted.  I agree to make all reasonable efforts to adhere to the 
attached protocol.  I agree to provide all subjects with a signed and dated copy of their informed 
consent document, as required by FDA and ICH regulations.  I further agree to report to Kadmon 
any adverse events in accordance with the terms of this protocol and FDA regulation 21 CFR 
312.64.   
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations.  
 
 
 
 
Investigator Signature 
 
 Date of Signature 
(DD MMM YYYY) 
Name of Investigator (please print) 
 


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4 
SYNOPSIS 
Study Title 
A Phase 1b/2a, Safety, Pharmacokinetic, Dose-Escalation Study of KD019 
in Subjects With Autosomal Dominant Polycystic Kidney Disease 
Number of Study 
Centers 
Approximately 10–13 sites in the United States 
Clinical Phase 
Phase 1b/2a 
Study Rationale 
Tesevatinib (formerly named KD019) was originally developed for a solid 
tumor indication, and is currently being investigated for the treatment of 
cancer.  In nonclinical studies, tesevatinib selectively inhibited key kinases 
and validated targets in animal models of polycystic kidney disease (PKD).  
In addition, it has shown either no or extremely weak inhibitory activity of 
other kinases that should reduce off-target effects.  Tesevatinib has also 
been shown to be a potent inhibitor of receptor and cytoplasmic tyrosine 
kinases (TKs).  The product was specifically optimized to simultaneously 
inhibit EGFR, human epidermal growth factor receptor 2 (HER2), Src, 
vascular endothelial growth factor receptor 2 (VEGFR2/ KDR), and ephrin 
receptor B4 (EphB4) tyrosine kinases with high potency, and demonstrated 
excellent activity in target-specific cellular functional assays.  In 
nonclinical animal models, tesevatinib had acceptable oral bioavailability 
and has shown sustained inhibition of its targets in vivo following a single 
oral dose. 
In Phase 1 and 2 clinical studies conducted in healthy subjects and subjects 
with solid tumors, over 300 subjects have been treated to date; at least 
185 of these have been treated at levels ≥ 300 mg daily. At least 53 subjects 
have received tesevatinib for ≥ 6 months, and safety and tolerability were 
acceptable. Tesevatinib is also in development for the treatment of breast 
cancer and non-small cell lung cancer (NSCLC).    
In summary, both the nonclinical results in PKD models and the clinical 
safety results in human oncology studies suggest that tesevatinib could be a 
promising therapeutic in autosomal dominant polycystic kidney disease 
(ADPKD). 
Study Objectives 
Phase 1b: 
Primary objective: 
 
To determine the safety, plasma pharmacokinetics (PK), and 
maximum tolerated dose (MTD) of tesevatinib when administered 
to subjects with ADPKD. 
Phase 2a: 
Primary objective: 
 
To evaluate the annualized change in glomerular filtration rate 
(GFR) in subjects with ADPKD when treated with tesevatinib. 


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Secondary Objectives:   
 
To evaluate subjects treated with tesevatinib with regard to: 
o Annualized percent change from baseline in total kidney 
volume (TKV)  
o Annualized change from baseline in the reciprocal of serum 
creatinine 
o Safety profile 
o Serum creatinine levels 
o PK and tolerability of 2 alternative dosing schedules (dosing 
on Monday, Wednesday, and Friday of each week, and dosing 
on Monday and Thursday of each week) 
Note: Exploratory measures of efficacy will also be performed throughout 
both phases of the study. 
Study Design 
This is an open-label, safety, PK, dose-escalation, multicenter study. 
Study Methodology 
In the Phase 1b portion of the study, approximately 24–30 subjects 
(8 subjects/cohort) have received 50 mg, 100 mg, or 150 mg of tesevatinib 
orally once daily for up to 24 months.   
At the end of each dosing cohort, a Data Safety Committee, which includes 
an independent safety monitor with clinical expertise in polycystic kidney 
disease, reviewed all safety data (PK, safety labs, ECGs, echocardiograms, 
and adverse events [AEs]) and decided whether dose escalation may occur.  
Dose escalation to the next higher dose was not started until the safety data 
from the preceding dose cohort was evaluated and deemed acceptable.  
Specifically, the decision to progress to the next higher dose was made after 
the safety data through a minimum of 28 days of follow-up was reviewed 
for at least 8 subjects in the preceding dose cohort and it was determined 
that it was safe to proceed to the next dose level. 
Dose escalation to the next planned tesevatinib dose cohort will be 
reviewed and dose adjustments may be made if any of the following safety 
criteria are met: 
 
≥ 25% of subjects in a cohort experience a severe (or higher) 
related AE in the same organ or body system 
 
Any other related AE occurs in a subject that is deemed by the 
investigator to pose an unacceptable risk to other participants in the 
study such as symptoms of cardiac tamponade 
For Phase 1b subjects dosed with 50 mg/day:  Following review of the 
100-mg cohort it was initially determined that 100 mg/day was not the 
MTD. Study enrollment was opened at the 150-mg dose, and subjects 
initially treated in the Phase 1b 50-mg dose cohort had the option of 
increasing their dose of tesevatinib to 100 mg/day after they had received a 
minimum of 6 months of treatment at the 50 mg/day dose. 
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24 additional subjects were enrolled in the Phase 2a portion of the study 
using alternative schedules of tesevatinib administration.  As the known 
toxicities of tesevatinib, including diarrhea and rash, may not be tolerable 
with daily dosing when used long-term in this subject population, 
alternative dosing schedules of 150 mg of tesevatinib on Monday, 
Wednesday, and Friday of each week and 150 mg on Monday and 
Thursday of each week were evaluated during this portion of the study.  
Several subjects are continuing on this dosing schedule to evaluate long 
term tolerability.  Approximately 5 subjects treated on each alternative 
dosing schedule had PK samples obtained so that safety, tolerability, and 
exposure could be evaluated.   
In addition, subjects active in the Phase 1b portion had their dose increased 
or decreased to the established MTD of 100 mg QD.  These subjects will 
continue on daily dosing in order to obtain data on longer term tolerability 
of daily dosing at the MTD. 
In both phases of the study, after the 28-day treatment period, subjects will, 
at the discretion of the investigator, continue to receive study treatment for 
24 months from their first dose or until the development of unacceptable 
toxicity, noncompliance, or withdrawal of consent by the subject, or 
investigator decision.  .   
Despite fulfilling the protocol criteria for determining the MTD for daily 
dosing, the 100 mg daily dose group exhibited a rate of QTc prolongation 
not acceptable for chronic use. Preliminary data from both the 50 mg daily 
cohort and the 150 mg Monday and Thursday cohort appear acceptable for 
chronic use and for further study in terms of safety.  The 50 mg daily dose 
appears to be favorable due to dosing simplicity and to the occurrence of a 
Grade 3 rash in the 150 mg Monday and Thursday cohort.  Additionally, 
the effect of missed dosing is reduced in the daily dosing cohort.  Because 
of these factors, the 50 mg tesevatinib treatment appears to be the best 
tolerated dose, and will likely be taken forward in additional studies in 
ADPKD.  In order to generate additional efficacy and safety information 
for this selected dosing regimen, 15 additional subjects were enrolled as an 
additional group in the Phase 2a portion of this protocol at a dose of 50 mg 
daily of tesevatinib. Each of the 15 subjects were required to complete 
either PK testing as described for other Phase 1b subjects in this protocol or 
iothalamate testing.   
Modeling of ADPKD subpopulations for a randomized Phase 3 clinical 
study has been performed.  Enrollment criteria being considered for Phase 
3 are ADPKD subjects with baseline eGFR ≥ 35 mL/min/1.73 m2 and ≤ 80 
mL/min/1.73 m2, and height-adjusted total kidney volume (htTKV) ≥ 1000 
mL.   
In order to study the safety profile in this specific ADPKD subpopulation, 
up to 50 additional subjects with PKD and baseline eGFR ≥ 35 
mL/min/1.73 m2 and ≤ 80 mL/min/1.73 m2, and htTKV ≥ 1000 mL will be 
enrolled (Safety in Larger Kidneys [SILK Cohort]).  


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In addition, all 50 subjects will undergo a mandatory 28-day drug holiday 
after completing the first month of treatment with tesevatinib.  During this 
drug holiday, and for 4 weeks after, subjects will return to the clinic weekly 
for creatinine and tesevatinib plasma measurements.  All subjects will 
resume tesevatinib treatment at the Month 2 study visit following 
completion of the 28-day drug holiday.     
Kidney volume will be determined by magnetic resonance imaging (MRI) 
at Screening (baseline measurement) and every 6 months thereafter. htTKV 
will be calculated using total kidney volume obtained from MRI divided by 
height in meters.  
Study Population: 
Approximately 120 male and female subjects with ADPKD will be 
enrolled. Approximately 30 subjects will be enrolled in the Phase 1b 
portion and approximately 90 subjects will be enrolled in the Phase 2a 
portion. 
Diagnosis and Main 
Entry Criteria  
Subjects will be eligible for enrollment as defined by the following 
inclusion and exclusion criteria. 
Inclusion Criteria: 
1. The subject has a confirmed diagnosis of ADPKD based on Ravine’s 
criteria.  Subjects < 30 years of age must have at least 2 cysts 
(unilateral or bilateral) while subjects ≥ 30 years of age must have at 
least 2 cysts in each kidney (ie, total ≥ 4 cysts).   
2. Cysts must be at least 1 cm in size to be considered. 
3.  Subject is ≥ 18 but ≤ 62 years of age at time of consent. 
4. The subject has an eGFR ≥ 35 mL/min/1.73 m2 and ≤ 
80 mL/min/1.73 m2, using the MDRD-4 variable formula 
(Appendix A).  
5. The subject has an htTKV ≥ 1000 mL (htTKV is calculated using total 
kidney volume obtained from MRI divided by height in meters). 
6. Subject has the following laboratory values: 
 
Platelets >LLN 
 
Hemoglobin > 9 g/dL  
 
Total bilirubin ≤ 1.5 mg/dL 
 
AST (SGOT) < 2.5 × upper limit of normal (ULN)  
 
ALT (SGPT) < 2.5 × ULN 
 
PT/PTT ≤ 1.5 × ULN  
 
Albumin ≥ lower limit of normal 
 
Amylase within normal limits 
 
Lipase within normal limits 
7. The subject has International Normalized Ratio (INR) ≤ 1.5, except 
those subjects taking warfarin who must have INR < 3.0.  


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8. The subject has serum potassium levels and serum magnesium levels 
within the normal range.     
9. The subject is capable of understanding and complying with the 
protocol and has signed the informed consent form. 
10. Female subjects of childbearing potential have a negative pregnancy 
test at Screening.  Females of childbearing potential are defined as 
sexually mature women without prior hysterectomy or who have had 
any evidence of menses in the past 12 months.  However, women who 
have been amenorrheic for 12 or more months are still considered to be 
of childbearing potential if the amenorrhea is possibly due to prior 
chemotherapy, anti-estrogens, or ovarian suppression.   
• 
Women of childbearing potential (i.e., menstruating women) 
must have a negative urine pregnancy test (positive urine tests 
are to be confirmed by serum test) documented within the 
24 hour period prior to the first dose of study drug. 
• 
Sexually active women of childbearing potential enrolled in the 
study must agree to use two forms of accepted methods of 
contraception during the course of the study and for 6 months 
after their last dose of study drug.  Effective birth control 
includes (a) IUD plus one barrier method; (b) on stable doses 
of hormonal contraception for at least 3 months (eg, oral, 
injectable, implant, transdermal) plus one barrier method; or 
(c) 2 barrier methods.  Effective barrier methods are male or 
female condoms, diaphragms, and spermicides (creams or gels 
that contain a chemical to kill sperm); or (d) a vasectomized 
partner 
11. For male subjects who are sexually active and who are partners of 
premenopausal women: agreement to use two forms of contraception 
as in criterion 10 above during the treatment period and for at least 6 
months after the last dose of study drug.   
12.   The subject has no history of another malignancy in the 5 years prior 
to study entry, except treated non-melanoma skin cancer or superficial 
bladder cancer or carcinoma in-situ of the cervix or Stage 1 or 2 
cancers of other sites that have been treated surgically and have not 
recurred.  
 
 
Exclusion Criteria: 
1. The subject has had a previous partial or total nephrectomy or a kidney 
transplant.  
2. The subject has tuberous sclerosis, Hippel-Lindau disease, or acquired 
cystic disease. 
3. The subject has congenital absence of 1 kidney and/or need for dialysis. 
4. Moderate hematuria. If due to cyst rupture, subject may be rescreened 


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after discussion with medical monitor. 
5. Uncontrolled hypertension (systolic blood pressure > 160 mmHg; 
diastolic blood pressure >100 mm Hg). 
6. Uncontrolled diabetes mellitus (HbA1c > 8%). 
7. Presence of renal or hepatic calculi (stones) causing symptoms. 
8. The subject has received any investigational therapy within 30 days 
prior to study entry. 
9. Active treatment (within 4 weeks of study entry) for urinary tract 
infection. 
10. History of pancreatitis or has known risk factors for pancreatitis 
11. The subject meets any of the following cardiac criteria: 
 
Mean corrected Fridericia (Fridericia’s formula, see Section 9.10)  
QTc interval (QTc[F]) of > 450 msec   
 
History of torsade de pointes, ventricular tachycardia or fibrillation, 
pathologic sinus bradycardia (<50 bpm), heart block (excluding 
first-degree block, being PR interval prolongation only), congenital 
long QT syndrome or new ST segment elevation or depression or 
new Q wave on ECG.  Subjects with a history of atrial arrhythmias 
should be discussed with the medical monitor. 
 
Family history of congenital long QT syndrome or unexplained 
sudden cardiac death. 
 
History of ventricular rhythm disturbances.  
 
Symptomatic heart failure (per NYHA guidelines), unstable angina, 
myocardial infarction, or cerebrovascular accident (CVA) within 
6 months prior to study entry. 
 
Has a cardiac pacemaker. 
 
History of pericardial effusion or presence of pericardial effusion 
on screening echocardiogram 
12. The subject is taking any medication known to inhibit the CYP3A4 
isozyme or any drugs that are CYP3A4 inducers, or any drugs 
associated with torsades de pointes or known to prolong the QTc(F) 
interval, including anti-arrhythmic medications within 2 weeks prior to 
Screening (refer to Appendix B for a sample listing of medications 
associated with QTc[F] prolongation).  A stable regimen (≥ 4 weeks) of 
antidepressants of the SSRI class is allowed (common SSRIs include 
escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, 
and fluoxetine).   
13. The subject has an uncontrolled intercurrent illness that would limit 
compliance with study requirements including, but not limited to 
ongoing or active infections or psychiatric illness.  
14. The subject is pregnant or nursing. 


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15. The subject is known to be positive for the human immunodeficiency 
virus (HIV), or hepatitis B or C, as indicated by a positive test at 
Screening. 
16. Subject is known to be immunocompromised. 
17. The subject has documented presence of renal vascular disease. 
18. The subject has received erlotinib, gefitinib, cetuximab, panitumumab, 
or an investigational EGFR inhibitor at any time.   
19. The subject has an allergy or hypersensitivity to components of either 
the tesevatinib or the formulation. 
20. The subject is unable or unwilling to participate in PK sampling.  
21. The subject is aphakic due to previous cataract surgery or congenital 
anomaly. 
Note: The sponsor has the option to exclude the enrollment of a subject if, 
based upon the subject’s medical history or screening results, it is 
felt that a subject’s safety may be at risk and/or if the safety data 
may confound the study results. 
Study Drug 
Tesevatinib is a new chemical entity that inhibits multiple tyrosine kinases 
(TKs) ErbB family members [EGFR and HER2/ErbB2], vascular 
endothelial growth factor receptor [VEGFR2/KDR]), and Src family 
kinases. 
Dose and 
Administration   
In the Phase 1b portion of the study, tesevatinib will be administered orally 
at doses of 50, 100, and 150 mg once daily.  Study drug may be taken with 
or without food, and should be taken at approximately the same time every 
morning.  Subjects should drink a full glass of water (approximately 
8 ounces [240 mL]) immediately after study drug administration. In the 
Phase 2a portion of the study, tesevatinib will be administered on 
alternative dosing schedules of 150 mg of tesevatinib on Monday, 
Wednesday, and Friday of each week or 150 mg on Monday and Thursday 
of each week.  Additionally, subjects active in the Phase 1b portion had 
their dose increased or decreased to the established MTD of 100 mg daily 
(continuing once-daily administration). 
 If subjects are unable to be seen in clinic on the appropriate protocol 
specified study day, the schedule may also be Tuesday and Friday or 
Wednesday and Saturday.  However, the same schedule must be adhered to 
throughout the study.      
Based on all information generated thus far, the 50 mg tesevatinib 
treatment is the best tolerated dose, and will likely be taken forward in 
additional studies in ADPKD.  In order to generate additional efficacy and 
safety information on this selected dosing regimen, 15 additional subjects 
were enrolled as an additional group in the Phase 2a portion of this protocol 
at a dose of 50 mg of tesevatinib. Up to 50 additional subjects, with eGFR 
≥ 35 mL/min/1.73 m2 and ≤ 80 mL/min/1.73 m2 and htTKV ≥ 1000 mL will 
receive 50 mg of tesevatinib daily and will be added to the Phase 2a portion 


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of the protocol.  Other subjects already enrolled in the study will continue 
to receive the dose and schedule to which they were assigned or to which 
they were transferred. 
Subjects in all cohorts of the study, after the initial 28-day treatment period, 
will, at the discretion of the investigator, continue to receive study 
treatment for at least 24 months from their first dose or until the 
development of unacceptable toxicity, noncompliance, withdrawal of 
consent by the subject, or investigator decision.  Subjects will be provided 
with an adequate supply of and instructions for taking the study drug.  
Study drug accounting will be performed at each visit.   
Duration of 
Treatment 
Subjects will receive study drug for 28 days after the initiation of treatment.  
After the initial 28-day safety and tolerability assessment period, subjects 
will, at the investigator’s discretion, continue to receive study drug for a 
total of 24 months from the initiation of treatment. Subjects will be 
followed for a period of 30 days following the last dose of tesevatinib.   
Concomitant 
Medications 
Subjects should avoid ingesting grapefruit, pomelo, or Seville fruit (and 
juice) with tesevatinib or at any time during the study.  Subjects should not 
take medications that are associated with a risk of QTc(F) interval 
prolongation and/or torsades de pointes.  Additionally, subjects are not 
permitted to take concomitant medications that inhibit the CYP3A4 
isozyme (eg, ketoconazole, itraconazole, erythromycin, clarithromycin) or 
inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampicin, or 
phenobarbital).  Tesevatinib is also highly protein bound, and other drugs 
that are also highly protein bound with the exception of warfarin (eg, 
diazepam, furosemide, dicloxacillin, propranolol, and phenytoin) should be 
avoided.   
Antiemetics and antidiarrheal medications should not be administered 
prophylactically before initial treatment with study drug. At the discretion 
of the investigator, treatment of symptoms with antiemetic and 
antidiarrheal medications may be undertaken per standard clinical practice. 
Since tesevatinib is a potent inhibitor of MATE transporter proteins, 
increased levels of concomitant medications that are secreted by the kidney 
proximal tubule cells into the renal tubule by MATE transporter proteins 
may occur.  Thus, subjects taking cephalexin, cimetidine, dofetilide, 
fexofenadine, metformin, procainamide, and pyrimethamine should be 
monitored carefully. 
Safety Assessments 
Safety assessments will be performed at regular study intervals (refer to 
Study Assessment table) and include AEs, physical examinations, vital sign 
measurements, clinical laboratory evaluations (especially renal function), 
ECGs, echocardiograms, concomitant medication, and pregnancy testing. 
The AE reporting period for a subject enrolled in the study will begin after 
informed consent through 30 days after the last dose of tesevatinib.  
Clinical laboratory tests (hematology, chemistry, urinalysis, coagulation, 


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and thyroid-stimulating hormone [TSH]) will include the following: 
 
Hematology will include complete blood count (CBC) with 
differential, and platelet count.  CBC includes red bloods cells 
(RBCs), hemoglobin, hematocrit, mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), and mean corpuscular 
hemoglobin concentration (MCHC), and white blood cells (WBCs) 
with differential count to include neutrophils, eosinophils, basophils, 
lymphocytes, and monocytes. 
 
Clinical chemistry will include albumin, amylase, alkaline 
phosphatase, ALT, AST, bicarbonate, BUN, calcium, chloride, 
creatinine, creatinine phosphokinase, lactate dehydrogenase, 
potassium, random glucose, sodium, total & direct bilirubin, total 
protein, and magnesium.  GFR will be estimated using the MDRD-4 
formula, the CKD-EPI2012cys equation, and CKD-EPI2012Scr-cys 
equation. 
 
Peripheral blood smears for analyses of any effect on bone marrow 
 
Urinalysis will include assessment of protein, blood, leukocytes, 
glucose, ketones, bilirubin, urobilinogen, pH, color, appearance, and 
specific gravity. 
 
Coagulation tests will include PT, PTT, and INR. 
 
Creatinine clearance and cystatin C levels.   
 
TSH levels will be evaluated at Screening and then every 3 months. 
Vital sign measurements will include sitting blood pressure, pulse rate, 
respiratory rate, and temperature (oral or tympanic). 
Cardiac safety will be determined by the use of 12-lead ECGs recorded at 
the site on validated digital recorders and analyzed by a core ECG 
laboratory.  Additionally, echocardiograms will be obtained and will 
include measurement of ejection fraction and evaluation for pericardial 
effusion and valvular abnormalities.  If pericardial effusion is diagnosed via 
echocardiogram, subject should be rechecked within 1–3 months to monitor 
for progression.  
Ocular evaluations will be performed on each enrolled subject.  Briefly, 
every 4 weeks, subjects will be asked if they have experienced any changes 
in vision, changes in color vision, or new loss of vision in any area.  
Additionally, at Screening, subjects newly enrolled into the study will have 
an evaluation of best corrected visual acuity and will be evaluated with 
fundoscopic exam with non-dilated pupils, slit lamp photography of the 
iris, non-mydriatic photography of retina within the arcade, ,and optical 
coherence tomography (OCT) of the optic nerve head and macula.  All 
ocular assessments should also be conducted at Months 3, 6, 9, 12, 18, and 
24 of the study. Subjects enrolled into the study prior to the requirement for 
these ocular tests will have the same ocular assessments performed at their 
next regularly scheduled study visit, and then will have the same ocular 


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assessments performed when they reach any assessment times that they 
have not already completed in the study (Months 3,6, 9, 12, 18, and 24).    
The initial data from the Phase 1b portion of this study (Protocol 
KD019-101) indicate that subjects with ADPKD may have elevations of 
creatinine without elevations in cystatin C.  This appears to be due to 
inhibition of MATE transporter proteins by tesevatinib, which should be 
reversible.  To demonstrate the reversible nature of the creatinine 
elevations, subjects on the Phase 1b portion of the study will have study 
drug held for a one-time drug holiday of at least 14 days and up to 28 days 
with creatinine and cystatin C measurements before and immediately after 
the drug holiday, as well as a predose PK sample prior to restarting study 
drug. All subjects in the SILK cohort will have weekly blood draws during 
the drug holiday period and during the 4 weeks immediately following the 
drug holiday period.  These samples will be collected and analyzed for 
serum creatinine and cystatin C and plasma tesevatinib levels. 
In order to provide definitive data on renal function that is independent of 
creatinine or cystatin C measurements, iothalamate testing of renal 
clearance will be conducted at selected sites.  In the Phase 2a 50 mg daily 
cohort of patients, only those subjects who can undergo iothalamate or PK 
testing will be enrolled. In addition, eGFR will be calculated using serum 
creatinine, serum cystatin-c, and using both serum creatinine and cystatin-c 
(CKD-EPI2012Scr-cys; see Appendix A for equation). 
Pharmacokinetics 
During the Phase 1b and Phase 2a 50 mg daily portions of the study, blood 
samples will be collected for PK analyses on Study Day 1 (predose, 1, 2, 4, 
8, and 24 hours postdose), Day 14 (predose, 1, 2, 4, and 24 hours postdose), 
and predose on Days 7, 21, and 28.  Additional samples will be collected 
predose at every monthly visit thereafter up to and including the Month 6 
visit for those subjects who continue dosing.   
In the Phase 2a portion of the study, approximately 70 subjects (5 in each 
alternative dosing schedule and 15 subjects in the 50 mg daily dosing 
schedule and 50 subjects in the SILK cohort) will have blood samples 
drawn for PK analyses.   
For subjects receiving 150 mg of KD019 on Monday, Wednesday, 
and Friday:  Samples will be collected on Study Day 1 (predose, and 
1, 2, 4, 8, and 24 hours postdose); predose on Days 3, 5, and 8; and on 
Day 12 (predose, and 1, 2, 4, and 24 hours postdose).   
For subjects receiving 150 mg of KD019 on Monday and Thursday:  
Samples will be collected on Study Day 1 (predose, and 1, 2, 4, 8, and 
24 hours postdose); predose on Days 8, 11, and 18; and on Day 25 
(predose, and 1, 2, 4, 8, and 24 hours postdose).  
For subjects receiving 50 mg of KD019 daily: 
Samples will be collected on Study Day 1 (predose, 1, 2, 4, 8, and 
24 hours postdose), Day 14 (predose, 1, 2, 4, and 24 hours postdose), 
and predose on Days 7, 21, and 28.  Additional samples will be 


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collected predose at every monthly visit thereafter up to and including 
the Month 6 visit for those subjects who continue treatment (Follow-Up 
Treatment Period).   
For subjects receiving 50 mg of tesevatinib daily (the SILK cohort):  
Samples will be collected on Study Day 1 (predose, 1, 2, 4, and 8 hours 
postdose), Day 14 (predose, 1, 2, 4, and 8 hours postdose), and predose 
on Days 7, 21, and 28.  Additional samples will be collected predose at 
every monthly visit thereafter up to and including the Month 6 visit. 
In addition, blood samples for PK analyses will be collected if the QTc(F) 
interval increases by > 60 msec above average predose value (average of 
Day 1 predose and screening values) or to the level of ≥ 480 msec.   
Exploratory Efficacy 
In the Phase 2a Cohort: 
 
Evaluate the 6-month annualized change in GFR. 
 
Evaluate the annualized change from baseline in the reciprocal of 
serum creatinine 
 
Evaluate the annualized percent change from baseline in total 
kidney volume (TKV). TKV will be determined by MRI at 
Screening (baseline measurement), at the 6-month visit, and every 
6 months thereafter.   
Statistical Methods 
Eight subjects per cohort are standard and a reasonable sample size for 
determination of safety and tolerability in this Phase 1b/2a study.  In the 
Phase 2a cohort, 24 subjects were enrolled at the MTD using alternative 
dosing schedules of 150 mg of tesevatinib on Monday, Wednesday, and 
Friday of each week, or 150 mg of tesevatinib on Monday and Thursday of 
each week. There were 15 additional subjects in the Phase 2a cohort dosed 
at 50 mg of tesevatinib daily and up to 50 additional subjects are planned.  
These subjects who receive 50 mg daily of tesevatinib will provide 75% 
likelihood of having at least 1 AE if the true incidence of an AE is 5%.   
Demographic (eg, gender, age, race) and baseline characteristics (height, 
weight) will be summarized by dose level and cohort. 
Safety analyses will be performed on all subjects who receive any quantity 
of tesevatinib.  Data generated from safety assessments will be presented in 
listings by subject and summarized by treatment cohort with the Phase 2a 
cohort being analyzed separately.  Treatment-emergent AEs will be 
summarized using version 18.1 or higher of MedDRA System Organ Class 
(SOC) and preferred term, classified from verbatim terms.  The incidence 
and percentage of subjects with at least 1 occurrence of a preferred term 
will be included, according to the most severe intensity.  The number of 
events per preferred term will also be summarized.   
Causality (relationship to study treatment) will be summarized separately.  
ECG (QT/QTc[F]) and PK data will be provided in a prospective statistical 
plan that will detail the statistical method of analyzing the ECG data and 
morphological findings.  


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Efficacy will be explored with regard to the effect of tesevatinib on eGFR.  
In the Phase 2a cohort, the 65 subjects in the 50 mg QD dose group will 
allow an 80% confidence interval of approximately ± 0.64 mL/min about 
an expected mean 6-month change from baseline of -2.5 mL/min when the 
standard deviation is 4.0 mL/min. Additional statistical details will be 
provided in a prospective statistical plan. 
 


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Table 4-1: 
Schedule of Events for Subjects Enrolled in the Safety in Larger Kidneys (SILK) 50 mg Daily Portion of the 
Study 
Assessments 
Screening
a 
(-28 Days) 
Early Treatment Periodb 
Drug 
Holiday 
Period 
Month 2 
Monthly 
Follow-Up 
Treatment 
Periodc 
 
End of 
Studyd 
 
Day 1 
Day 7 
(±1 day) 
Day 14 
(±1 day) 
Day 21 
(±1 day) 
Day 28 
(±1 day) 
4 Weekly 
Visits 
Beginning at 
Day 28 Visit 
(± 1 day) 
4 Weekly 
Visits 
Beginning 
at Month 2 
Visit 
(± 1 day) 
Every 28 Days 
Beginning at 
Month 3 
(± 3 days) 
(30 Days 
from 
Last 
Dose) 
(± 3 
days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical and PKD 
history  
(including genotype, 
if available)  
X 
 
 
 
 
 
 
 
 
 
Physical examination  
(including weight)e 
X 
X 
X 
X 
X 
X 
 
Xo 
X 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
 
Xo 
X 
X 
Supine 12-Lead ECGg 
X 
X 
X 
X 
X 
X 
 
Xo 
X 
X 
Clinical laboratory 
testsh 
X  
X 
X 
X 
X 
X 
X 
Xo 
X 
X 
Ocular evaluationi 
X 
 
 
 
 
 
 
 
X 
 
Echocardiogramj 
X 
 
 
 
 
X 
 
 
X 
X 
 
Pregnancy testk   
X 
X 
 
 
 
X 
 
 
 
X 
MRIl 
X 
 
 
 
 
 
 
 
 
X 
Study drug 
administration 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Concomitant 
medications p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


KD019 
Protocol Number KD019-101 
Amendment Number 13 
 
 
 
 
 
 
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Page 18 of 148 
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Table 4-1: 
Schedule of Events for Subjects Enrolled in the Safety in Larger Kidneys (SILK) 50 mg Daily Portion of the 
Study 
Assessments 
Screening
a 
(-28 Days) 
Early Treatment Periodb 
Drug 
Holiday 
Period 
Month 2 
Monthly 
Follow-Up 
Treatment 
Periodc 
 
End of 
Studyd 
 
Day 1 
Day 7 
(±1 day) 
Day 14 
(±1 day) 
Day 21 
(±1 day) 
Day 28 
(±1 day) 
4 Weekly 
Visits 
Beginning at 
Day 28 Visit 
(± 1 day) 
4 Weekly 
Visits 
Beginning 
at Month 2 
Visit 
(± 1 day) 
Every 28 Days 
Beginning at 
Month 3 
(± 3 days) 
(30 Days 
from 
Last 
Dose) 
(± 3 
days) 
Adverse eventsp 
To be collected from the time informed consent signed until 30 days after last dose of study drug. 
PK samplingm  
 
X 
X 
X 
X 
X 
 
Xo 
 
 
Plasma concentration 
 
 
 
 
 
 
X 
X 
 
 
Dispense/Collect 
study drug 
 
X 
X 
X 
X 
X 
 
 
Xo 
X 
 


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a. 
Screening evaluations may be combined with Day 1 pre-treatment laboratory evaluations if both are done within 4 days before first dose of study drug.   
b. All protocol-specified clinic visits during the Treatment Period should occur within ± 1 day of the nominal visit day unless otherwise specified. 
c. 
Follow-up Treatment Period visits to be performed monthly (every 28 ± 1 day).  For those subjects continuing on study beyond 12 months, visits will occur 
every 2 months ± 3 days.  
d. End-of-Study visit is to be performed 30 days (± 3 days) after last dose of study drug.  
e. 
A complete physical examination is to be done at the Screening and End-of-Study visits.  Height is only included in the Screening PE.  Limited PEs will be 
performed on Days 1, 7, 14, 21, 28 and Day 1 of Months 2 and beyond (See Section 9, Study Assessments, for a description of the body systems, including 
evaluation for dry mouth, cardiac tamponade by history and examination, and changes in vision to be examined at each visit).  
f. 
Vital sign measurements consist of sitting blood pressure, pulse rate, respiratory rate, and oral or tympanic temperature.  On Day 1, measurements should be 
performed predose and 1 and 4 hours postdose.  See Section 9 for appropriate blood pressure measuring technique.     
g. Supine 12-Lead ECGs will be performed performed, immediately prior to blood sample collection, at Screening, predose, 1, 4, and 8 hours postdose on Days 
1 and 14; predose on Days 7, 21, 28 and Day 1 of Months 2 and beyond; and at End-of-Study visit (repeat 3 times consecutively within 30 minutes [must 
have an interval of at least 1-2 minutes between ECGs]).  Time-matched tesevatinib plasma concentration will be determined at selected pre-dose and post-
dose timepoints.  If QTc(F) is prolonged to > 60 msec above baseline at any evaluation or to the level of ≥ 480 msec based on local ECG read, refer to 
Section 11.3.3.1 for procedure to be followed. 
h. Clinical laboratory tests consist of hematology, serum chemistry panel, coagulation, TSH, and urinalysis (see Section 9.9 for a complete list of assessments).   
TSH levels will be evaluated at Screening and then every 3 months.  All subjects will return to the clinic weekly for 3 weeks after the Month 2 visit for 
collection of blood samples for serum creatinine, cystatin C, and tesevatinib concentration. 
i. 
Ocular evaluations are to be performed at Screening and at Months 3, 6, 9, 12, 18, and 24. The following assessments should be performed: evaluation 
of best corrected visual acuity, fundoscopic exam with non-dilated pupils, slit lamp photography of the iris, non-mydriatic photography of retina within 
the arcade, pils, and optical coherence tomography (OCT) of the optic nerve head and macula.  
j. 
Echocardiograms are to be obtained at Screening, on Day 28, and at Months 3, 6 every 6 months thereafter, and End-of-Study visits and are to include 
measurement of ejection fraction and assessment for pericardial effusion and valvular abnormalities.  Note:  If subject has had echocardiogram within 
2 months of End-of-Study visit, there is no need to obtain echocardiogram at End of Study visit.  For those subjects who have already had their Month 12 
visit, this may be performed at Month 13 and then subsequent echocardiograms may be performed on the same schedule as the MRIs. If pericardial effusion 
is diagnosed via echocardiogram, subject should be rechecked within 1–3 months to monitor for progression. 
k. Pregnancy tests will be done using urine samples in women of childbearing potential.  Subjects must have a negative urine pregnancy test documented 
within the 24-hour period prior to the first dose of study drug.  Pregnancy tests are to be performed at Screening, predose on Day 1, Day 28, Month 3 (and 
every 3 months thereafter), and End-of-Study visits only.  Confirm with serum testing if urine sample is positive.   
l. 
Screening MRI will be performed after informed consent form has been signed and prior to other screening assessments.  MRI to be performed at Month 6 
and then every 6 months thereafter.  Note:  If subject has had MRI within 3 months of End of Study visit, there is no need to obtain MRI at End-of-Study 
visit.  
m. Blood samples will be collected for PK analyses on Study Day 1 (predose, 1, 2, 4, and 8 hours postdose), Day 14 (predose, 1, 2, 4, and 8 hours postdose), 
and predose on Days 7, 21, and 28.  PK samples will also be drawn if the QTc(F) interval increases by > 60 msec above average baseline or to the level of 


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≥ 480 msec (see Section 11.3.3).   
n. PK samples will be collected predose at every monthly visit up to and including Month 6 visit. 
o. These assessments are to be performed ONLY at the Month 2 visit, not at the 3 weekly visits which follow during the Month 2 period. 
p. Blood draws during the drug holiday or Month 2 visits may be performed by a visiting nurse at the subject’s home; if the subject chooses this option, the 
study team should call the subject on the same day of the visit to inquire about concomitant medications and AEs.  
 


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Protocol Number KD019-101 
Amendment Number 13 
 
 
 
 
 
 
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Table 4-2: 
Schedule of Events for Subjects Enrolled in Phase 1b and Phase 2a 50 mg Daily Portions of the Study 
Assessments 
Screeningh 
(-28 Days) 
Early Treatment Periodi 
Monthly 
Follow-Up 
Treatment 
Periodq 
 
End of Studyk 
 
Day 1 
Day 3 
(+1 day) 
Day 7 
(±1 day) 
Day 14 
(±1 day) 
Day 21 
(±1 day) 
Day 28 
(±1 day) 
Every 28 Days 
(± 3 days)j 
(30 Days from 
Last Dose) 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical and PKD history  
(including genotype, if available)  
X 
 
 
 
 
 
 
 
 
Physical examination  
(including weight)a 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Supine 12-Lead ECGc 
X 
X 
 
X 
X 
X 
X 
X 
X 
Clinical laboratory testsd 
Xh  
Xh 
X 
X 
X 
X 
X 
X 
X 
Ocular evaluatione 
X 
 
 
 
 
 
 
X 
 
Peripheral blood smear 
X 
 
 
 
 
 
 
 
X 
Echocardiogram 
X 
 
 
 
 
 
Xl 
Xl 
X 
Pregnancy testf   
X 
X 
 
 
 
 
X 
X  
Every 3 Months 
X 
MRI 
X 
 
 
 
 
 
 
Xm  
Every 6 Months 
X 
Study drug administration 
 
X 
X 
X 
X 
X 
X 
Xn 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
To be collected from the time informed consent signed until 30 days after last dose of study drug. 
PK samplingg  
 
X 
 
X 
X 
X 
X 
Xo 
 
Iothalamate testingp 
 
X 
 
 
X 
 
 
 
 
Dispense/Collect study drug 
 
X 
 
X 
X 
X 
X 
X 
X 
 


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a. 
A complete physical examination (PE) is to be done at the Screening and End-of-Study visits.  Height is only recorded at the Screening PE.  Thereafter, limited PEs will be 
performed on Days 1, 3, 7, 14, 21, 28 and Day 1 of Months 2 and beyond (See Section 9, Study Assessments, for a description of the body systems, including evaluation for 
dry mouth and cardiac tamponade by history and exam, and changes in vision to be examined at each visit).  
b. 
Vital sign measurements consist of sitting blood pressure, pulse rate, respiratory rate, and oral or tympanic temperature.  On Day 1, measurements should be performed 
predose and 1 and 4 hours postdose.  See Section 9 for appropriate blood pressure measuring technique.     
c. 
Supine 12-Lead ECGs will be performed at Screening, predose, and , 4 and 8 hours postdose on Days 1 and 14; predose on Days 7, 21, 28 and Day 1 of Months 2 and beyond; 
and at End-of-Study visit (repeat 3 times consecutively within 30 minutes [must have an interval of at least 1-2 minutes between ECGs]).  If QTc(F) is prolonged to > 60 msec 
above baseline at any evaluation or to the level of ≥ 480 msec, refer to Section 11.3.3.1 for procedure to be followed. 
d. 
Clinical laboratory tests consist of hematology, serum chemistry panel, coagulation, TSH, and urinalysis (see Section 9.9 for a complete list of assessments).   TSH levels will 
be evaluated at Screening and then every 3 months.  (Need not be repeated if screening visit occurred within 4 days prior to Day 1 visit.) 
Ocular evaluations are to be performed at Screening and at Months 3, 6, 9, 12, 18, and 24. The following assessments should be performed: evaluation of best corrected visual 
acuity, slit lamp photography of the iris, non-mydriatic photography of retina within the arcade, pils, and optical coherence tomography (OCT) of the optic nerve head and 
macula. 
f. 
Pregnancy tests will be done using urine samples in women of childbearing potential.  To be performed at screening, predose on Day 1, Day 28, Month 3 (and every 3 months 
thereafter), and End-of-Study visits only.  Confirm with serum testing if urine sample is positive.   
g. 
In the Phase 1b and Phase 2a 50 mg daily portions of the study, blood samples will be collected for PK analyses on Study Day 1 (predose, 1, 2, 4, 8, and 24 hours postdose), 
Day 14 (predose, 1, 2, 4, and 24 hours postdose), and predose on Days 7, 21, and 28.  PK samples will also be drawn if the QTc(F) interval increases by > 60 msec above 
average baseline or to the level of ≥ 480 msec (see Section 11.3.3).   
h. 
Screening must occur within 28 days of first dose of study drug.  Screening evaluations may be combined with Day 1 pre-treatment laboratory evaluations if both are done 
within 4 days before first dose of study drug.   
i. 
All protocol-specified clinic visits during the Treatment Period should occur within ± 1 day of the nominal visit day unless otherwise specified.  
j. 
Follow-up Treatment Period visits to be performed monthly (every 28 ± 3 days).  These visits are only for those subjects who are continuing on study treatment beyond the 
initial 28-day Early Treatment Period.  For those subjects continuing on study beyond 12 months, visits will occur every 2 months ± 3 days. Now that the MTD for daily 
dosing has been established, if it results in a dose increase for subjects not already receiving the MTD, the study assessments required for the monthly follow-up visits (ie, PK 
and postdose ECG and vital sign measurements not required) should be performed on Days 1 and 14 of the first month, then monthly for a total of 6 months, then every 
2 months thereafter.  The same schedule of evaluation will apply to any subjects increased from 50 mg/day to 100 mg/day after 6 months of treatment at 50 mg/day and after 
the 100 mg dose group is determined not to be a DLT dose cohort.  Section 9.6 for study assessments to be performed and the timing of visits.   
k. 
End-of-Study visit is to be performed 30 days (± 3 days) after last dose of study drug.   
l. 
Echocardiograms are to be obtained at Screening, on Day 28, and at Months 3, 6 every 6 months thereafter, and End-of-Study visit and are to include measurement of ejection 
fraction and assessment for pericardial effusion.  Note:  If subject has had echocardiogram within 2 months of End-of-Study visit, no need to obtain echocardiogram at End of 
Study visit.  For those subjects who have already had their Month 12 visit, this may be performed at Month 13 and then subsequent echocardiograms may be performed on the 
same schedule as the MRIs. If pericardial effusion is diagnosed via echocardiogram, subject should be rechecked within 1–3 months to monitor for progression.  
m. Screening MRI should be performed following informed consent and prior to other Screening assessments.  Results must be reviewed before the first dose of study drug is 
administered. MRI to be performed at Month 6 and then every 6 months thereafter.  Note:  If subject has had MRI within 3 months of End of Study visit, there is no need to 
obtain MRI at End-of-Study visit.  
n. 
Subjects on the Phase 1b portion of the study will have study drug held for a one-time drug holiday of at least 14 and up to 28 days with creatinine and cystatin C 
measurements performed before and immediately after the drug holiday, as well as a predose PK sample prior to restarting study drug. 
o. 
PK samples will be collected predose at every monthly visit up to and including Month 6 visit for those subjects in the Phase 1b and Phase 2a 50 mg daily portions of the 


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Protocol Number KD019-101 
Amendment Number 13 
 
 
 
 
 
 
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Page 23 of 148 
Confidential and Proprietary 
06 October 2016 
 
 
study who continue treatment (Follow-Up Treatment Period).  NOTE:  For subjects re-starting study drug after study drug holiday, collect a predose PK sample prior to 
restarting study drug. 
p. 
Required for Phase 2a 50 mg subjects electing not to participate in PK testing.  Based upon the results of testing, a third timepoint may be performed within the first two 
months of study drug dosing and after consultation with the medical monitor. 
q. 
Follow-up Treatment Period visits to be performed monthly (every 28 ± 3 days).  For those subjects continuing on study beyond 12 months, visits will occur every 2 months ± 
3 days. 
 
 


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Protocol Number KD019-101 
Amendment Number 13 
 
 
 
 
 
 
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Table 4-3: 
Schedule of Events for Subjects in Phase 2a Portion of Study Dosed on Monday, Wednesday, and Friday 
Assessments 
Screeningj 
(-28 Days) 
Early Treatment Periodk 
Follow-Up 
Treatment 
Period 
End of Studym 
 
Day 1 
Day 3  
Day 5  
Day 8 
Day 12  
(±1 day) 
Day 26  
(±1 day) 
Every 28 Days 
(± 3 days)l 
30 Days from 
Last Dose 
(± 3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical and PKD history  
(including genotype, if 
available)  
X 
 
 
 
 
 
 
 
 
Physical examination  
(including weight)a 
X 
Xl 
 
 
 
X 
X 
X 
X 
Vital signsb 
X 
X 
 
 
 
X 
X 
X 
X 
Supine 12-Lead ECGc 
X 
X 
 
 
 
X 
X 
X 
X 
Clinical laboratory testsd 
Xi  
Xi 
 
 
 
X 
X 
X 
X 
Ocular evaluatione 
X 
 
 
 
 
 
 
X 
 
Peripheral blood smear 
X 
 
 
 
 
 
 
 
X 
Iothalamate testingf  
X 
 
 
 
 
X 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
Xn 
Xn 
X 
Pregnancy testg  
X 
X 
 
 
 
 
X 
X  
Every 3 Months 
X 
MRI 
X 
 
 
 
 
 
 
Xo  
Every 6 Months 
X 
Study drug administrationh 
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
Collect from the time informed consent signed until 30 days after last dose of study drug. 


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Protocol Number KD019-101 
Amendment Number 13 
 
 
 
 
 
 
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Confidential and Proprietary 
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PK samplingi 
 
 
X 
X 
X 
X 
 
 
 
Dispense/Collect study drug 
 
X 
 
 
 
 
X 
X 
X 
a. 
Complete PE to be done at Screening and End-of-Study visits.  Height is only included in the Screening PE.   Thereafter, limited PEs will be performed on Days 1, 12, 26, 
and Day 1 of Months 2 and beyond (See Section 9, Study Assessments, for a description of the body systems, including evaluation for cardiac tamponade and dry mouth by 
history and exam, and changes in vision to be examined at each visit).  
b. 
Vital sign measurements consist of sitting blood pressure, pulse rate, respiratory rate, and oral or tympanic temperature.  On Day 1, measurements should be performed 
predose and 1 and 4 hours postdose.  See Section 9 for appropriate blood pressure measuring technique.  For subjects participating in PK, vital signs are also to be measured 
8 hours postdose on Day 1.     
c. 
Supine 12-Lead ECGs will be performed at Screening, predose, and 1 and 4 hours postdose on Days 1 and 12; predose on Day 26 and Day 1 of Months 2 and beyond; and at 
End-of-Study visit (repeat 3 times consecutively within 30 minutes [must have an interval of at least 1-2 minutes between ECGs]).  If QTc(F) is prolonged to > 60 msec 
above baseline at any evaluation or to the level of ≥ 480 msec, refer to Section 11.3.3.1 for procedure to be followed.  For subjects participating in PK, ECGs are also to be 
performed 8 hours postdose on Day 1. 
d. 
Clinical laboratory tests consist of hematology, serum chemistry panel, coagulation, and urinalysis (see Section 9.9 for a complete list of assessments).  
e. 
Ocular evaluations are to be performed at Screening and at Months 3, 6, 9, 12, 18, and 24. The following assessments should be performed: evaluation of best corrected 
visual acuity, fundoscopic exam with non-dilated pupils, slit lamp photography of the iris, non-mydriatic photography of retina within the arcade, pils, and optical coherence 
tomography (OCT) of the optic nerve head and macula. 
f. 
Optional; to be conducted at selected sites in 3–7 subjects. Second time point should be done on Day 12, 13, 14 or 15, and all study related procedures required on Day 12 
may be done at this visit.   Based upon the results of testing, a third timepoint may be performed within the first 2 months of study drug dosing and after consultation with 
the medical monitor.  
g. 
Urine pregnancy tests are to be done in women of childbearing potential at Screening, predose on Day 1, Day 26, at Month 3 (and every 3 months thereafter up through 
Month 12), and End-of-Study visits only.  For subjects continuing on study past 12 months who have visits every 2 months, testing should be done every 2 months to 
coincide with their visit schedule. Confirm with serum testing if urine sample is positive.   
h. 
Subjects will start Phase 2a with an alternative dosing schedule of 150 mg of KD019 on Monday, Wednesday, and Friday of each week. 
i. 
In the Monday, Wednesday, and Friday dosing schedule of the Phase 2a portion of the study, approximately 5 subjects will have blood samples drawn for PK analyses.  If 
accrual goals have nearly been met, only those who can undergo iothalamate or PK testing will be enrolled.  Blood samples will be collected on Study Day 1 (predose, 1, 2, 
4, 8, and 24 hours postdose), predose on Study Days 3, 5, and 8, and Study Day 12 (predose, and 1, 2, 4, and 24 hours postdose).  (Subjects undergoing iothalamate testing 
will not undergo PK sampling.)  Also, collect PK sample if QTc(F) interval increases by > 60 msec above average baseline or to the level of ≥ 480 msec (see 
Section 11.3.3.1). 
j. 
Screening must occur within 28 days of first dose of study drug.  Screening evaluations may be combined with Day 1 pre-treatment laboratory evaluations if both are done 
within 4 days before first dose of study drug.  Results must be reviewed before the first dose of study drug is administered. 
k. 
All protocol-specified clinic visits during the Treatment Period should occur within ± 1 day of the nominal visit day unless otherwise specified.  
l. 
Follow-up Treatment Period visits to be performed monthly (± 3 days) for the first 12 months the subject is on study.  Thereafter, Follow-up visits are to be performed bi-
monthly (every 60 ± 3 days).  For those subjects continuing on study beyond 12 months, visits will occur every 2 months.  See Section 9.6 for study assessments to be 
performed and the timing of visits. 
m. End-of-Study visit is to be performed 30 days (± 3 days) after last dose of study. 
n. 
Echocardiograms are to be obtained at Screening, on Day 26, at Months 3, 6 and every 6 months thereafter, and at End-of-Study visit and are to include measurement of 
ejection fraction and assessment for pericardial effusion.  Note:  If subject has had echocardiogram within 2 months of End-of-Study visit, no need to obtain echocardiogram 
at End-of-Study visit.  If pericardial effusion is diagnosed via echocardiogram, subject should be rechecked within 1–3 months to monitor for progression. 
o. 
MRI to be performed at Screening, Month 6 and then every 6 months thereafter.  Note:  If subject has had MRI within 3 months of End-of-Study visit, there is no need to 


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obtain MRI at End-of-Study visit. 
 


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Table 4-4: 
Schedule of Events for Subjects in Phase 2a Portion of Study Dosed on Monday and Thursday 
Assessments 
Screeningj 
(-28 Days) 
Early Treatment Periodk 
Follow-Up 
Treatment 
Period 
End of Studyn 
 
Day 1 
Day 8l 
(PK 
Subjects)  
Day 11 
(±1 day)  
Day 18l 
(PK 
Subjects) 
Day 25  
(±1 day) 
Every 28 Days 
(±3 days)m 
(30 Days from 
Last Dose) 
(±3 days) 
Informed consent 
X 
 
 
 
 
 
 
 
Medical and PKD history  
(including genotype, if available)  
X 
 
 
 
 
 
 
 
Physical examination  
(including weight)a 
X 
X 
 
X 
 
X 
X 
X 
Vital signsb 
X 
X 
 
X 
 
X 
X 
X 
Supine 12-Lead ECGc 
X 
X 
 
X 
 
X 
X 
X 
Clinical laboratory testsd 
Xj  
Xi 
 
X 
 
X 
X 
X 
Ocular evaluatione 
X 
 
 
 
 
 
X 
 
Peripheral blood smear 
X 
 
 
 
 
 
 
X 
Iothalamate testingf  
X 
 
 
 
 
X 
 
 
Echocardiogram 
X 
 
 
 
 
Xn 
Xo 
X 
Pregnancy testg   
X 
X 
 
 
 
X 
X  
Every 3 Months 
X 
MRI 
X 
 
 
 
 
 
Xp  
Every 6 Months 
X 
Study drug administrationh 
 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
Collect from the time informed consent signed until 30 days after last dose of study drug. 
PK samplingi 
 
X 
X 
X 
X 
X 
 
 


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Dispense/Collect study drug 
 
X 
 
 
 
X 
X 
X 
a. 
Complete PE to be done at Screening and End-of-Study visits.  Height is only included in the Screening PE.   Thereafter, limited PEs will be performed on Days 1, 
11, 25, and Day 1 of Months 2 and beyond (See Section 9, Study Assessments, for a description of the body systems, including evaluation for cardiac tamponade and 
dry mouth by history and exam, and changes in vision to be examined at each visit).  
b. 
Vital sign measurements consist of sitting blood pressure, pulse rate, respiratory rate, and oral or tympanic temperature.  On Day 1 measurements should be 
performed predose and 1 and 4 hours postdose.  For subjects participating in PK, vital signs also are also to be measured 8 hours postdose on Day 1.  See Section 9 for 
appropriate blood pressure measuring technique.     
c. 
Supine 12-Lead ECGs will be performed at Screening, predose, and 1 and 4 hours postdose on Days 1 and 25; predose on Day 11 and Day 1 of Months 2 and beyond; 
and at End-of-Study visit (repeat 3 times consecutively within 30 minutes [must have an interval of at least 1-2 minutes between ECGs]).  For subjects participating in 
PK, ECGs also are to be performed 8 hours postdose on Days 1 and 25.  If QTc(F) is prolonged to > 60 msec above baseline at any evaluation or to the level of ≥ 480 
msec, refer to Section 11.3.3.1 for procedure to be followed.   
d. 
Clinical laboratory tests consist of hematology, serum chemistry panel, coagulation, and urinalysis (see Section 9.9 for a complete list of assessments). (Need not be 
repeated if screening visit occurred within 4 days prior to Day 1 visit.)  
e. 
Ocular evaluations are to be performed at Screening and at Months 3, 6, 9, 12, 18, and 24. The following assessments should be performed: evaluation of best 
corrected visual acuity, slit lamp photography of the iris, non-mydriatic photography of retina within the arcade, pils, and optical coherence tomography (OCT) of the 
optic nerve head and macula. 
f. 
Optional; to be conducted at selected sites in 3–7 subjects. Second time point should be done between Day 22 and 25 and all study related procedures required on Day 
25 may be done at this visit.   Based upon the results of testing, a third timepoint may be performed within the first 2 months of study drug dosing and after 
consultation with the medical monitor.  
g. 
Urine pregnancy tests are to be done in women of childbearing potential at Screening, predose Day 1, Day 25, at Month 3 (and every 3 months through Month 12), 
and End-of-Study visits only.  For subjects continuing on study past 12 months who have visits every 2 months, testing should be done every 2 months to coincide 
with their visit schedule. Confirm with serum testing if urine sample is positive.   
h. 
Subjects will start Phase 2a with an alternative dosing schedule of 150 mg on Monday and Thursday of each week. 
i. 
In the Monday/Thursday dosing schedule of the Phase 2a portion of the study, approximately 5 subjects will have blood samples drawn for PK analyses.  If accrual 
goals have nearly been met, only those who can undergo iothalamate or PK testing will be enrolled.  Blood will be collected on Study Day 1 (predose, and 1, 2, 4, 8, 
and 24 hours postdose); predose on Days 8, 11, and 18; and on Day 25 (predose, and 1, 2, 4, 8, and 24 hours postdose), and predose at every monthly visit thereafter 
(up to and including the Month 6 visit) (Subjects undergoing iothalamate testing will not undergo PK sampling.)  Also, collect PK sample if QTc(F) interval increases 
by > 60 msec above average baseline or to the level of ≥ 480 msec (see Section 11.3.3.1). 
j. 
Screening must occur within 28 days of first dose of study drug.  Screening evaluations may be combined with Day 1 pre-treatment laboratory evaluations if both are 
done within 4 days before first dose of study drug.  Results must be reviewed before the first dose of study drug is administered. 
k. 
All protocol-specified clinic visits during the Treatment Period should occur within ± 1 day of the nominal visit day unless otherwise specified.  
l. 
This visit is for subjects participating in PK sampling only. 
m. Follow-up Treatment Period visits to be performed monthly (± 3 days) for the first 12 months the subject is on study.  Thereafter, Follow-up visits are to be performed 
bi-monthly (every 60 ± 3 days).  For those subjects continuing on study beyond 12 months, visits will occur every 2 months.  See Section 9.6 for study assessments 
to be performed and the timing of visits. 
n. 
End-of-Study visit is to be performed 30 days (± 3 days) after last dose of study drug.  
o. 
Echocardiograms are to be obtained at Screening, on Day 25, at Months 3, 6 and every 6 months thereafter, and at End-of-Study visit and are to include measurement 
of ejection fraction and assessment of pericardial effusion. Note:  If subject has had echocardiogram within 2 months of End-of-Study visit, no need to obtain 
echocardiogram at End-of-Study visit.  If pericardial effusion is diagnosed via echocardiogram, subject should be rechecked within 1–3 months to monitor for 
progression.    


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p. 
MRI to be performed at Screening, Month 6, and then every 6 months thereafter.  Note:  If subject has had MRI within 3 months of End-of-Study visit, there is no 
need to obtain MRI at End-of-Study visit. 


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Table 4-5: 
Timing Window Allowances for PK Sampling, Vital Sign Measurements, and 
ECGs 
Pharmacokinetic Sampling 
 
Timepoint 
Tolerance Window 
0 hour 
-240 minutes to 0 hour 
>0 hour – 2 hour 
-2 minutes/+ 2 minutes 
4 hour – 8 hour 
-5 minutes/+ 5 minutes 
24 hour  
-30 minutes/+ 30 minutes 
 
Vital Signs 
 
Timepoint 
Tolerance Window 
0 hour 
-240 minutes to 0 hour 
>0 hour – 4 hour 
-10 minutes/+ 10 minutes 
>4 hour – 8 hour 
-30 minutes/+ 30 minutes 
 
ECG 
 
Timepoint 
Tolerance Window 
0 hour 
-240 minutes to 0 hour 
>0 hour – 4 hour 
-10 minutes/+ 10 minutes 
>4 hour – 8 hour 
-30 minutes/+ 30 minutes 
 
 


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TABLE OF CONTENTS 
1 
PROCEDURES IN CASE OF EMERGENCY ..........................................................2 
2 
SPONSOR SIGNATURE ...........................................................................................3 
3 
INVESTIGATOR SIGNATURE................................................................................4 
4 
SYNOPSIS ..................................................................................................................5 
5 
BACKGROUND AND RATIONALE .....................................................................39 
5.1 
Polycystic Kidney Disease ...............................................................................39 
5.2 
Tesevatinib .......................................................................................................40 
5.2.1 
Tesevatinib Nonclinical Toxicology ....................................................40 
5.2.2 
Clinical Experience with KD019 .........................................................40 
5.3 
Safety Profile of Tesevatinib ...........................................................................49 
5.3.1 
Tesevatinib ...........................................................................................49 
5.4 
Rationale ..........................................................................................................53 
5.4.1 
Rationale for the ADPKD Indication ...................................................53 
5.4.2 
Rationale for Dosage Selection ............................................................54 
5.5 
Compliance Statement .....................................................................................57 
5.5.1 
Good Clinical Practice .........................................................................58 
6 
STUDY OBJECTIVES .............................................................................................59 
6.1 
Phase 1b Objective ...........................................................................................59 
6.2 
Phase 2a Objectives .........................................................................................59 
7 
STUDY DESIGN......................................................................................................60 
7.1 
Study Sites .......................................................................................................60 
7.2 
Overview of Study Design ...............................................................................60 
7.2.1 
Screening Period ..................................................................................61 
7.2.2 
Treatment Period ..................................................................................61 
7.3 
Randomization and Blinding ...........................................................................63 
8 
STUDY POPULATION ...........................................................................................64 
8.1 
Target Population .............................................................................................64 
8.2 
Inclusion Criteria .............................................................................................64 
8.3 
Exclusion Criteria ............................................................................................66 


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9 
STUDY ASSESSMENTS AND PROCEDURES ....................................................69 
9.1 
Screening Period ..............................................................................................69 
9.2 
Subjects Enrolled in SILK Cohort ...................................................................70 
9.2.1 
Screening Visit .....................................................................................70 
9.2.2 
Early Treatment Period ........................................................................70 
9.2.2.1 Day 1 ....................................................................................................70 
9.2.2.2 Days 7, 21, and 28................................................................................71 
9.2.2.3 Day 14 ..................................................................................................72 
9.2.3 
Drug Holiday .......................................................................................72 
9.2.5 
Monthly Follow-Up Treatment Period ................................................73 
9.2.5.1 Months 3–12 ........................................................................................73 
9.3 
Subjects Enrolled in Phase 1b and Phase 2a 50 mg Daily Portions of the Study 
(does not apply to SILK cohort) ......................................................................74 
9.3.1 
Screening Visit .....................................................................................74 
9.3.2 
Early Treatment Period ........................................................................75 
9.3.2.1 Day 1 ....................................................................................................75 
9.3.2.2 Day 3 ....................................................................................................76 
9.3.2.3 Days 7, 14, and 21................................................................................76 
9.3.2.4 Day 28 ..................................................................................................76 
9.3.3 
Monthly Follow-Up Treatment Period for Those Subjects Continuing 
Study Drug ...........................................................................................77 
9.3.3.1 Months 2–12 ........................................................................................77 
9.3.4 
Study Drug Holiday Visits ...................................................................78 
9.4 
For Subjects Enrolled in Phase 2a Portion of Study and Dosed on Mondays, 
Wednesday, and Fridays ..................................................................................79 
9.4.1 
Screening Visit .....................................................................................79 
9.4.2 
Early Treatment Period ........................................................................80 
9.4.2.1 Day 1 ....................................................................................................80 
9.4.2.2 Days 3, 5, and 8 (PK Subjects Only) ...................................................80 
9.4.2.3 Day 12 ..................................................................................................81 
9.4.2.4 Day 26 ..................................................................................................81 
9.5 
For Subjects Enrolled in Phase 2a Portion of Study and Dosed on Mondays, 
and Thursdays ..................................................................................................82 
9.5.1 
Screening Visit .....................................................................................82 
9.5.2 
Early Treatment Period ........................................................................83 
9.5.2.1 Day 1 ....................................................................................................83 
9.5.2.2 Days 8 and 18 (PK Subjects Only) ......................................................84 


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9.5.2.3 Day 11 ..................................................................................................84 
9.5.2.4 Day 25 ..................................................................................................85 
9.5.3 
Monthly Follow-Up Treatment Period for Those Subjects Continuing 
on Study Drug – Both Phase 2a Dosing Schedules .............................86 
9.5.3.1 Months 2–12 ........................................................................................86 
9.6 
Phase 1b and 2a Subjects Continuing KD019 beyond 12 Months ..................86 
9.7 
End-of-Treatment Visit (End-of-Study) – All Subjects ...................................87 
9.8 
Unscheduled/AE Resolution Visits:  To Occur as Needed ..............................88 
9.9 
Laboratory Assessments ..................................................................................89 
9.10 
Electrocardiogram Assessments ......................................................................91 
9.11 
Echocardiogram Assessments ..........................................................................92 
9.12 
Ocular Evaluations ...........................................................................................93 
9.13 
Pharmacokinetic Assessments .........................................................................93 
9.14 
Magnetic Resonance Imaging for Exploratory Efficacy Assessments ............94 
9.15 
Iothalamate Testing ..........................................................................................95 
10 
REMOVING SUBJECTS FROM STUDY ..............................................................96 
10.1 
Subject Withdrawal (Stopping Rules) .............................................................96 
10.2 
Study Discontinuation ......................................................................................97 
10.3 
Replacements ...................................................................................................97 
11 
STUDY DRUG .........................................................................................................98 
11.1 
Tesevatinib Administration ..............................................................................99 
11.2 
Dose Escalation and Entry of Subjects into the Next Cohort ........................100 
11.3 
Warnings, Precautions, and Management ......................................................101 
11.3.1 
Diarrhea..............................................................................................101 
11.3.2 
Skin Rash ...........................................................................................102 
11.3.2.1 Suggestions for Rash Management ....................................................102 
11.3.3 
QT Interval Prolongation ...................................................................104 
11.3.3.1 Response to QTc(F) Interval Prolongation ........................................104 
11.3.4 
Elevated Amylase ..............................................................................105 
11.3.5 
Elevated Creatinine Phosphokinase ...................................................105 
11.3.6 
Pulmonary Toxicity ...........................................................................105 
11.3.7 
Hepatotoxicity ....................................................................................106 
11.3.8 
Pericardial Effusion ...........................................................................106 
11.4 
Study Drug Accountability and Subject Treatment Compliance ...................107 


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12 
CONCOMITANT MEDICATION AND TREATMENT ......................................109 
12.1 
Additional Therapy ........................................................................................109 
12.2 
Interaction of Tesevatinib with Other Medications .......................................109 
12.2.1 
Tesevatinib .........................................................................................109 
12.2.2 
Management of Subjects Requiring Concomitant Medications 
Associated with QT Interval Prolongation ........................................110 
13 
SAFETY .................................................................................................................111 
13.1 
Safety Parameters...........................................................................................111 
13.2 
Adverse Event Definition ..............................................................................111 
13.3 
Evaluating Adverse Events ............................................................................112 
13.3.1 
Serious Adverse Events .....................................................................112 
13.3.2 
Unexpected Adverse Events ..............................................................114 
13.3.3 
Non-Serious Adverse Events .............................................................114 
13.3.4 
Protocol-Related Adverse Events ......................................................114 
13.3.5 
Relationship/Causality to Study Drug ...............................................114 
13.3.6 
Recording Adverse Events .................................................................115 
13.3.7 
Adverse Event Monitoring and Follow-Up .......................................115 
13.3.8 
Laboratory and ECG Abnormalities ..................................................116 
13.3.9 
Pregnancy ...........................................................................................117 
13.3.10 Serious Adverse Event Reporting ......................................................117 
13.3.11 Regulatory Reporting .........................................................................120 
13.3.12 Follow-up Information on a Serious Adverse Event .........................120 
13.4 
Other Safety Considerations ..........................................................................120 
13.4.1 
Medication Errors ..............................................................................120 
13.4.2 
Follow-Up of Serious Adverse Events ..............................................120 
13.5 
Safety Monitoring ..........................................................................................121 
14 
STATISTICAL CONSIDERATIONS....................................................................122 
14.1 
General Design...............................................................................................122 
14.2 
Sample Size Justification ...............................................................................123 
14.3 
Statistical Considerations ...............................................................................123 
14.3.1 
Study Populations ..............................................................................123 
14.3.2 
Subject Accountability, Demographics, and Baseline Characteristics124 
14.3.3 
Tesevatinib Exposure .........................................................................124 
14.3.4 
Concomitant Medications ..................................................................124 
14.3.4.1 Interim Analyses ................................................................................124 
14.3.5 
Pharmacokinetics ...............................................................................124 


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14.3.6 
Efficacy/Activity ................................................................................125 
14.3.7 
MRI ....................................................................................................125 
14.3.8 
Safety Data .........................................................................................125 
15 
DATA QUALITY ASSURANCE ..........................................................................128 
16 
ETHICAL ASPECTS .............................................................................................130 
16.1 
Local Regulations ..........................................................................................130 
16.2 
Informed Consent...........................................................................................130 
16.3 
Institutional Review Board ............................................................................131 
16.4 
Future Use of Subject Samples ......................................................................131 
17 
CONDITIONS FOR MODIFYING THE PROTOCOL.........................................132 
18 
CONDITIONS FOR TERMINATING THE STUDY ...........................................133 
19 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING .....................134 
19.1 
Investigator’s Files and Retention of Documents ..........................................134 
19.2 
Source Documents and Background Data .....................................................135 
19.3 
Audits and Inspections ...................................................................................136 
19.4 
Electronic Case Report Forms .......................................................................136 
20 
MONITORING THE STUDY ................................................................................137 
21 
CONFIDENTIALITY OF STUDY DOCUMENTS AND SUBJECT RECORDS138 
22 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS..........139 
23 
REFERENCES .......................................................................................................140 
 
 
 
 


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LIST OF TABLES 
Table 4-1: 
Schedule of Events for Subjects Enrolled in the Safety in Larger Kidneys 
(SILK) 50 mg Daily Portion of the Study ................................................. 17 
Table 4-2: 
Schedule of Events for Subjects Enrolled in Phase 1b and Phase 2a 50 mg 
Daily Portions of the Study ....................................................................... 21 
Table 4-3: 
Schedule of Events for Subjects in Phase 2a Portion of Study Dosed on 
Monday, Wednesday, and Friday ............................................................. 24 
Table 4-4: 
Schedule of Events for Subjects in Phase 2a Portion of Study Dosed on 
Monday and Thursday .............................................................................. 27 
Table 4-5: 
Timing Window Allowances for PK Sampling, Vital Sign Measurements, 
and ECGs .................................................................................................. 30 
Table 5-1: 
Summary of KD019-101 Dose / Schedule, Demographics and Median 
TKV (mL) ................................................................................................. 44 
Table 5-2: 
QT Prolongation: Cases Confirmed by Central Laboratory Review (By 
Study) ........................................................................................................ 52 
Table 9-1: 
Clinical Laboratory Panels ........................................................................ 90 
 
 
LIST OF APPENDICES 
Appendix A: Equations to Predict Glomerular Filtration Rate (MDRD-4, CKD-
EPI2012cys, and CKD-EPI2012Scr-cys) .......................................................... 142 
Appendix B: Concomitant Medications Associated With a Risk of QTc(F) Interval 
Prolongation and/or Torsades de Pointes ................................................ 144 
Appendix C: Clinical Symptom and Adverse Event Grading Scale ............................ 145 
Appendix D: QTc(F) Calculation ................................................................................. 146 
Appendix E: Topical Steroid Potency Chart ................................................................ 147 
 


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LIST OF ABBREVIATIONS 
ADPKD 
autosomal dominant polycystic kidney disease 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ARPKD 
autosomal recessive polycystic kidney disease 
AUC 
area under the plasma drug concentration time curve 
AUC0-x 
area under the plasma drug concentration time curve from 0 to X hours 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CKD-EPI2012cys 
cystatin C-based CKD-EPI equation 
CKD-EPI2012Scr-cys 
serum creatinine- and cystatin C-based CKD-EPI equation 
Cmax 
maximum plasma concentration 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
HER2 
human epidermal growth factor receptor 2 
HIV 
human immunodeficiency virus 
htTKV 
height-adjusted total kidney volume 
ICH 
International Conference on Harmonization 
ICF 
informed consent form 
ILD 
Interstitial Lung Disease 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
KDR 
kinase insert domain receptor 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
MDRD-4 
4-Variable Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 


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MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NOAEL 
No Observed Adverse Effect Level 
NSCLC 
non-small cell lung cancer 
P-gp 
P-glycoprotein  
PK 
pharmacokinetic 
PKD 
polycystic kidney disease 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QTc(F) 
QT interval, corrected 
SAE 
serious adverse event 
SILK 
safety in larger kidneys 
SOC 
system organ class  
SUSAR 
suspected unexpected serious adverse reaction 
Tmax 
observed time to reach peak plasma concentration 
TK 
tyrosine kinase 
TKV 
total kidney volume 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal  
VEGFR2 
vascular endothelial growth factor receptor 2 
 


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5 
BACKGROUND AND RATIONALE 
5.1 
Polycystic Kidney Disease 
Polycystic kidney disease (PKD) is the most common inherited kidney disease in the United States, 
occurring in approximately 1 in every 1,000 live births.  It affects more than 600,000 people in the 
United States and 12 million worldwide (Wilson, 2004).  It is the third most common single cause 
of kidney failure.  
Polycystic kidney disease is characterized by the growth of numerous renal cysts, which cause 
abnormalities in both structure and function of the kidneys.  Cysts also develop in other organs, 
particularly in the liver.  Other manifestations of polycystic kidney disease include high blood 
pressure, urinary tract infections, kidney stones, hematuria, and aneurysms.  Pain in the back, 
abdomen, and pelvis affects many PKD patients. 
There are 2 types of polycystic kidney disease, autosomal dominant (ADPKD) and autosomal 
recessive (ARPKD).  In the more common form, autosomal dominant PKD, the abnormal PKD 
gene (PKD1 or PKD2) is inherited from 1 parent who also has PKD. Affected individuals become 
aware of the disease at varying times from childhood to adulthood. If a family history exists, 
individuals are assessed regularly for manifestations of the disease. Others may have cysts detected 
during routine medical evaluations for hematuria or hypertension or an ultrasound examination for 
other medical symptoms and conditions. There is, however, a small percentage of people with 
autosomal dominant PKD who do not have a family member with the disease. ARPKD is 
associated with abnormal function of the kidneys and liver, and is usually diagnosed by ultrasound 
during fetal development or shortly after birth. Unlike ADPKD, a mutant PKHD1 gene must be 
contributed by each parent in order for ARPKD to occur in an offspring.  Parents are usually 
unaware of being carriers of the mutant gene because they are asymptomatic. 
ADPKD is caused by a mutation in either the polycystin 1 or 2 (PKD1 or PKD2) genes, resulting in 
the abnormal, uncontrolled growth of renal tubular epithelial cells (Chapman, 2008). In individuals 
with ADPKD, epithelial growth factor receptor (EGFR) is overexpressed and mislocated from the 
basolateral to the luminal surface of renal tubular cells (Torres et al, 2007). EGFR ligands are 
secreted by tubular cells and are found in human PKD cyst fluids. The combination of EGFR 
mislocation and ligand secretion establishes an autocrine loop resulting in persistent renal tubular 
cell proliferation (Torres, 2010). Chronic proliferation results in renal cyst formation (Belibi et al, 


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2004). The cysts then cause a structural distortion of the renal architecture, impeding normal 
nephron function. Cyst enlargement results in a massive increase in kidney volume and a 
progressive impairment of renal function (Grantham et al, 2006). Associated clinical symptoms 
include hypertension, recurrent flank pain, hematuria, and recurrent pyelonephritis. Currently, there 
are no disease-modifying therapies for ADPKD; all existing treatment strategies are palliative and 
aimed at controlling symptoms (Grantham, 2008). 
5.2 
Tesevatinib 
Tesevatinib (formerly named XL647 and KD019) is a new chemical entity that inhibits multiple 
tyrosine kinases (TKs) (ErbB family members [EGFR and HER2], vascular endothelial growth 
factor receptor 2 [VEGFR2/KDR]), and Src family kinases. 
5.2.1 
Tesevatinib Nonclinical Toxicology  
Tesevatinib nonclinical toxicology has been characterized in multiple species using a variety of 
dosing regimens. Details can be found in the Investigator’s Brochure. 
5.2.2 
Clinical Experience with KD019 
Tesevatinib has been evaluated in over 300 subjects, including 195 subjects with solid tumor 
malignancies in 3 Phase 1 studies, 3 Phase 2 studies, and 1 Phase 3 study; 66 healthy volunteer 
subjects in 4 clinical pharmacology studies; and 64 subjects with polycystic kidney disease (in this 
study, KD019-101).  In these studies, at least 185 subjects have been treated at levels ≥ 300 mg 
daily and at least 53 subjects were treated with tesevatinib for ≥ 6 months.  The MTD was 
determined to be 300 mg once daily.  
5.2.2.1 
Daily Administration 
5.2.2.1.1 Phase 1 
In the daily dosing Phase 1 study XL647-002, “A Phase 1 Dose-Escalation Study of the Safety and 
Pharmacokinetics of KD019 Administered Orally Daily to Subjects with Solid Tumors,” 
31 subjects were enrolled in successive cohorts to receive tesevatinib as a single oral dose daily. 
Subjects continued to receive tesevatinib on study in the absence of unacceptable tesevatinib -
related toxicity or progressive disease (PD). The MTD was determined based on dose-limiting 
toxicities (DLTs) occurring in the first 28 days of treatment. Tumor imaging was conducted at 
baseline and approximately every 2 months thereafter while subjects received study drug.  


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A total of 31 subjects were treated across 5 dose levels: 75 mg (n = 3), 150 mg (n = 3), 200 mg 
(n = 3), 300 mg (n = 18), and 350 mg (n = 4). One DLT of Grade 3 drug-induced pneumonitis was 
observed at 300 mg, resulting in expansion of the 300 mg cohort to a total of 6 subjects. Two of 4 
subjects enrolled at 350 mg experienced a DLT of Grade 3 QTc(F) prolongation (machine read), 
both clinically asymptomatic. These events were downgraded to Grade 2 following digital re-reads 
by a validated central ECG laboratory. The MTD was determined to be 300 mg and an additional 
12 subjects were enrolled at this dose level.  
The most common adverse events (AEs) considered either possibly or probably related to 
tesevatinib (frequency ≥ 10% of subjects) reported were Grade 1 and 2 diarrhea, dysgeusia, fatigue, 
rash, and clinically asymptomatic QTc(F) prolongation. One subject receiving a 300 mg daily dose 
of tesevatinib experienced 2 serious adverse events (SAEs) of Grade 3 drug-induced pneumonitis 
and Grade 4 myocardial infarction, which were both assessed by the investigator as related to study 
drug. Two additional subjects experienced SAEs assessed by the investigator as related to study 
drug: clinically asymptomatic Grade 3 QTc(F) prolongations (machine read), subsequently 
downgraded to Grade 2 following digital re-read by a validated central ECG laboratory (also DLTs, 
see above). 
5.2.2.1.2  Phase 2 
In the Phase 2 study, “A Phase 2 Study of KD019 in Subjects with Non-Small Cell Lung Cancer 
Who have Progressed after Responding to Treatment with Either Gefitinib or Erlotinib” 
(XL647-203), 41 subjects with relapsed or recurrent NSCLC (Stage IIIB or IV) with documented 
progressive disease after benefit from single agent erlotinib or gefitinib, including stable disease 
(SD), or with a known EGFR T790M mutation were enrolled to receive tesevatinib, 300 mg orally 
daily. Tumor imaging was conducted at baseline and approximately every 2 months thereafter 
while study drug was received. Subjects were allowed to stay on study in the absence of 
unacceptable tesevatinib -related toxicity or progressive disease. 
A total of 41 subjects were treated and the most frequently reported AEs were diarrhea, nausea, 
cough, dry skin, and ECG QT prolonged.  Adverse events that occurred in ≥ 10% of subjects and 
were considered related to tesevatinib consisted of diarrhea, rash, dry skin, fatigue, cough, and 
electrocardiogram QT prolonged. The majority of these events were Grades 1 and 2. 


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There were 22 SAEs reported for 12 of the 41 subjects enrolled in the study. Eight SAEs assessed 
by the investigator as related to tesevatinib were reported in 4 subjects. One subject experienced 
Grade 3 diarrhea (2 occurrences), Grade 3 abdominal pain, Grade 3 nausea, and Grade 3 vomiting. 
Each of the following SAEs were experienced by 1 subject: Grade 4 bilateral pulmonary emboli, 
Grade 3 ventricular ectopy (in a subject with a history of atrial fibrillation and MI), and Grade 3 
QTc(F) prolongation (based on machine-read value). Two deaths were reported during the course 
of the study (within 30 days of the last dose of study drug), both of which were assessed as not 
related to study drug (tesevatinib).  Both deaths were reported to be due to progressive disease.   
5.2.2.2 
Intermittent Administration 
5.2.2.2.1 Phase 1 
In the Phase 1 study, “A Phase 1 Dose-Escalation Study of the Safety and Pharmacokinetics of 
KD019 Administered Orally to Subjects with Solid Tumors” (XL647-001), subjects with advanced 
solid tumors were enrolled in successive cohorts to receive tesevatinib orally daily on Days 1-5, 
followed by a 9-day break, with cycles repeating every 14 days. This regimen is referred to as the 
“intermittent 5 & 9” schedule. Tumor imaging was conducted at baseline and approximately every 
2 months thereafter while study drug was being received. Subjects were allowed to stay on study in 
the absence of unacceptable tesevatinib -related toxicity or progressive disease. 
In this study, a total of 41 subjects were treated across 11 dose levels. Subjects received study drug 
as either a powder-in-bottle (PIB) formulation at 0.06, 0.12, 0.19, 0.28, 0.39, 0.78, 1.56, 3.12, 4.68, 
and 7.0 mg/kg, or a fixed-dose tablet formulation of 350 mg. One subject in the 3.12-mg/kg cohort 
had a DLT of asymptomatic QTc(F) prolongation, resulting in expansion of that cohort, with no 
further DLTs. The first 2 subjects who received 7.0 mg/kg experienced DLTs of Grade 3 diarrhea, 
despite treatment, requiring dose reduction to 4.68 mg/kg. The reduced dose was well tolerated in 
both of these subjects. Expansion of the 4.68-mg/kg cohort to 6 subjects occurred without further 
DLTs; therefore, 4.68 mg/kg was considered the MTD. All ongoing subjects had their tesevatinib 
dose converted to a fixed dose of 350 mg. One of these subjects developed Grade 3 diarrhea, 
requiring dose reduction. Five additional subjects were enrolled into the 350-mg cohort.  
The most common AEs considered either possibly or probably related to tesevatinib 
(frequency > 10 % of subjects) consisted of Grade 1 or 2 diarrhea, rash, nausea, fatigue, dysgeusia, 
anorexia, vomiting, and dry skin. A total of 3 SAEs assessed by the investigator as related to 
tesevatinib were reported in 3 subjects: 1 subject at 0.28 mg/kg experienced a Grade 4 pulmonary 


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embolism, 1 subject at 7.0 mg/kg experienced Grade 3 diarrhea, and 1 subject receiving 350 mg 
and concomitant warfarin experienced a Grade 3 elevation in INR. The SAEs of diarrhea were 
assessed as probably related to tesevatinib, and the SAEs of pulmonary embolism and increased 
INR were assessed as possibly related to tesevatinib. 
5.2.2.2.2 Phase 2 
In this study “A Phase 2 Study of KD019 in Subjects with Non-Small Cell Lung Cancer,” 
(XL647-201), selected subjects with NSCLC of adenocarcinoma histology, Stage IIIB, with 
malignant pleural effusion, or Stage IV were enrolled to receive 350 mg of oral tesevatinib daily on 
Days 1-5, followed by a 9-day break, with cycles repeating every 14 days. Subjects with clinical 
characteristics predictive of response to EGFR inhibitors (Asian, female, and/or minimal and 
remote smoking history) were enrolled. Tumor imaging was conducted at baseline and 
approximately every 2 months thereafter during study drug administration. Subjects were allowed 
to stay on study in the absence of unacceptable tesevatinib -related toxicity or progressive disease.  
A total of 41 subjects were enrolled in the intermittent 5 & 9 dosing cohort. The majority of AEs 
reported were Grade 1 (71.0%) or Grade 2 (22.5%) and the most frequently reported AEs were 
diarrhea, fatigue, nausea, rash, and cough. The most frequently reported Grade 3 AEs were pleural 
effusion (experienced by 4/41 [9.8%] subjects), diarrhea, and electrocardiogram QT prolonged 
(each experienced by 3/41 [7.3%] subjects). Grade 4 pulmonary embolism was reported for 
3/41 (7.3%) subjects.  A total of 5 SAEs assessed by the investigator as possibly or probably 
related to tesevatinib were reported in 4 subjects. One subject experienced SAEs of Grade 3 
gastrointestinal (GI) hemorrhage and duodenal ulcer, and the following SAEs were experienced by 
1 subject each: Grade 3 pneumonia, Grade 2 hemoptysis, and clinically asymptomatic Grade 3 
QTc(F) prolongation (machine-read, downgraded to Grade 2 following digital re-reads by a 
validated central ECG laboratory). 
A second cohort in this study enrolled 14 subjects to receive KD019 orally daily at a dose of 
300 mg. The majority of AEs reported in this cohort were Grade 1 (68.3%) or Grade 2 (22.2%). 
The most frequently reported AEs with daily dosing were diarrhea, fatigue, nausea, rash, and 
cough.  The most frequently reported Grade 3 AEs were diarrhea, electrocardiogram QT 
prolonged, and pleural effusion (each reported by 2/14 subjects, 14.3%).  Thirteen SAEs were 
reported in 6 of the 14 subjects. Three SAEs were assessed by the investigator as related to 


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tesevatinib: Grade 3 GI hemorrhage, Grade 3 hypercalcemia, and Grade 2 increased blood 
creatinine.  
5.2.2.2.3 Initial Data from ADPKD Protocol KD019-101 
Sixty-one subjects were enrolled into 5 dosing cohorts in the Phase 1b and Phase 2a portions of the 
study: 9 subjects into Cohort 1 at 50 mg daily, 8 subjects into Cohort 2 at 100 mg daily, 5 subjects 
into Cohort 3 at 150 mg daily, 14 subjects into Cohort 4 at 150 mg Monday, Wednesday, and 
Friday, 10 subjects into Cohort 5 at 150 mg Monday and Thursday, and an additional 15 Phase 2a 
subjects at 50 mg daily (Table 5-1).   
Table 5-1: 
Summary of KD019-101 Dose / Schedule, Demographics and Median TKV 
(mL) 
Dose/Schedule No. Subjects 
Gender (Male [M]/Female [F]) 
Median Age (Years) 
Median TKV (mL) 
50 mg/day 
24 
9M / 15F 
39 
1401* 
100 mg/day 
8 
5M / 3 F 
37 
1525 
150 mg/day 
5 
2M / 3 F 
41 
1094 
150 mg MWF 
14 
4M / 10 F 
36 
1344 
150 mg MT 
10 
4M / 6 F 
37 
795 
Total 
61 
24M / 37F 
38 (19-55) 
1333.5* (411-4432) 
*2 subjects did not yet have TKV values 
Safety reviews after the first 2 cohorts deemed these cohorts to have adequate safety and to be 
tolerable.  In Cohort 3, 3 of 5 subjects enrolled have withdrawn consent primarily due to concerns 
with rash.  It was noted that all 5 subjects in this cohort experienced rash within the first 28 days of 
treatment. In comparison, 4 out of 9 subjects in the 50-mg cohort and 1 out of 8 subjects in the 100-
mg cohort experienced rash within the first 28 days.  While rash at the 150 mg dose level did not 
meet strict safety criteria for defining the MTD, this dose level was considered intolerable for long-
term administration in this population. Therefore, the MTD for daily dosing was determined to be 
100 mg daily.  While the MTD dose of 100 mg/day was based on criteria defined in the protocol, 
the occurrence of moderate QTc prolongation in 2 subjects dosed at that level led to a decision later 
in the study to recommend 50 mg/day as the best tolerated daily dose. 
As the known toxicities of tesevatinib, including diarrhea and rash, have been seen in all 3 Phase 
1b dosing cohorts, an alternative dosing schedule of dosing 150 mg of KD019 on Monday, 


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Wednesday, and Friday of each week was explored in the Phase 2a portion of the study to 
determine if it is more tolerable when used chronically in this subject population.  The safety data 
of the 14 subjects who received 150 mg tesevatinib every Monday, Wednesday and Friday has 
been reviewed by the Data Safety Committee.  There were 3 moderate events: 1 subject had 
moderate QTc(F) prolongation which resolved with dose modification as well as moderate 
diarrhea, and 1 subject with moderate rash which improved with topical corticosteroids and 
emollients.  While the tolerability of this schedule appears to be superior to that of dosing 
tesevatinib 150 mg on a daily schedule, another dosing schedule of tesevatinib 150 mg 
administered on Monday and Thursday of each week was explored to determine if this dose and 
schedule would result in fewer moderate toxicities, particularly QTc(F) prolongation.  To date, of 
the 10 subjects receiving 150 mg Monday and Thursday, there was no QTc(F) prolongation; 
however, 1 subject had a severe (Grade 3) maculopapular skin rash.  Thus, while the 150 mg 
Monday and Thursday administration of tesevatinib generally appears to be a tolerable regimen, 
the occurrence of the Grade 3 maculopapular skin rash, together with the significant effect of 
missing any single dose in this regimen, has led to the decision to further evaluate the dose level of 
50 mg daily prior to using this dose in a randomized study. 
Following the enrollment of the additional 15 subjects in the Phase 2 50 mg dosing cohort, it was 
concluded that tesevatinib 150 mg in various schedules was associated with skin rash that was not 
well tolerated.  Incidence of moderate QTc prolongation not acceptable for chronic use was 
associated with tesevatinib 100 mg daily.  Tesevatinib 50 mg daily appeared to be a well-tolerated 
dose in patients with ADPKD, although some acneiform rash occurred.  The study will enroll 
approximately 50 more subjects at the dose of 50 mg daily in order to increase the robustness of the 
safety data in subjects with ADPKD treated with tesevatinib.    
The initial data from this study (Protocol KD019-101) indicate that subjects with ADPKD 
receiving tesevatinib have experienced elevations of creatinine without elevations in cystatin C.  
The median changes from screening values for creatinine and cystatin C from all 9 subjects in the 
50-mg dose cohort reveal that creatinine values were increased by 7.5% at Day 3, by 22% at Day 7, 
and increased by 13% at Day 28.  Data after Day 28, including 2 subjects who have received 
tesevatinib for 16 months, do not indicate any significant ongoing change in creatinine.  Cystatin C 
levels, during the same time periods, did not change (median decreases of 4.5%, 1%, and 4% at 
Days 3, 7, and 28, respectively).  Data from the 8 subjects enrolled into the 100-mg dose cohort, as 
well as subjects enrolled in subsequent cohorts, exhibited a similar pattern.  This increase in 


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creatinine occurs early and after approximately 7 days, does not continue to increase, similar to the 
increase in serum creatinine seen with cimetidine.  Increases in creatinine were seen in previous 
clinical studies of tesevatinib.  For example, increases in serum creatinine in 10% of subjects were 
reported in Study XL647-201.  However, most of the previous studies were in subjects with 
malignancies, and in previous studies, cystatin C levels were not evaluated, so increases in serum 
creatinine that may not represent renal dysfunction were not recognized.   
In order to further investigate the effects of tesevatinib on serum creatinine levels, the effects of 
tesevatinib on a panel of transporter molecules (including OCT2 and MATE) were evaluated in 
vitro.  Preliminary results indicate that tesevatinib potently inhibits MATE1 and MATE2-K 
transporter proteins.  MATE transporter proteins carry creatinine out of kidney proximal tubule 
cells into the tubule lumen. Inhibition of MATE transporter proteins decreases secretion of 
creatinine into the proximal tubule lumen and leads to an increase in serum creatinine levels.  To 
demonstrate the reversible nature of the creatinine elevations, subjects on the Phase 1b portion of 
the study will have study drug held for a one-time drug holiday of at least 14 and up to 28 days 
with creatinine and cystatin C measurements before and immediately after the drug holiday, as well 
as a predose PK sample prior to restarting study drug. 
In addition, in order to have an independent method of evaluating renal function, 3–7 subjects in 
the Phase 2a portion of this study will be evaluated by iothalamate renal clearance testing before 
and after tesevatinib administration.  If accrual goals have nearly been met and goals for subjects 
with PK or iothalamate testing have not been met, only those who can undergo iothalamate or PK 
testing will be enrolled.  Iothalamate is a contrast agent widely utilized in renal clearance testing 
because, unlike creatinine, it is filtered at the glomerulus and not secreted in the proximal tubule.  
Testing is performed by injection of iothalamate with serum samples obtained for iothalamate 
evaluation over 3 hours post iothalamate injection.  Thus, iothalamate renal clearance testing will 
provide an independent method for verification of renal function before and after tesevatinib 
administration.   
In the current study, there have been 18 cases of asymptomatic subjects with elevated amylase 
levels.  Fourteen of these elevations were mild (> ULN – 1.5 x ULN), 2 were moderate (> 1.5 X 
ULN – 2.0 x ULN), and 2 were severe (> 2.0 x ULN).  Three subjects had elevated amylase levels 
at Screening and in 2 of these subjects’ amylase levels rose to moderate levels, leading to 
discontinuation from the study.  Other subjects with amylase elevations have not had progressive 


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increases in amylase levels during tesevatinib administration.  One subject developed severe 
elevated amylase during infection with mononucleosis, and amylase levels returned to normal after 
recovery from that illness.  A second subject with a baseline amylase level of 185 U/L had levels 
which continued to rise to a maximum of 365 U/L at Day 110.  While this subject remained 
asymptomatic, with no clinical signs or symptoms of pancreatitis, subjects were discontinued from 
the study.  Both of these subjects with severe amylase elevations had elevations of both lipase and 
pancreatic amylase isozyme.      
Previous studies of tesevatinib have been reviewed for cases of elevated amylase or pancreatitis.  
Amylase was not routinely evaluated in any of these previous studies.  There was only 1 AE of an 
increased amylase level or of possible pancreatitis.  This was an elevation of amylase to 922 U/L in 
a subject with Stage IV non-small cell lung cancer who received tesevatinib at a dose of 300 
mg/day.  The subject was admitted to the hospital with diarrhea and abdominal pain, but lipase was 
normal and there were no CT findings consistent with pancreatitis.  On serum amylase isoenzyme 
analysis, the subject had an elevation in salivary amylase.  The investigator’s conclusion was that 
the subject appeared to have an increase in amylase due to salivary amylase secretion by the tumor.   
Quantitative Whole Body Autoradiography was performed in rats with C14–labeled tesevatinib.  
Among other findings, there was a high concentration (approximately 10 times that found in the 
blood) of tesevatinib in the salivary glands and pancreas.  While tesevatinib could concentrate there 
for many reasons, it’s at least possible that tesevatinib at high concentrations in the salivary gland 
and pancreas could lead to increased serum levels of amylase.   
In summary, mild asymptomatic increases in amylase levels have been seen frequently during the 
study, including in subjects in the 50 mg daily cohort, and appear to be due to increases in 
pancreatic amylase.  Subjects with baseline elevations in amylase are no longer eligible for 
tesevatinib ADPKD studies.  If amylase levels rise to 1.5 x ULN, evaluation of lipase, amylase 
isoenzymes, and lipid levels are performed.  Ongoing evaluations for the presence of pancreatic 
cysts will be performed using MRIs obtained to evaluate TKV.  There were 28 subjects with 
elevations of CPK above the normal range.  Twelve subjects experienced moderate CPK elevation 
(> 2.5 x ULN – 5.0 x ULN), and 3 subjects experienced severe CPK elevation (> 5.0 x ULN).  In 
each case of severe CPK elevation, it appeared that the elevation was associated with exercise and 
did not recur after rechallenge or continued tesevatinib exposure.  Quantitative whole body 
radiography in rats indicates relatively low accumulation of tesevatinib in skeletal muscle.  In this 


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study, muscle AEs correlate poorly with CPK levels.  While elevations of CPK commonly occur 
with exercise, the lack of a control group in this study makes it difficult to fully evaluate the 
relationship between tesevatinib and CPK elevations.   
One subject on the current study in the 50 mg/day cohort developed a small pericardial effusion 
while on study.  An echocardiogram performed per protocol on Day 28 revealed trace pericardial 
effusion, which was not seen on the screening echocardiogram.  This result was reported an as AE 
and assessed by the investigator to be of moderate intensity and probably related to study drug.  
The subject was asymptomatic.  Subsequent echocardiograms performed over the following 
6 months while the subject continued to receive tesevatinib revealed no change in the pericardial 
effusion. 
During this clinical trial there have been 4 incidences of asymptomatic prolongation of QTc 
interval to > 480ms or > 60 ms over the baseline value.  One subject in cohort 2 (100 mg daily) at 
month 5 of dosing had a mean QTc(F) of 510 msec.  The subject had study drug interrupted and 
was dose reduced to 50 mg daily with resolution of QTc(F) prolongation.  Another subject on 
cohort 2 (100 mg daily) presented on Day 7 of study with a mean QTc(F) of 487 msec.  Study drug 
was held.  On rechallenge at the same dose, the QTc(F) was again prolonged at 485 msec.  Study 
drug again was held and restarted at a reduced dose of 50 mg with resolution of QTc(F) 
prolongation.  One subject receiving 150 mg every Monday, Wednesday and Friday on Day 12 
presented with a mean QTc(F) of 485 msec.  Study drug was held and restarted at 100 mg every 
Monday, Wednesday, and Friday with resolution of QTc(F) prolongation.  One subject receiving 
150 mg every Monday and Thursday presented on Month 12 with a mean QTc(F) of 484 msec.  
Study drug was held and restarted at 50 mg daily with resolution of QTc(F) prolongation.    
5.2.2.3 
Clinical Pharmacokinetics  
A preliminary noncompartmental analysis of tesevatinib pharmacokinetics (PK) from Phase 1 
studies of intermittent dosing indicated that tesevatinib was rapidly absorbed following oral 
administration, with a median observed time to reach peak plasma concentration (Tmax) of 4-
8 hours. Area under the plasma drug concentration time curve (AUC) and the maximum plasma 
concentration (Cmax) generally increased approximately in proportion with dose over the full dose 
range (ie, 3.4 to 586 mg). Mean terminal half-lives after 5 consecutive daily doses ranged from 50 
to 92 hours, and appeared generally independent of dose. High inter-subject variability in exposure 
was observed with CV % values of 46% and 43% for dose normalized Cmax and AUC0-24, 


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respectively. Results from 5 subjects in the Phase 2 study who received 350 mg KD019 on the 
intermittent schedule showed that the concentration of tesevatinib appeared unchanged from cycle 
to cycle. These results suggest that tesevatinib does not accumulate significantly from one 14-day 
cycle to the next. 
A preliminary noncompartmental PK analysis has been completed for 15 subjects given tesevatinib 
once daily for at least 29 consecutive days. Tesevatinib was rapidly absorbed following oral 
administration (cohort mean Tmax ranged from 3.3 to 7.3 hours) and steady state appeared to have 
been reached by about Day 15. The estimated median value of accumulation was 4.6 at the MTD 
(ie, 300 mg/day). The median Tmax at the MTD was 4 hours. 
Average exposure was calculated at the MTD for both the once daily (ie, 300 mg/day) and 
intermittent 5 & 9 (ie, 350 mg/day) dosing regimens. At the MTD, the estimated average 
concentration over 28 days for once-daily dosing was 399 ng/mL, which was approximately 2-fold 
higher than the 28-day average concentration determined for intermittent dosing of 199 ng/mL, but 
was generally consistent with the 24-hour average concentration observed after the fifth dose of the 
Intermittent schedule (375 ng/mL). 
5.3 
Safety Profile of Tesevatinib 
5.3.1 
Tesevatinib 
Adverse events of special interest noted in Study KD019-101 include asymptomatic increase in 
serum amylase, pericardial effusion, and asymptomatic QTc(F) prolongation, as described above in 
Section 5.2.2.2.3. 
The most common AEs observed in subjects receiving 300 mg tesevatinib were diarrhea, rash, 
nausea, increased CPK, increased creatinine, vomiting, increased amylase, acne, back pain, and 
fatigue. 
Interstitial Lung Disease: Non-fatal interstitial lung disease (ILD) has been reported in 
association with the use of tesevatinib in 1 subject with NSCLC of 152 subjects exposed to 
tesevatinib.  
QTc(F) Prolongation: In clinical studies of tesevatinib, cases of QTc(F) prolongation have been 
observed. This section summarizes available data regarding cases of QTc(F) prolongation that were 
confirmed by a review by a central ECG laboratory. 


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Using non-standardized digital machines that provided an analysis of the data, including QTc(F) 
values, 12-lead ECG tracings were obtained.  In most of the studies, multiple ECGs were scheduled 
to be taken at tesevatinib concentration nadir and Tmax, but the timing was not exact in some 
protocols and the conditions were uncontrolled for the effects of diurnal variation, food, or 
concomitant medications. The preponderance of ECG testing was performed during the first 
4-week cycle, but ECGs were obtained during subsequent cycles. The machine RECIST QTc(F) 
intervals were recorded directly onto the case report forms. 
CTCAEv3 was used to assign the severity grade for QTc(F) AEs, and the criteria for each grade are 
presented below: 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Prolonged 
QTc(F) interval
QTc(F) >450–
470 msec 
QTc(F) > 470–500 msec 
or ≥ 60 msec above 
baseline 
QTc(F) > 500 msec QTc(F) > 500 msec with life 
threatening signs or 
symptoms; Torsades de 
pointes 
 
In the 169 subjects with malignancies treated in 4 uncontrolled studies, the majority of whom had 
advanced, metastatic non-small cell lung cancer, 33 (20%) were found to have QT prolongation 
based on machine read ECGs at some time during treatment that met the CTCAE v3 definition of 
an AE: Grade 1 (7 [4%] subjects), Grade 2 (14 [8%] subjects), and Grade 3 (12 [7%] subjects). The 
majority of these subjects received ≥ 300 mg daily or 350 mg given for 5 days with 9 days off. 
There were no clinical findings associated with the ECG changes. There were no reports of QTc(F) 
prolongation in 32 healthy volunteer subjects who received a single 300 mg dose of KD019. 
Clinical study data available for review encompassed Studies XL647-001, XL647-002, 
XL647-201, XL647-203, and XL647-004. Other studies (XL647-005) did not have data confirmed 
by central ECG laboratory. In terms of total exposure, 201 subjects received tesevatinib 
(169 subjects with cancer and 32 normal volunteers). Electrocardiograms for 178 of these subjects 
have been reviewed by the central ECG laboratory. 
QTc(F) Summary 
No SAEs of convulsion; sudden death; ventricular tachycardia, fibrillation, or flutter; or torsades de 
pointes have been received for the > 250 subjects exposed to tesevatinib, as per review of the 
Kadmon safety database. There was an SAE of ventricular extrasystole. 


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Digital ECG files from 178 subjects were supplied to a vendor (eRT) for analysis. ECGs from 
60 subjects had further review by a cardiologist, including all 41 subjects in XL647-203, and an 
additional 19 subjects from XL647-001 (2), XL647-002 (12), and XL647-201 (5), because they 
were reported to have noteworthy QTc(F) prolongation on the ECG machine analysis. eRT then 
reclassified the findings using a different algorithm: 
 Absolute QTc(F) value ≥ 500 msec 
 QTc(F) increase > 60 msec above baseline with QTcF > 470 msec 
 QTc(F) increase > 60 msec above baseline with QTcF ≤ 470 msec 
 QTc(F) value > 470 msec with an increase ≤ 60 msec above baseline 
Of these 60 subjects, eRT analyzed the digital files and identified 23 (38%) subjects who had no 
outlier findings, 5 (8%) subjects who had no QTc(F) prolongation on the digital analysis, and 
2 (3%) subjects who eRT could not completely exclude as being product related, but whose 
prolonged QTc(F) value obtained on the machine read ECG was not felt to be measurable due to 
underlying RBBB or atrial fibrillation. 
Of the 30 (50%) remaining subjects, eRT identified 25 with prolonged QTc(F) values of 
≤ 60 msec, which eRT could not completely exclude as being product related. There were 
3 subjects with QTc(F) > 60 msec that were felt to be possibly/probably related to drug treatment 
and 2 subjects who had QTc(F) values > 500 msec, which were felt to be probably related to drug 
treatment.  The results of the central laboratory analysis are shown in Table 5-2. 


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Table 5-2: 
QT Prolongation: Cases Confirmed by Central Laboratory Review (By Study) 
Study No. 
Study 
Population 
No. of 
Subjects 
Reviewed 
by eRT 
Prolonged 
QTc(F) 
Marked 
Based on 
Machine 
eRT 
Findings 
of 
Prolonged 
QTc(F) 
Prolonged 
QTc(F) 
≤ 60 msec 
Prolonged 
QTc(F) 
> 60 msec 
QTc(F) 
≥ 500 
msec 
XL647-001 
All comers 
41 
2 
2 
2 
0 
0 
XL647-002 
All comers 
31 
12 
10 
10 
0 
0 
XL647-201 
(5 days on/9 
days off) 
NSCLC 
39 
5 
3 
3 
0 
0 
XL647-201 
(Daily Dosing) 
NSCLC 
2 
XL647-203 
NSCLC 
41 
41 
15 
10 
3 
2 
XL647-004 
Normal 
volunteers 
24 
0 
0 
0 
0 
0 
Total 
178 
60 
30 
25 
3 
2 
 
QTc(F)/Concentration Analysis 
A preliminary analysis of delta QTc(F) (change from baseline value) versus plasma concentration 
was carried out using pooled data from studies with intermittent 5 days on and 9 days off dosing 
(Study XL647-001), single doses with crossover food effects (Study XL647-004), and once-daily 
dosing (Studies XL647-002 and XL647-203) regimens. Concentration-matched ECGs were 
available from 1104 records from 125 subjects. This analysis was done using QTc(F) values 
obtained from the central ECG laboratory.  All ECGs digitized and read at a central laboratory and 
QTc(F) values were Fridericia corrected.  The QTc(F) versus concentration relationship was 
described using linear, power, and Emax mixed effects models. Using bootstrap population 
parameter estimates pooled across all 3 models (ie, ~ 1000 bootstrap estimates per model). 
Analyses showed that the concentration-QTc(F) relationship appears to be consistent across Studies 
XL647-001, XL647-002, XL647-004, and XL647-203 (ie, suitable for pooling, and argues against 
a marked time effect because XL647-004 is single dose).  In these studies, QTc(F) prolongation 
increased with increasing plasma concentration.  Based on these limited data, the 
concentration-QTc(F) relationship appears to be adequately described using a power model.  In 
order to evaluate potential saturation of QTc(F) prolongation, additional data are needed at 
concentrations > 1000 ng/mL.  At the projected Cmax (552 ng/mL), the estimated 95% CI on 


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QTc(F) prolongation ranges from 34 to 43 msec.  It should be noted that results extrapolated at 
concentrations > 600 ng/mL should be viewed with caution. 
An initial evaluation of QTc duration was performed with data from 37 subjects in the KD019-101 
ADPKD study who received daily doses of 50 mg to 150 mg.  The 50 mg daily dose of tesevatinib, 
which is expected to be the clinical dose for further evaluation in autosomal dominant polycystic 
kidney disease, produced modest QTcF increases.  The time-averaged increase in QTcF averaged 
4-6 ms.  The timepoint analyses demonstrated a peak increase in QTcF at 4 hours post-dosing on 
Day 14 of 11-15 ms.  At the mean Cmax of 72.5 mg/mL for the pooled 50 mg dose groups, the 
PK/PD model predicted a mean QTcF increase of 13.3 ms, with a one-sided upper 95% confidence 
bound of 16.8 ms.  The magnitude of the QTc effect of the tesevatinib 50 mg dose is similar to that 
produced by moxifloxacin 400 mg. 
5.4 
Rationale 
5.4.1 
Rationale for the ADPKD Indication 
This study is a Phase 1b/2a, multi-center, open-label, pharmacokinetic, dose-escalation study with 
safety and tolerability as the primary endpoint.  
In nonclinical studies conducted under IND 69,215, tesevatinib has been shown to be a potent 
inhibitor of receptor and cytoplasmic tyrosine kinases (TKs). The product was specifically 
optimized to simultaneously inhibit the EGFR, human epidermal growth factor receptor 2 (HER2), 
Src, vascular endothelial growth factor receptor 2 (VEGFR2/KDR), and ephrin receptor B4 
(EphB4) tyrosine kinases with high potency, and demonstrated excellent activity in target-specific 
cellular functional assays. In nonclinical animal models, tesevatinib had good oral bioavailability 
and has shown sustained inhibition of its targets in vivo following a single oral dose. 
In clinical studies, over 250 subjects have been treated with tesevatinib in Phase 1 and Phase 2 
clinical studies; 166 of these have been treated at levels ≥ 300 mg daily. Forty-four (44) subjects 
were treated with tesevatinib for ≥ 6 months. These clinical studies have shown minimal renal 
excretion, and established tesevatinib administration at 300 mg/day is safe for chronic dosing of an 
oncology patient population.  The MTD was determined to be 300 mg once daily in patients with 
metastatic cancer.  


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In nonclinical studies, tesevatinib selectively inhibited key kinases and validated targets in animal 
models of PKD.  Results from nonclinical efficacy studies demonstrated that tesevatinib possesses 
significant potential to prevent the formation of cysts due to an increased proliferation of renal 
ductal epithelial cells. Nonclinical studies using 2 rodent models (BPK mouse and PCK rat) of PKD 
have demonstrated that tesevatinib reaches its target, the kidneys, and inhibits the signaling pathway 
for MEK/ERK by inhibiting the phosphorylation of EGFR (and Src, Erb2, VEGFR2/KDR). The 
decreased phosphorylation of EGFR and Erb2 contributes towards decreased proliferation of 
epithelial cells in the kidneys and reduces renal enlargement in these 2 disease models. 
In addition, tesevatinib has shown either no or extremely weak inhibitory activity against numerous 
other kinases, which should reduce off-target toxicity.  In summary, both the nonclinical and 
clinical results to date suggest that tesevatinib may be a promising therapeutic for ADPKD.  
5.4.2 
Rationale for Dosage Selection  
In the Phase 1b portion of the study, the planned starting dose in this study is 50 mg/person/day 
(approximately 0.83 mg/kg/day). This dose was selected based on the available nonclinical data, 
including no observed adverse effect levels (NOAEL), Cmax, and AUC0-24 data for rats, dogs and 
monkeys. In addition, clinical safety and pharmacokinetic data from Phase 1 studies in healthy 
subjects and patients with cancer also support the starting dose. Repeat-dose toxicokinetic studies 
in rats demonstrated a NOAEL of 10 mg/kg for tesevatinib, when administered by oral gavage for 
14 or 90 days.  The Cmax and AUC0-24 measured after the final NOAEL dose in the 14- and 90-day 
studies was 138/183 ng/mL and 2013/3433 ng·hr/mL, respectively.  In a third repeat-dose toxicity 
study, 10 mg/kg for 182 days (26 weeks) was considered above the NOAEL of 3 mg/kg, a dose 
associated with a Cmax and AUC0-24 of 48-61 ng/mL (male-female) and 818-1090 ng·hr/mL (male-
female, respectively).  In the 14-day study, a Cmax and AUC0-24 of 319 ng/mL and 5741 ng·hr/mL, 
(male and female, respectively), for the 30 mg/kg dose was above the NOEL due to generally 
reversible findings consistent with dehydration, inflammation, renal dysfunction, and stress.  In the 
180-day study, a Cmax and AUC0-24 of 175–234 ng/mL (male-female) and 3470-4450 ng·hr/mL 
(male-female), respectively, for the 10 mg/kg dose was above the NOAEL due to toxicities that 
included death or moribund conditions not observed with 10 mg/kg dosing for 90 days in a separate 
toxicity study.  Based on this data, the threshold Cmax and AUC0-24 for adverse effects in rats is 
estimated to be approximately 175 ng/mL and 3470 ng·hr/mL, respectively. 


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In non-human primates, the NOAEL for tesevatinib was 2 and 6 mg/kg, when administered for 
14 days by oral gavage and 26–39 weeks by nasogastric intubation, respectively.  Cmax and AUC0-24 
for the oral gavage/nasogastric intubation NOAEL doses was (Male-Female) 28–38/77–70 ng/mL 
and 488–450/1080–995 ng·hr/mL, respectively.  In the 14-day study a Cmax and AUC0-24 of 106–
116 ng/mL and 1855–1690 ng·hr/mL, respectively, for the 6 mg/kg dose was above the NOAEL 
due to findings of QTc(F) interval prolongation, heart rate decrease, and minimal increases in urea 
nitrogen and creatinine.  It is noteworthy that in the toxicity study, in which the monkeys received 
tesevatinib for 26-39 weeks, 6 mg/kg was not associated with ECG findings or other findings 
considered adverse.  Nevertheless, based on this data, the threshold Cmax and AUC0-24 for adverse 
effects in non-human primates is estimated to be approximately 106 ng/mL and 1690 ng·hr/mL, 
respectively. 
In a Phase 1 study of the safety and pharmacokinetics of tesevatinib administered to human 
subjects with solid tumors, a dose of 0.78 mg/kg was found to achieve a mean Cmax (ng/ml) and 
AUC0-24 of 38.5 ng/mL and 763 ng·hr/mL, respectively, after a single oral dose on Day 1, and 
125 ng/mL and 2680 after the final dose of a Day 1, 5, 6, 7, and 8 dosing regimen.  In a separate 
Phase 1 study in subjects with solid tumors, a single dose of 75 mg tesevatinib was associated with 
a Cmax and AUC0-24 of 37 ng/mL and 560 ng·hr/mL, respectively.  Given this data, a starting dose 
of 50 mg/dose (approximately 0.83 mg/kg) in this proposed study is likely to result in a Cmax and 
AUC0-24 below the thresholds for adverse effects predicted from rat and non-human primate 
toxicity studies discussed above.  Moreover, the Cmax achieved with a 50 mg/dose in subjects will 
be significantly below the Cmax of 939–1612 ng/mL (male-female) observed in dogs to be the 
NOAEL for cardiovascular parameters.  With continued daily dosing at 50 mg/dose in subjects, PK 
parameters will approach the thresholds estimated for rats and non-human primates, although 
adverse effects in humans at this dose are still not expected based on prior clinical work.  In 
particular, a total of 16 healthy volunteers from two Phase 1 studies have received a single dose of 
tesevatinib at 6 times the planned starting dose (300 mg/dose) with unremarkable changes in 
clinical safety assessments, including 12-lead ECGs.  Cmax in these studies reached 158-226 ng/mL.  
Thus, a starting dose of 50 mg once daily should be considered a safe starting dose for the planned 
study in subjects with PKD.  
Twenty-two subjects were enrolled into 3 dosing cohorts in the Phase 1b portion of the study: 
9 subjects into Cohort 1 at 50 mg daily, 8 subjects into Cohort 2 at 100 mg daily, and 5 subjects 
into Cohort 3 at 150 mg daily.  Safety reviews after the first 2 cohorts deemed these cohorts to have 


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adequate safety and to be tolerable.  In Cohort 3 at 150 mg daily, 3 of 5 subjects enrolled have 
withdrawn consent primarily due to concerns with rash.  It was noted that all 5 subjects in this 
cohort experienced rash within the first 28 days of treatment. In comparison, 4 out of 9 subjects in 
the 50-mg cohort and 1 out of 8 subjects in the 100-mg cohort experienced rash within the first 
28 days. While rash in the 150-mg cohort did not meet strict safety criteria for defining the MTD, 
this dose level was considered intolerable for long term administration in this population. 
Therefore, the MTD for daily dosing was determined to be 100 mg daily. 
PK modeling indicates that a Monday, Wednesday, Friday schedule for tesevatinib administration 
would decrease the Cmax but retain most of the exposure to tesevatinib when compared to daily 
administration.  This modeling takes into account the tesevatinib half-life of approximately 70 
hours.   
Thus, an alternative dosing schedule of 150 mg of tesevatinib administered on Monday, 
Wednesday, and Friday of each week was explored in the Phase 2a portion of the study to 
determine if it is more tolerable than daily administration when used chronically in this patient 
population.  The safety data of the 14 subjects who received tesevatinib 150 mg every Monday, 
Wednesday, and Friday has been reviewed.  There were 3 moderate events: 1 subject had moderate 
QTc(F) prolongation which resolved with dose modification and moderate diarrhea, and 1 subject 
with moderate rash which improved with topical corticosteroids and emollients.  While the 
tolerability of this schedule appears to be superior to that of dosing tesevatinib 150 mg on a daily 
schedule, another dosing schedule of tesevatinib 150 mg administered on Monday and Thursday of 
each week was also explored to determine if this dose and schedule results in fewer moderate 
toxicities, particularly QTc(F) prolongation.  One subject in the tesevatinib 150 mg Monday and 
Thursday cohort had a severe rash. 
PK modeling suggests that reducing the tesevatinib schedule to 150 mg administered on a Monday, 
Thursday schedule would reduce the tesevatinib Cmax slightly while reducing tesevatinib exposure 
more significantly.  Thus, PK modeling predicts a Cmax and AUC0-24 of 188 ng/mL and 4120 
(ng•hr/mL) for the 150 mg Monday, Wednesday, Friday schedule for KD019 administration, and a 
Cmax and AUC0-24 of 139 ng/mL and 2450 (ng•hr/mL) for the 150 mg Monday and Thursday 
schedule for tesevatinib administration.  The effect of this change in schedule on the side effect 
profile, particularly the occurrence of QTc(F) prolongation, will be evaluated. 


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Approximately 5 subjects treated on each alternative schedules had PK samples obtained so that 
safety, tolerability, and exposure could be evaluated.  If accrual goals have nearly been met and 
goals for subjects with PK or iothalamate testing have not been met, only those who can undergo 
iothalamate or PK testing will be enrolled.  
Despite fulfilling the protocol criteria for determining the MTD for daily dosing, the 100 mg daily 
dose group exhibited a rate of QTc prolongation not acceptable for chronic use. Preliminary data 
from both the 50 mg daily cohort and the 150 mg Monday and Thursday cohort suggest that both 
dosing regimens appear acceptable for further study in terms of safety.  However, the 50 mg daily 
schedule is less complex, and thereby less likely to have significant compliance issues, and a severe 
rash occurred in 1 subject in the 150 mg Monday and Thursday cohort.  Because of the long half-
life of tesevatinib, daily dosing reduces the effect of a missed dose when compared with twice 
weekly dosing.  In preparation for randomized studies, 15 additional subjects were treated with 
50 mg of tesevatinib daily to further evaluate efficacy and safety at this dose.   
Modeling of ADPKD subpopulations for a randomized Phase 3 clinical study has been performed.  
Enrollment criteria being considered are ADPKD subjects with baseline eGFR 
≥ 35 mL/min/1.73 m2 and ≤ 80 mL/min/1.73 m2, and height-adjusted total kidney volume (htTKV) 
≥ 1000 mL.   
In order to study the safety profile in this specific ADPKD subpopulation, up to 50 additional 
subjects with PKD and baseline eGFR ≥ 35 mL/min/1.73 m2 and ≤ 80 mL/min/1.73 m2, and htTKV 
≥ 1000 mL will be enrolled (SILK Cohort).  Up to 50 subjects will be enrolled and required to 
complete PK testing as described for other Phase 2a subjects in this protocol or iothalamate testing.   
In addition, all 50 subjects will undergo a mandatory 28-day drug holiday after completing the first 
month of treatment with tesevatinib.  During this drug holiday, and for 4 weeks after, subjects will 
return to the clinic weekly for creatinine and tesevatinib plasma measurements.  All subjects will 
resume tesevatinib treatment at the Month 2 study visit following completion of the 28-day drug 
holiday.     
5.5 
Compliance Statement 
This study will be conducted in compliance with Good Clinical Practice (GCP), including 
International Conference on Harmonization (ICH) Guidelines, and the Declaration of Helsinki. In 


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addition, the investigator agrees to adhere to the protocol and to all applicable local laws and 
regulatory requirements relevant to the use of new therapeutic agents in the countries involved. 
The appropriate Institutional Review Boards (IRBs) must approve the protocol and any 
amendments and the subject informed consent form (ICF) prior to implementation.  
Voluntary written informed consent must be obtained from every subject prior to participation in 
this clinical study. The rights, safety, and well-being of participating subjects are the most 
important considerations and should prevail over interests of science and society. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s). This study will not use the services of study 
personnel where sanctions have been invoked based upon scientific misconduct or fraud (eg, loss 
of medical licensure, debarment). 
5.5.1 
Good Clinical Practice 
The principal investigator will ensure that the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 
50 (1998) and 21 CFR, part 56, (1998) are followed.  
Since this is a covered clinical study, the principal investigator is adhered to 21 CFR, part 54, 
(1998).  A covered clinical study is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.”  This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Kadmon or proprietary interests in the drug being studied. This 
documentation must be provided prior to the participation of the principal investigator and any 
sub-investigator. The principal investigator and sub-investigator agree to notify Kadmon of any 
change in reportable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date that the last subject has completed the protocol-defined 
activities. 
 


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6 
STUDY OBJECTIVES 
6.1 
Phase 1b Objective 
The primary objective of the Phase 1b study is to determine the safety, plasma pharmacokinetics, 
and maximum tolerated dose (MTD) of tesevatinib when administered to subjects with ADPKD. 
6.2 
Phase 2a Objectives 
The primary objective of the Phase 2a portion of the study is to evaluate the annualized change in 
glomerular filtration rate (GFR) in subjects with ADPKD when treated with tesevatinib. 
The secondary objectives are to evaluate subjects treated with KD019 with regard to: 
 
Annualized percent change from baseline in total kidney volume (TKV)  
 
Annualized change from baseline in the reciprocal of serum creatinine 
 
Safety profile 
 
Serum creatinine levels 
 
PK and tolerability of 2 alternative dosing schedules (dosing on Monday, Wednesday, and 
Friday of each week and dosing on Monday and Thursday) 
In addition, exploratory measures of efficacy will be performed throughout both phases of the 
study. 
 
 
 


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7 
STUDY DESIGN 
7.1 
Study Sites 
This study will be conducted at approximately 11 to 13 sites in the United States. 
7.2 
Overview of Study Design 
This is a Phase 1b/2a, multicenter, open-label, dose-escalation, safety, MTD, and PK study in 
subjects with ADPKD.  The Phase 1b portion of the study has been completed and the MTD for 
daily dosing was determined to be 100 mg daily. In this portion of the study, subjects received 50, 
100, or 150 mg of tesevatinib orally once daily for 28 days or until the development of 
unacceptable toxicity, noncompliance, or withdrawal of consent by the subject, or investigator 
decision. After the initial 28-day safety and tolerability assessment period, subjects may have, at 
the discretion of the investigator, continued to receive study drug for a total of 24 months from the 
initiation of treatment.   
For those subjects who had received a minimum of 6 months of treatment at the 50 mg/day dose, 
dose escalation to 100 mg/day was allowed after the 100 mg/day was evaluated for safety. 
After the MTD for daily dosing had been established (100 mg QD), 24 additional subjects were 
enrolled in the Phase 2a portion of the study and treated using alternative dosing schedules of 
150 mg/day of tesevatinib on Monday, Wednesday, and Friday of each week and 150 mg on 
Monday and Thursday of each week.  These subjects consented to Amendment 10 were on the 
Monday and Thursday dosing schedule, with the exception of up to 3 subjects undergoing 
Iothalamate testing, where the goal was to have 1-2 subjects on each of the alternative dosing 
schedules undergo this testing. Also, subjects active in the Phase 1b portion had their dose 
increased or decreased to the established daily dose MTD of 100 mg (while continuing once-daily 
dosing to obtain long-term safety data). 
Fifteen additional subjects, consented to Amendment 11, received 50 mg of tesevatinib daily.  All 
subjects in this additional cohort were required to participate in either PK testing as described in 
the Phase 1b cohort summary or iothalamate testing as described for Phase 2a subjects.   
Modeling of ADPKD subpopulations for a randomized Phase 3 clinical study has been performed.  
Enrollment criteria being considered are ADPKD subjects with baseline eGFR ≥ 35 mL/min/1.73 
m2 and ≤ 80 mL/min/1.73 m2, and htTKV ≥ 1000 mL.   


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In order to study the safety profile in this specific ADPKD subpopulation, up to 50 additional 
subjects with PKD and baseline eGFR ≥ 35 mL/min/1.73 m2 and ≤ 80 mL/min/1.73 m2, and htTKV 
≥ 1000 mL will be enrolled (SILK Cohort).  Each of the subjects to be enrolled will be required to 
complete PK testing as described for other Phase 2a subjects in this protocol.  In addition, all 50 
subjects will undergo a mandatory 28-day drug holiday after completing the first month of 
treatment with tesevatinib.  During this drug holiday, and for 4 weeks after, subjects will return to 
the clinic weekly for creatinine and tesevatinib plasma measurements.  Blood draws during the 
drug holiday may be performed by a visiting nurse at the subject’s home; if the subject chooses this 
option, the study team should call the subject on the same day of the visit to inquire about 
concomitant medications and AEs. All subjects will resume tesevatinib treatment at the Month 2 
study visit following completion of the 28-day drug holiday.     
Subjects in all cohorts of the study, after the 28-day treatment period, will, if they desire and at the 
discretion of the investigator, continue to receive study treatment for 24 months from their first 
dose or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent 
by the subject, or investigator decision.   
7.2.1 
Screening Period 
Subjects will undergo screening evaluations to determine study eligibility, including medical 
history, physical examination, ECG, echocardiogram, ocular testing, hematology, serum chemistry 
and coagulation studies, and urinalysis.  MRI will be performed to measure kidney volume..  
Screening will be conducted within 28 days prior to the first dose of tesevatinib. 
7.2.2 
Treatment Period 
After completion of the screening assessments and confirmation of study eligibility, subjects 
received tesevatinib in a dose-escalating manner.  The Phase 1b portion of the study has been 
completed and the MTD for daily dosing was determined to be 100 mg daily.  In this portion of the 
study, subjects received 50, 100, or 150 mg of tesevatinib for 28 days or until the development of 
unacceptable toxicity, noncompliance, or withdrawal of consent by the subject, or investigator 
decision.  The first dose of study drug was administered in the clinic on Study Day 1. Subsequent 
doses were taken on an outpatient basis for the remainder of the 28-day Treatment Period.  Subjects 
returned to the clinic for weekly safety and tolerability assessments. 


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At the end of each dosing cohort, a Data Safety Committee, including an independent safety 
monitor with significant clinical expertise in polycystic kidney disease, reviewed all safety data 
(PK, safety labs, ECGs, echocardiograms, and AEs) and decided whether dose escalation may 
occur.  Dose escalation to the next higher dose was not started until the safety data from the 
preceding dose cohort was evaluated and deemed acceptable.  Specifically, the decision to progress 
to the next higher dose was made after the safety data through a minimum of 28 days of follow-up 
was reviewed for at least 8 subjects in the preceding dose cohort and it was determined that it was 
safe to proceed to the next dose level.   
For those subjects in the Phase 1b portion of the study who had received a minimum of 6 months of 
treatment at the 50 mg/day dose, dose escalation to 100 mg/day was allowed after the 100 mg/day 
was evaluated for safety.   
After the MTD for daily dosing had been established (100 mg QD), 24 additional subjects were 
enrolled in the Phase 2a portion of the study and treated at the MTD using 2 alternative dosing 
schedules of 150 mg of tesevatinib on Monday, Wednesday, and Friday of each week and 150 mg 
on Monday and Thursday of each week.  Also, subjects active in the Phase 1b portion had their 
dose increased or decreased to the established MTD of 100 mg (while continuing once-daily dosing 
to obtain long-term safety data).   
Despite fulfilling the protocol criteria for determining the MTD for daily dosing, the 100 mg daily 
dose group exhibited a rate of QTc prolongation not acceptable for chronic use. Preliminary data 
from both the 50 mg daily cohort and the 150 mg Monday and Thursday cohort appear acceptable 
for further study in terms of safety.  The 50 mg daily dose appears to be favorable due to dosing 
simplicity and the occurrence of a severe rash in the 150 mg Monday and Thursday cohort.  
Additionally, the effect of missed dosing is reduced in the daily dosing cohort.  Because of these 
factors, the 50 mg tesevatinib treatment appears to be the best tolerated dose, and will likely be 
taken forward in additional studies.  In order to generate additional efficacy and safety information 
on this selected dosing regimen, 15 additional subjects were enrolled as an additional group in the 
Phase 2a portion of this protocol at a dose of 50 mg of tesevatinib.  Each of the 15 subjects were 
required to complete either PK testing as described for other Phase 1b subjects in this protocol or 
iothalamate testing.  Fifteen subjects were enrolled in the Phase 2a portion of the protocol instead 
of the 20 subjects planned.   


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Modeling of ADPKD subpopulations for a randomized Phase 3 clinical study has been performed.  
Enrollment criteria for Phase 3 are ADPKD subjects with baseline eGFR ≥ 35 mL/min/1.73 m2 and 
≤ 80 mL/min/1.73 m2, and htTKV ≥ 1000 mL.  In order to study the safety profile in this specific 
ADPKD subpopulation, up to 50 additional subjects with PKD and baseline eGFR ≥ 35 
mL/min/1.73 m2 and htTKV ≥ 1000 mL will be enrolled.   
Each of the 50 subjects to be enrolled will be required to complete PK testing as described for other 
Phase 2a subjects in this protocol.   
In both phases of the study, after the 28-day treatment period, subjects will, at the discretion of the 
investigator, continue to receive study treatment for 24 months from their first dose or until the 
development of unacceptable toxicity, noncompliance, or withdrawal of consent by the subject, or 
investigator decision.  .   
Subjects will continue to undergo safety evaluations, including physical examination, ECG, AE 
collection, concomitant medication collection, echocardiogram, visual acuity testing, hematology, 
serum chemistry, coagulation studies, pregnancy testing, and urinalysis.  MRI also will be 
performed.   
Additionally, in order to evaluate reversibility of creatinine increases, subjects on the Phase 1b 
portion of the study will have study drug held for a one-time drug holiday of at least 14 and up to 
28 days with creatinine and cystatin C measurements before and immediately after the drug 
holiday, as well as a predose PK sample prior to restarting study drug.  This can be done 14 days 
after dose escalation to the MTD or any time after 6 months of KD019 administration. 
7.3 
Randomization and Blinding 
This is an open-label, nonrandomized study. 
 


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8 
STUDY POPULATION 
8.1 
Target Population 
This study will be conducted in subjects with autosomal dominant polycystic kidney disease 
(ADPKD). Approximately 120 male and female subjects with ADPKD will be enrolled. 
Approximately 30 subjects will be enrolled in the Phase 1b portion and approximately 90 subjects 
will be enrolled in the Phase 2a portion. 
8.2 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for the study: 
1. The subject has a confirmed diagnosis of ADPKD based on Ravine’s criteria.  Subjects 
< 30 years of age must have at least 2 cysts (unilateral or bilateral) while subjects ≥ 30 years 
of age must have at least 2 cysts in each kidney (ie, total ≥ 4 cysts).   
2. Cysts must be at least 1 cm in size to be considered. 
3. Subject is ≥ 18 but ≤ 62 years of age at time of consent. 
4. The subject has an eGFR ≥ 35 mL/min/1.73 m2 and ≤ 80 mL/min/1.73 m2 using the MDRD-
4 variable formula (Appendix A).  
5. The subject has an htTKV ≥ 1000 mL (htTKV is calculated using total kidney volume 
obtained from MRI divided by height in meters).   
6. Subject has the following laboratory values: 
 Platelets >LLN 
 Hemoglobin > 9 g/dL  
 Total bilirubin ≤ 1.5 mg/dL 
 AST (SGOT) < 2.5 × upper limit of normal (ULN)  
 ALT (SGPT) < 2.5 × ULN 
 PT/PTT ≤ 1.5 ULN  
 Albumin ≥ lower limit of normal 
 Amylase within normal limits 


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 Lipase within normal limits 
7. The subject has International Normalized Ratio (INR) ≤ 1.5, except those subjects taking 
warfarin who must have INR < 3.0.  
8. The subject has serum potassium levels and serum magnesium levels within the normal 
range.   
9. The subject is capable of understanding and complying with the protocol and has signed the 
informed consent form. 
10. Female subjects of childbearing potential have a negative pregnancy test at Screening.  
Females of childbearing potential are defined as sexually mature women without prior 
hysterectomy or who have had any evidence of menses in the past 12 months.  However, 
women who have been amenorrheic for 12 or more months are still considered to be of 
childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-
estrogens, or ovarian suppression.   
• 
Women of childbearing potential (ie, menstruating women) must have a negative urine 
pregnancy test (positive urine tests are to be confirmed by serum test) documented 
within the 24-hour period prior to the first dose of study drug. 
• 
Sexually active women of childbearing potential enrolled in the study must agree to use 
two forms of accepted methods of contraception during the course of the study and for 
6 months after their last dose of study drug.  Effective birth control includes (a) IUD 
plus one barrier method; (b) on stable doses of hormonal contraception for at least 3 
months (eg, oral, injectable, implant, transdermal) plus one barrier method; or 
(c) 2 barrier methods.  Effective barrier methods are male or female condoms, 
diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); or 
(d) a vasectomized partner 
11. For male subjects who are sexually active and who are partners of premenopausal women: 
agreement to use two forms of contraception as in criterion 10 above during the treatment 
period and for at least 6 months after the last dose of study drug. 


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12. The subject has no history of another malignancy in the 5 years prior to study entry, except 
treated non-melanoma skin cancer or superficial bladder cancer or carcinoma in-situ of the 
cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and have not 
recurred.       
8.3 
Exclusion Criteria 
A subject who meets any of the following criteria is ineligible for the study: 
1. The subject has had a previous partial or total nephrectomy or a kidney transplant.  
2. The subject has tuberous sclerosis, Hippel-Lindau disease, or acquired cystic disease. 
3. The subject has congenital absence of 1 kidney and/or need for dialysis. 
4. Moderate hematuria (≥ moderate).  If due to cyst rupture, subject may be rescreened after 
discussion with medical monitor. 
5. Uncontrolled hypertension (systolic blood pressure > 160 mmHg; diastolic blood pressure 
> 100 mm Hg). 
6. Uncontrolled diabetes mellitus (HbA1c > 8%). 
7. Presence of renal or hepatic calculi (stones) causing symptoms. 
8. The subject has received any investigational therapy within 30 days prior to study entry. 
9. Active treatment (within 4 weeks of study entry) for urinary tract infection. 
10. History of pancreatitis or has known risk factors for pancreatitis. 
11. The subject meets any of the following cardiac criteria: 
 Mean corrected Fridericia (Fridericia’s formula, see Section 9.10) QTc interval 
(QTc[F]) of > 450 msec  
 History of torsade de pointes, ventricular tachycardia or fibrillation, pathologic sinus 
bradycardia (<50 bpm), heart block (excluding first-degree block, being PR interval 
prolongation only), congenital long QT syndrome or new ST segment elevation or 
depression or new Q wave on ECG. Subjects with a history of atrial arrhythmias should 
be discussed with the medical monitor. 


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 Family history of congenital long QT syndrome or unexplained sudden cardiac death. 
 History of ventricular rhythm disturbances.  
 Symptomatic heart failure (per NYHA guidelines), unstable angina, myocardial 
infarction, or cerebrovascular accident (CVA) within 6 months prior to study entry. 
 Has a cardiac pacemaker. 
 History of pericardial effusion or presence of pericardial effusion on screening 
echocardiogram 
12. The subject is taking any medication known to inhibit the CYP3A4 isozyme or any drugs 
that are CYP3A4 inducers, or any drugs associated with torsades de pointes or known to 
prolong the QTc(F) interval, including anti-arrhythmic medications within 2 weeks prior to 
Screening (refer to Appendix B for a sample listing of medications associated with QTc[F] 
prolongation). A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class is allowed 
(common SSRIs include escitalopram oxalate, citalopram, fluvoxamine, paroxetine, 
sertraline, and fluoxetine).  
13. The subject has an uncontrolled intercurrent illness that would limit compliance with study 
requirements including, but not limited to ongoing or active infections or psychiatric illness.  
14. The subject is pregnant or nursing. 
15. The subject is known to be positive for the human immunodeficiency virus (HIV), or 
hepatitis B or C, as indicated by a positive test at Screening. 
16. Subject is known to be immunocompromised. 
17. The subject has documented presence of renal vascular disease. 
18. The subject has received erlotinib, gefitinib, cetuximab, panitumumab, or an investigational 
EGFR inhibitor at any time. 
19. The subject has an allergy or hypersensitivity to components of either the tesevatinib or the 
formulation. 
20. The subject is unable or unwilling to participate in PK sampling. 


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21. The subject is aphakic due to previous cataract surgery or congenital anomaly.  
Note:  The sponsor has the option to exclude the enrollment of a subject if, based upon the 
subject’s medical history or screening results, it is felt that a subject’s safety may be at risk 
and/or if the safety data may confound the study results. 
 


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9 
STUDY ASSESSMENTS AND PROCEDURES  
9.1 
Screening Period 
Informed consent must be obtained before any study-specific samples are taken or study-specific 
tests or evaluations are conducted.  The following screening assessments should be performed 
within 28 days before the first dose of study drug is administered on Day 1. Study eligibility will be 
based on satisfying all of the study inclusion and exclusion criteria.  Laboratory panels for serum 
chemistry, coagulation, hematology, urinalysis, and pregnancy testing as necessary, are defined in 
Section 9.9. 
Please note that blood pressure measurements are to be performed using appropriate technique (per 
guidelines of the American Heart Association).  Specifically, subjects should be seated quietly for 
at least 5 minutes in a chair with their backs supported, their feet flat on floor (legs uncrossed), and 
their arms bared on a hard surface, with the arm slightly abducted and bent, with palm up and the 
midpoint of upper arm at heart level.  Correct cuff and bladder size should be utilized.  Two or 
more readings separated by 1–2 minutes should be averaged.  If the first two readings differ by 
more than 5 mm Hg, additional (1 to 2) readings should be obtained and averaged.  Record cuff 
size, arm used, and subject's position (if not seated).  
At study visits in which a complete physical examination is required, the investigator should 
perform a thorough examination of all body systems (exception: genitourinary and reproductive 
should be symptom-directed).  At study visits in which a limited physical examination is required, 
the investigator should inquire about signs/symptoms, general appearance, eyes (pupillary reaction, 
ophthalmoscopy, eye movements), oral mucosa, heart and pulses, lungs, abdomen (liver/spleen), 
kidneys, and neurological (symptom-directed and may include mental state, speech, gait/posture, 
arm swinging, facial movements, tongue, muscle wasting (power and tone), coordination, reflexes, 
and sensation.) 
In addition, at each visit, subjects should be assessed for toxicities that may be associated with 
tesevatinib.  This includes assessing for the following: 
 Pericardial effusions and complications such as cardiac tamponade by assessing for 
tachycardia, dyspnea, edema, and neck vain distention 
 Ocular toxicity due to photo absorbance at wavelengths between 290 and 370 nm, positive 
phototoxic potential, and distribution into the skin and eye 
 Xerostomia due to absorption of tesevatinib in the salivary gland.   
 


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9.2 
Subjects Enrolled in SILK Cohort  
9.2.1 
Screening Visit 
At the screening visit (-28 days), information will be collected and subjects will have clinical 
evaluations as follows: 
 Informed consent 
 Medical history and PKD history (including genotype if known) 
 Complete physical examination, including height and weight 
 Vital sign measurements (sitting blood pressure, pulse, respiratory rate, oral/tympanic 
temperature) 
 Supine 12-Lead ECG (repeat 3 times consecutively within 30 minutes [must have an 
interval of at least 1–2 minutes between ECGs]; perform ECG immediately prior to 
blood sample collection) 
 Clinical laboratory tests by central laboratory (hematology, coagulation, serum 
chemistry panel, and urinalysis) 
 Ocular evaluation including evaluation of best corrected visual acuity, fundoscopic 
exam with non-dilated pupils, slit lamp photography of the iris, non-mydriatic 
photography of retina within the arcade, pils, and optical coherence tomography (OCT) 
of the optic nerve head and macula 
 Echocardiogram 
 Urine pregnancy test, if applicable.  Subject must have a negative urine pregnancy test 
documented within the 24-hour period prior to the first dose of study drug.  Positive 
results are to be confirmed with serum testing. 
 MRI (As htTKV ≥ 1000 mL is an inclusion criterion, screening MRI will be performed 
after informed consent form has been signed and prior to other screening assessments.) 
htTKV is calculated using total kidney volume obtained from MRI divided by height in 
meters. 
 Concomitant medications 
9.2.2 
Early Treatment Period 
9.2.2.1 
Day 1  
Results of clinical and laboratory evaluations, including ECGs, must be reviewed prior to dosing to 
confirm that the subject continues to meet eligibility criteria.  At the Day 1 (± 1 day) visit, the 
following procedures and evaluations will be performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems 
to be examined/reviewed)  


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 Vital sign measurements (predose and 1 and 4 hours postdose)  
 Supine 12-Lead ECG (to be performed predose, and 1, 4, and 8 hours postdose prior to 
any time-matched blood sample collection) (repeat 3 times consecutively within 
30 minutes [must have an interval of at least 1-2 minutes between ECGs]) 
 Clinical laboratory tests by central laboratory.  (Need not be repeated if screening visit 
occurred within 4 days prior to Day 1 visit.) 
 Pregnancy test (urine) for women of childbearing potential (if positive, perform serum 
pregnancy test) 
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 
 Blood samples for PK analysis (to be collected at predose and 1, 2, 4, and 8 hours 
postdose) 
 Dispense up to a 1-month supply of study drug 
9.2.2.2 
Days 7, 21, and 28 
At Days 7, 21, and 28 (± 1 day) visit, the following evaluations will be performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems 
to be examined/reviewed) 
 Vital sign measurements  
 Supine 12-Lead ECG (to be performed predose); perform ECG before any time-
matched blood sample collection) (repeat 3 times consecutively within 30 minutes 
[must have an interval of at least 1-2 minutes between ECGs]) 
Note:  If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  
This should be done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory  
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 
 Blood samples for PK analysis (to be collected at predose and 1, 2, 4, and 8 hours 
postdose)  
 Echocardiogram (Day 28 only) 


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 Pregnancy test (urine) for women of childbearing potential (if positive, perform serum 
pregnancy test) (Day 28 only) 
 Dispense/collect study drug 
9.2.2.3 
Day 14 
 Limited physical examination, including weight (See Section 9 for a listing of systems 
to be examined/reviewed)  
 Vital sign measurements (predose and 1 and 4 hours postdose)  
 Supine 12-Lead ECG (to be performed predose, and 1, 4, and 8 hours postdose prior to 
any time-matched blood sample collection) (repeat 3 times consecutively within 
30 minutes [must have an interval of at least 1-2 minutes between ECGs]) 
 Clinical laboratory tests by central laboratory. 
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 
 Blood samples for PK analysis (to be collected at predose and 1, 2, 4, and 8 hours 
postdose) 
9.2.3 
Drug Holiday 
All subjects will undergo a 28-day drug holiday after 28 days of treatment with tesevatinib.  During 
this drug holiday and for 4 weeks after the holiday, subjects will have the following procedures 
performed: 
 Serum creatinine and serum cystatin C tests by central laboratory 
 Tesevatinib plasma concentration 
 Concomitant medications 
 Adverse events 
The blood samples for serum creatinine, serum cystatin C, and tesevatinib plasma concentration 
can be drawn in the clinic or at the subject’s home, by the study’s remote nursing vendor.  
If the subject has the blood samples drawn at home, the study team should call the subject on that 
same day to collect the concomitant medication and adverse event information 
The first day of the drug holiday will be the day after the Day 28 Study Visit.  At the completion of 
the 28-day drug holiday, subjects will return for the month 2 study visit.   


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9.2.4 
Month 2 
Following the 28-day drug holiday subjects will return to the clinic for the month 2 visit (± 1 day) 
and the following procedures will be performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed) 
 Vital sign measurements  
 Supine 12-Lead ECG (to be performed predose prior to collection of any time-matched 
blood samples (repeat 3 times consecutively within 30 minutes [must have an interval of at 
least 1-2 minutes between ECGs]) 
Note:  If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  
This should be done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory 
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 
 Blood samples for PK analysis (to be collected predose at the Month 2, 3, 4, 5 and 6 visits 
only) 
 Dispense/collect study drug 
All subjects will have a collection of blood samples for serum creatinine, cystatin C, and 
tesevatinib concentration weekly for an additional 3 weeks after the Month 2 visit, to be 
collected pre-dose. These blood samples can be drawn in the clinic or at the subject’s home, 
by the study’s remote nursing vendor.  
Adverse event and concomitant medication information will also be collected at these weekly 
visits. If the subject has the blood samples drawn at home, the study team should call the 
subject on the same day to collect this information 
9.2.5 
Monthly Follow-Up Treatment Period  
9.2.5.1 
Months 3–12 
Subjects will return to the clinic monthly (every 28 ± 3 days) and the following procedures will be 
performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems 
to be examined/reviewed) 
 Vital sign measurements  


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 Supine 12-Lead ECG (to be performed predose prior to collection of any blood 
samples) (repeat 3 times consecutively within 30 minutes [must have an interval of at 
least 1-2 minutes between ECGs]) 
Note:  If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  
This should be done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory 
 Ocular evaluation including evaluation of best corrected visual acuity, slit lamp 
photography of the iris, non-mydriatic photography of retina within the arcade, pils, and 
OCT of the optic nerve head and macula (to be performed at Months 3 and 6 and every 
6 months thereafter). 
 Echocardiogram (to be obtained at Months 3 and 6 and every 6 months thereafter).  
Note that if pericardial effusion is diagnosed via echocardiogram, subject should be 
rechecked within 1–3 months to monitor for progression.   
 Pregnancy test (urine) for women of childbearing potential (to be performed at the 
Month 3 visit and every 3 months thereafter); if positive perform serum pregnancy test 
 MRI (to be obtained at Month 6 and every 6 months thereafter) 
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 
 Blood samples for PK analysis (to be collected predose at the Month 2, 3, 4, 5 and 6 
visits only) 
 Dispense/collect study drug 
9.3 
Subjects Enrolled in Phase 1b and Phase 2a 50 mg Daily Portions of the Study 
(does not apply to SILK cohort) 
9.3.1 
Screening Visit 
At the screening visit, information will be collected and subjects will have clinical evaluations as 
follows: 
 Informed consent 
 Medical history and PKD history (including genotype if known) 
 Complete physical examination, including height and weight 
 Vital sign measurements (sitting blood pressure, pulse, respiratory rate, oral/tympanic 
temperature) 


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 Supine 12-Lead ECG (repeat 3 times consecutively within 30 minutes [must have an 
interval of at least 1–2 minutes between ECGs]; perform ECG immediately prior to blood 
sample collection) 
 Echocardiogram 
 MRI  
 Clinical laboratory tests by central laboratory (hematology, coagulation, serum chemistry 
panel, and urinalysis) 
 Ocular evaluation evaluation of best corrected visual acuity, fundoscopic exam with non-
dilated pupils, slit lamp photography of the iris, non-mydriatic photography of retina within 
the arcade, pils, and OCT of the optic nerve head and macula 
 Peripheral blood smear 
 Pregnancy test (urine) for women of childbearing potential (if positive, perform serum 
pregnancy test) 
 Concomitant medications 
 Adverse event assessment 
9.3.2 
Early Treatment Period 
9.3.2.1 
Day 1  
Results of clinical and laboratory evaluations, including ECGs, must be reviewed prior to dosing to 
confirm that the subject continues to meet eligibility criteria.  At the Day 1 Visit, the following 
procedures and evaluations will be performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed)  
 Vital sign measurements (predose and 1 and 4 hours postdose)  
 Supine 12-Lead ECG (to be performed predose, and 1 and 4 hours postdose prior to any 
blood sample collection) (repeat 3 times consecutively within 30 minutes [must have an 
interval of at least 1-2 minutes between ECGs]) 
 Clinical laboratory tests by central laboratory.  (Need not be repeated if screening visit 
occurred within 4 days prior to Day 1 visit.) 
 Pregnancy test (urine) for women of childbearing potential (if positive, perform serum 
pregnancy test) 
 Study drug administration 
 Concomitant medications 
 Blood samples for PK analysis (to be collected at predose and 1, 2, 4, 8, and 24 hours 
postdose) 
 Iothalamate testing (if the subject elects not to participate in PK sampling) 


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 Adverse event assessment 
 Dispense up to a 1-month supply of study drug/collect study drug 
9.3.2.2 
Day 3 
At the Day 3 visit (+ 1 day), the following evaluations will be performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed) 
 Vital sign measurements  
 Clinical laboratory tests by central laboratory  
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 
9.3.2.3 
Days 7, 14, and 21 
At the Days 7, 14, and 21 visits (± 1 day), the following evaluations will be performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed) 
 Vital sign measurements  
 Supine 12-Lead ECG (to be performed predose); perform ECG before any blood sample 
collection) (repeat 3 times consecutively within 30 minutes [must have an interval of at 
least 1-2 minutes between ECGs]) 
Note:  If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  
This should be done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory  
 Perform drug accountability and dispense adequate supply of study drug (if subject was not 
dispensed a 1-month supply on Day 1) 
 Study drug administration 
 Concomitant medications 
 Predose blood samples for PK analysis  
 Iothalamate test (only on Day 14) 
 Adverse event assessment 
9.3.2.4 
Day 28 
At the Day 28 visit (± 1 day), the following evaluations will be performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed) 


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 Vital sign measurements  
 Supine 12-Lead ECG (to be performed predose); perform ECG before any blood sample 
collection (repeat 3 times consecutively within 30 minutes [must have an interval of at least 
1-2 minutes between ECGs]) 
Note:  If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  
This should be done based upon the local site analysis. 
 Echocardiogram 
 Note that if pericardial effusion is diagnosed via echocardiogram, subject should be 
rechecked within 1–3 months to monitor for progression. 
 Pregnancy test (urine) for women of childbearing potential (if positive, perform serum 
pregnancy test) 
 Clinical laboratory tests by central laboratory  
 Study drug administration 
 Concomitant medications 
 Predose blood samples for PK analysis 
 Adverse event assessment 
 Perform drug accountability and dispense adequate supply of study drug (for those subjects 
continuing on study) 
9.3.3 
Monthly Follow-Up Treatment Period for Those Subjects Continuing Study Drug 
9.3.3.1 
Months 2–12 
Subjects will return to the clinic monthly (every 28 ± 3 days) and the following procedures will be 
performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed) 
 Vital sign measurements  
 Supine 12-Lead ECG (to be performed predose prior to collection of any blood samples) 
(repeat 3 times consecutively within 30 minutes [must have an interval of at least 1-
2 minutes between ECGs]) 
Note:  If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  
This should be done based upon the local site analysis. 
 Echocardiogram (to be obtained at Months 3 and 6 and every 6 months thereafter).  Note 
that if pericardial effusion is diagnosed via echocardiogram, subject should be rechecked 
within 1–3 months to monitor for progression.   


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 MRI (to be obtained at Month 6 and every 6 months thereafter) 
 Pregnancy test (urine) for women of childbearing potential (to be performed at the Month 3 
visit and every 3 months thereafter); if positive perform serum pregnancy test 
 Clinical laboratory tests by central laboratory 
 Perform drug accountability and dispense adequate supply of study drug 
 Study drug administration 
 Concomitant medications 
 Blood samples for PK analysis (to be collected predose at the Month 2, 3, 4, 5 and 6 visits 
only) 
 Adverse event assessment 
9.3.4 
Study Drug Holiday Visits  
Study drug holidays will be at least 14 and up to 21 days in length.  On the first day of the study 
drug holiday (during which time study drug will not be administered), subjects will come to the 
clinic and the following evaluations will be performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed) 
 Vital sign measurements  
 Blood sample collection for creatinine and cystatin C measurements 
 Concomitant medications 
 Adverse event assessment 
Immediately after the study drug holiday (on the first day that study drug will be restarted), 
subjects will come to the clinic and the following evaluations will be performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed) 
 Vital sign measurements  
 Blood sample collection for creatinine and cystatin C measurements (to be collected 
predose) 
 Blood sample for PK analysis (to be collected predose) 
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 


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NOTE: 
This visit can be done 14 days after dose escalation to the MTD or any time after 
6 months of tesevatinib administration. 
9.4 
For Subjects Enrolled in Phase 2a Portion of Study and Dosed on Mondays, 
Wednesday, and Fridays 
9.4.1 
Screening Visit 
At the screening visit, information will be collected and subjects will have clinical evaluations as 
follows: 
 Informed consent 
 Medical history and PKD history (including genotype if known) 
 Complete physical examination, including height and weight 
 Vital sign measurements (sitting blood pressure, pulse, respiratory rate, oral/tympanic 
temperature) 
 Supine 12-Lead ECG (repeat 3 times consecutively within 30 minutes [must have an 
interval of at least 1–2 minutes between ECGs]; perform ECG immediately prior to blood 
sample collection) 
 Clinical laboratory tests by central laboratory (hematology, coagulation, serum chemistry 
panel, and urinalysis) 
 Ocular evaluation including evaluation of best corrected visual acuity, slit lamp 
photography of the iris, non-mydriatic photography of retina within the arcade, pils, and 
OCT of the optic nerve head and macula 
 HIV and Hepatitis B & C tests by central laboratory 
 Peripheral blood smear 
 Iothalamate testing  
 In a subset of 3–7 subjects at selected sites, optional iothalamate testing may be 
performed by injection of iothalamate with serum samples obtained for 
iothalamate evaluation over 3 hours post iothalamate injection.  Sites may use 
their site-specific protocol for testing.   
 Echocardiogram 
 Pregnancy test (urine) for women of childbearing potential (if positive, perform serum 
pregnancy test) 
 MRI 
 Concomitant medications 
 Adverse event assessment 


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9.4.2 
Early Treatment Period 
9.4.2.1 
Day 1  
Results of clinical and laboratory evaluations, including ECGs, must be reviewed prior to dosing to 
confirm that the subject continues to meet eligibility criteria.  
At the Day 1 Visit, the following procedures and evaluations will be performed: 
 Limited physical examination, including weight (see Section 9 for a listing of systems to be 
examined/reviewed)  
 Vital sign measurements (predose and 1 and 4 hours postdose).  For subjects participating 
in PK analysis, vital sign measurements also to be performed 8 hours postdose.  
 Supine 12-Lead ECG (to be performed predose, and 1 and 4 hours post-dose prior to any 
blood sample collection) (repeat 3 times consecutively within 30 minutes [must have an 
interval of at least 1-2 minutes between ECGs]).  For subjects participating in PK analysis, 
an ECG is also to be performed 8 hours postdose. 
Note:  
If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  This 
should be done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory.  (Need not be repeated if screening visit 
occurred within 4 days prior to Day 1 visit.) 
 Pregnancy test (urine) for women of childbearing potential (if positive, perform serum 
pregnancy test) 
 Study drug administration (using an alternate dosing schedule of 150 mg of KD019 on 
Monday, Wednesday, and Friday of each week) 
 Collect blood samples from approximately 5 subjects for PK analyses (predose, 1, 2, 4, 8, 
and 24 hours postdose).  (Subjects undergoing iothalamate testing will not undergo PK 
sampling.)   
 Concomitant medications 
 Adverse event assessment 
 Dispense an adequate supply of study drug 
9.4.2.2 
Days 3, 5, and 8 (PK Subjects Only) 
On Days 3, 5, and 8, the following procedures and evaluations will be performed for only those 
subjects undergoing PK sampling: 
 Study drug administration  
 Collect predose blood samples for PK analyses Concomitant medications 


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 Adverse event assessment 
9.4.2.3 
Day 12 
At the Day 12 visit (± 1 day), the following evaluations will be performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed) 
 Vital sign measurements 
 Supine 12-Lead ECG (to be performed predose, and 1 and 4 hours postdose); perform ECG 
before any blood sample collection (repeat 3 times consecutively within 30 minutes [must 
have an interval of at least 1-2 minutes between ECGs]) 
Note:  If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  
This should be done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory  
 Iothalamate testing  
 In a subset of 3–7 subjects at selected sites, optional iothalamate testing may be 
performed by injection of iothalamate with serum samples obtained for 
iothalamate evaluation over 3 hours post iothalamate injection.  Sites may use 
their site-specific protocol for testing.   
 Note:  The second time point should be done on Day 12, 13, 14, or 15 and all 
study-related procedures required on Day 12 may be done at this visit. 
 Collect blood samples from subjects undergoing PK analyses (predose, and 1, 2, 4, and 24 
hours postdose).  (Subjects undergoing iothalamate testing will not undergo PK sampling.)  
Also, collect PK sample if QTc(F) interval increases by > 60 msec above average baseline 
or to the level of ≥ 480 msec (see Section 11.3.3). 
 Perform drug accountability and dispense adequate supply of study drug (if subject was not 
dispensed an adequate supply on Day 1) 
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 
9.4.2.4 
Day 26 
At the Day 26 visit (± 1 day), the following evaluations will be performed: 
 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed) 
 Vital sign measurements  


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 Supine 12-Lead ECG (to be performed predose); perform ECG before any blood sample 
collection (repeat 3 times consecutively within 30 minutes [must have an interval of at least 
1-2 minutes between ECGs]) 
Note:  If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  
This should be done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory  
 Echocardiogram.  Note that if pericardial effusion is diagnosed via echocardiogram, subject 
should be rechecked within 1–3 months to monitor for progression.   
 Pregnancy test (urine) for women of childbearing potential (if positive, perform serum 
pregnancy test) 
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 
 Perform drug accountability and dispense adequate supply of study drug  
9.5 
For Subjects Enrolled in Phase 2a Portion of Study and Dosed on Mondays, and 
Thursdays 
9.5.1 
Screening Visit 
At the screening visit, information will be collected and subjects will have clinical evaluations as 
follows: 
 Informed consent 
 Medical history and PKD history (including genotype if known) 
 Complete physical examination, including height and weight 
 Vital sign measurements (sitting blood pressure, pulse, respiratory rate, oral/tympanic 
temperature) 
 Supine 12-Lead ECG (repeat 3 times consecutively within 30 minutes [must have an 
interval of at least 1–2 minutes between ECGs]; perform ECG immediately prior to blood 
sample collection) 
Note:  If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  This 
should be done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory (hematology, coagulation, serum chemistry 
panel, and urinalysis) 


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 Ocular evaluation including evaluation of best corrected visual acuity, fundoscopic exam 
with non-dilated pupils, slit lamp photography of the iris, non-mydriatic photography of 
retina within the arcade, pils, and OCT of the optic nerve head and macula 
 HIV and Hepatitis B & C tests by central laboratory 
 Peripheral blood smear 
 Iothalamate testing  
 In a subset of 3–7 subjects at selected sites, optional iothalamate testing may be 
performed by injection of iothalamate with serum samples obtained for 
iothalamate evaluation over 3 hours post iothalamate injection.  Sites may use 
their site-specific protocol for testing.   
 Echocardiogram 
 Pregnancy test (urine) for women of childbearing potential (if positive, perform serum 
pregnancy test) 
 MRI 
 Concomitant medications 
 Adverse event assessment 
9.5.2 
Early Treatment Period 
9.5.2.1 
Day 1  
Results of clinical and laboratory evaluations, including ECGs, must be reviewed prior to dosing to 
confirm that the subject continues to meet eligibility criteria.  
At the Day 1 Visit, the following procedures and evaluations will be performed: 
 Limited physical examination, including weight (see Section 9 for a listing of systems to be 
examined/reviewed)  
 Vital sign measurements (predose and 1 and 4 hours postdose). For subjects participating in 
PK analysis, vital sign measurements also are to be performed 8 hours post-dose.  
 Supine 12-Lead ECG (to be performed predose, and 1 and 4 hours postdose prior to any 
blood sample collection) (repeat 3 times consecutively within 30 minutes [must have an 
interval of at least 1-2 minutes between ECGs]).  For subjects participating in PK analysis, 
ECGs are also to be performed 8 hours post dose. 
Note:  
If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  This 
should be done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory.  (Need not be repeated if screening visit 
occurred within 4 days prior to Day 1 visit.) 


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 Pregnancy test (urine) for women of childbearing potential (if positive, perform serum 
pregnancy test) 
 Study drug administration 
 Collect blood samples from approximately 5 subjects for PK analyses (predose, 1, 2, 4, 8, 
and 24 hours postdose).  (Subjects undergoing iothalamate testing will not undergo PK 
sampling.)   
 Concomitant medications 
 Adverse event assessment 
 Dispense up to a 3-month supply of study drug 
9.5.2.2 
Days 8 and 18 (PK Subjects Only) 
On Days 8 and 18, the following procedures and evaluations will be performed only for those 
subjects undergoing PK sampling: 
 Collect predose blood samples for PK analyses 
 Study drug administration  
 Concomitant medications 
 Adverse event assessment 
9.5.2.3 
Day 11 
At the Day 11 visit (± 1 day), the following evaluations will be performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed) 
 Vital sign measurements  
 Supine 12 Lead ECG (to be performed predose, prior to any blood sample collection) 
(repeat 3 times consecutively within 30 minutes [must have an interval of at least 1–
2 minutes between ECGs]).   
Note:  
If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  This 
should be done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory  
 Collect blood samples from subjects undergoing PK analyses (predose).  Also collect PK 
sample if QTc(F) interval increases by > 60 msec above average baseline or to the level of 
≥ 480 msec (see Section 11.3.3). 
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 


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9.5.2.4 
Day 25 
On Day 25, subjects are to return to the clinic and the following evaluations will be performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed) 
 Vital sign measurements (to be performed predose, and 1 and 4 hours postdose); for 
subjects participating in PK analysis, vital sign measurements also are to be performed 
8 hours postdose.  
 Supine 12-Lead ECG (to be performed predose, and 1 and 4 hours postdose); for subjects 
participating in PK analysis, an ECG is also to be performed 8 hours postdose. Perform 
ECG before any blood sample collection whenever possible (repeat 3 times consecutively 
within 30 minutes [must have an interval of at least 1-2 minutes between ECGs]) 
Note:  If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  
This should be done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory  
 Echocardiogram  
 Note: If pericardial effusion is noted on the echocardiogram, a follow-up 
echocardiogram should be performed within 1–3 months to monitor for progression 
 Iothalamate testing  
 In a subset of 3–7 subjects at selected sites, optional iothalamate testing may be 
performed by injection of iothalamate with serum samples obtained for 
iothalamate evaluation over 3 hours post iothalamate injection.  Sites may use 
their site-specific protocol for testing.     
o For those subjects undergoing iothalamate testing, Day 25 visit may be 
done on Days 22, 23, 24, or 25 
 Collect blood samples from subjects undergoing PK analyses (predose, and 1, 2, 4, 8, and 
24 hours postdose).  (Subjects undergoing iothalamate testing will not undergo PK 
sampling.)  Also, collect PK sample if QTc(F) interval increases by > 60 msec above 
average baseline or to the level of ≥ 480 msec (see Section 11.3.3). 
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 
 Perform drug accountability and dispense adequate supply of study drug if appropriate 


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9.5.3 
Monthly Follow-Up Treatment Period for Those Subjects Continuing on Study 
Drug – Both Phase 2a Dosing Schedules 
9.5.3.1 
Months 2–12 
Subjects will return to the clinic monthly (every 28 ± 3 days) and the following procedures will be 
performed: 
 Limited physical examination, including weight (See Section 9 for a listing of systems to be 
examined/reviewed) 
 Vital sign measurements  
 Supine 12-Lead ECG (to be performed predose prior to collection of any blood samples) 
(repeat 3 times consecutively within 30 minutes [must have an interval of at least 1-
2 minutes between ECGs]) 
Note:  If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  
This should be done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory 
 Echocardiogram (to be obtained at Months 3 and 6, and every 6 months thereafter) 
 Note: If pericardial effusion is noted on the echocardiogram, a follow-up 
echocardiogram should be performed within 1–3 months to monitor for progression 
 Pregnancy test (urine) for women of childbearing potential (to be performed at the Month 3 
visit and every 3 months thereafter); if positive perform serum pregnancy test 
 MRI (to be obtained at Month 6 and every 6 months thereafter) 
 Perform drug accountability and dispense adequate supply of study drug 
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 
9.6 
Phase 1b and 2a Subjects Continuing KD019 beyond 12 Months  
For subjects continuing to receive study drug beyond 12 months, the following safety 
assessments should be performed every 2 months (± 3 days): 
 Limited physical examination, including weight (See Section 9 of protocol for a listing of 
systems to be examined/reviewed) 
 Vital sign measurements  
 Supine 12-Lead ECG (to be performed predose prior to collection of any blood samples) 
(repeat 3 times consecutively within 30 minutes [must have an interval of at least 2 minutes 
between ECGs]) 


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Note:  If QTc(F) is > 60 msec above highest average predose reading (average of baseline 
and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  This should be 
done based upon the local site analysis. 
 Clinical laboratory tests by central laboratory 
 Pregnancy test (urine) for women of childbearing potential (if positive, perform serum 
pregnancy test) 
 Perform drug accountability and dispense adequate supply of study drug 
 Study drug administration 
 Concomitant medications 
 Adverse event assessment 
The following safety assessments should be performed every 6 months: 
 Echocardiogram (for those subjects who have already had their Month 12 visit, this may be 
performed at Month 13 and then subsequent echocardiograms may be performed on the 
same schedule as the MRIs) 
Note:  If pericardial effusion is diagnosed via echocardiogram, subject should be 
rechecked within 1–3 months to monitor for progression. 
 MRI 
For Phase 1b subjects experiencing a dose increase from 50 mg to 100 mg, now that the MTD 
for daily dosing has been established: The study assessments in Section 9.6 (above) should be 
performed as follows: 
 Days 1 and 14 of the first month, then monthly for a total of 6 months  
 Every 2 months thereafter  
An echocardiogram and MRI should still be performed every 6 months  
9.7 
End-of-Treatment Visit (End-of-Study) – All Subjects 
Thirty days (± 3 days) after the last dose of study drug, subjects are to return to the study site to 
complete all end-of-treatment assessments as follows: 
 Complete physical examination, including weight (See Section 9 for a listing of systems to 
be examined/reviewed) 
 Vital sign measurements 
 Supine 12-Lead ECG (prior to any blood sample collection; repeat 3 times consecutively 
within 30 minutes [must have an interval of at least 1-2 minutes between ECGs])  
 Clinical laboratory tests by central laboratory (hematology, coagulation, serum chemistry 
panel, and urinalysis) 


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 Ocular evaluation including evaluation of best corrected visual acuity, slit lamp 
photography of the iris, non-mydriatic photography of retina within the arcade, pils, and 
OCT of the optic nerve head and macula (to be performed at Months 3 and 6 and every 6 
months thereafter). 
 Echocardiogram (if not performed within 2 months of this visit).  Note that if pericardial 
effusion is diagnosed via echocardiogram, subject should be rechecked within 1–3 months 
to monitor for progression.     
 MRI (if not performed within 3 months of this visit) 
 Peripheral blood smear 
 Pregnancy test (urine) for women of childbearing potential (if positive, perform serum 
pregnancy test) 
 Concomitant medications 
 Adverse event assessment 
 Final return and accounting of study drug 
9.8 
Unscheduled/AE Resolution Visits:  To Occur as Needed 
If additional visits are needed (eg, for resolution of an AE), the following procedures and 
evaluations may be performed as needed: 
 Complete physical examination, including weight (See Section 9 for a listing of systems to 
be examined/reviewed) 
 Vital sign measurements (sitting blood pressure, pulse, respiratory rate, oral/tympanic 
temperature) 
 Supine 12-Lead ECG (repeat 3 times consecutively within 30 minutes [must have an 
interval of at least 1-2 minutes between ECGs]. 
Note:  If QTc(F) is > 60 msec above highest average predose reading (average of 
baseline and screening) or to the level of ≥ 480 msec, refer to Section 11.3.3.  
This should be done based upon the local site analysis. 
 PK sampling (if appropriate; see Section 0 for additional information) 
 Clinical laboratory tests (hematology, coagulation, serum chemistry panel, and urinalysis) 
 Pregnancy test (urine) for women of childbearing potential (if positive perform serum 
pregnancy test)  
 Adverse event assessment 
 Concomitant medications 
 Echocardiogram 


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9.9 
Laboratory Assessments 
A central laboratory will perform hematology, serum chemistry, coagulation, and urinalysis tests 
and results will be provided to the investigator.  The peripheral blood smears will be analyzed to 
monitor for effect of study drug on bone marrow.  Blood and urine samples for hematology, 
coagulation, serum chemistry, and urinalysis will be prepared using standard procedures. 
Laboratory panels are defined as listed in Table 9-1.  At the investigator’s discretion, any subset of 
the laboratory panels in Table 9-1 may be duplicated in local laboratories for an immediate medical 
assessment.  However, inclusion and exclusion criteria as well as the final statistical analysis will 
be based on results from the central laboratory. 


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Table 9-1: 
Clinical Laboratory Panels 
Hematology 
Serum Chemistry 
Urinalysis 
 
Red blood cell count 
 
WBC with differential (including 
neutrophils, basophils, eosinophils, 
lymphocytes, monocytes) 
 
hemoglobin 
 
hematocrit 
 
platelet count 
 
mean corpuscular volume (MCV) 
 
Mean corpuscular hemoglobin 
(MCH) 
 
Mean corpuscular hemoglobin 
concentration (MCHC) 
 
Peripheral blood smeara 
 
albumin 
 
amylase 
 
alkaline phosphatase 
 
ALT 
 
AST 
 
bicarbonate 
 
BUN 
 
calcium 
 
chloride 
 
creatinine 
 
CPK 
 
lactate dehydrogenase 
 
phosphorous 
 
potassium 
 
random glucose 
 
sodium 
 
total & direct bilirubin 
 
total protein 
 
magnesium 
 
TSHb 
 
appearance 
 
color 
 
pH 
 
specific gravity 
 
ketones 
 
leukocytes 
 
protein 
 
glucose 
 
bilirubin 
 
urobilinogen 
 
occult blood (microscopic 
examination of sediment will be 
performed only if the results of the 
urinalysis dipstick evaluation are 
positive) 
Coagulation 
Other 
 
 
PT 
 
PTT 
 
INR 
 
Creatinine clearancec 
 
Cystatin C 
 
Fasting triglyceridesd 
 
Lipasee 
 
Amylase isoenzymesf 
 
CPK isoenzymesf  
 
HIV and Hepatitis testingg 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; INR = international normalized 
ratio; MCHC = mean cell hemoglobin concentration; MCV = mean cell volume; PT = prothrombin time; PTT = partial 
thromboplastin time 
a. 
To be collected prior to dosing at Screening and at the End-of-Study visit. 
b. 
To be collected at Screening and every 3 months thereafter. 
c. 
To be calculated using serum creatinine, serum cystatin-c (CKD-EPI2012cys), and using both serum creatinine and cystatin-c 
(CKD-EPI2012Scr-cys). 
d. 
To be collected in the event that serum amylase increases to > 1.5 × ULN 
e. 
To be collected at Screening and in the event of that serum amylase increases to > 1.5 × ULN 
f. 
To be collected in the event that CPK increases to > 2.0 x ULN. 
g. 
To be collected only at screening visit. 
  


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Abnormalities in clinical laboratory tests that lead to a change in subject management (eg, dose 
delay, requirement for additional medication or monitoring) are considered clinically significant for 
the purposes of this study, and will be recorded on the AE electronic case report form (eCRF) page. 
If laboratory values constitute part of an event that meets criteria defining it as serious, the event 
(and associated lab values) must be reported as an SAE (see Section 13.3.1). 
9.10 
Electrocardiogram Assessments 
For subjects enrolled in the SILK cohort, ECGs are to be performed at Screening; predose, 1, 4 and 
8 hours postdose on Days 1 and 14; predose on Days 7, 21, and 28; on Day 1 of Months 2 and 
beyond; and at the End-of-Study visit.  Time-matched tesevatinib plasma concentrations will be 
collected at predose, 1, 4, and 8 hours postdose on Days 1 and 14; and predose on Days 7, 21, and 
28. 
For subjects enrolled into the Phase 1b and Phase 2a 50 mg daily portions of the study, ECGs are to 
be performed at Screening; predose and 1 and 4 hour postdose on Days 1 and 14; predose on Days 
7, 21, and 28; on Day 1 of Months 2 and beyond; and at the End-of-Study visit.   
For subjects enrolled into the Monday, Wednesday, Friday dosing schedule of the Phase 2a portion 
of the study, supine 12-Lead ECGs will be performed at Screening; predose, and 1 and 4 hours 
postdose on Days 1 and 12; predose on Day 26; and on Day 1 of Months 2 and beyond; and at End-
of-Study visit  
For subjects enrolled into the Monday, Thursday dosing schedule of the Phase 2a portion of the 
study, supine 12-Lead ECGs will be performed at Screening; predose, and 1 and 4 hours postdose 
on Days 1 and 25; predose on Day 11; and on Day 1 of Months 2 and beyond; and at End-of-Study 
visit.  
 Note: An 8-hour postdose ECG should also be performed for those subjects in either dosing 
schedule of the Phase 2a undergoing PK sampling 
When possible, ECGs are to be performed before any blood sample collection. 
ECGs are to be repeated 3 times consecutively within 30 minutes (must have an interval of at least 
1–2 minutes between ECGs).   


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During the study, all ECGs will be digitally analyzed by a validated ECG laboratory. This central 
vendor will place ECG machines at sites under contract with Kadmon. ECGs will be transmitted 
electronically to the central vendor for analysis. Reports, including clinical alerts resulting from the 
analysis of the ECGs, will be provided back to sites. Sites will be trained on the use of the ECG 
machines, and instructions for performing ECG assessments will be provided in the ECG manual. 
The QT interval will be corrected using Fridericia’s formula1: 
 
Refer to Appendix D for sample calculation. 
Prior to enrollment, all subjects must demonstrate an average screening QTc(F) value of 
< 450 msec by central digital analysis. Immediate clinical management of subjects will initially be 
based on results of machine-read ECGs at the sites. However, the central digital analysis will 
prevail as it becomes available. In addition, the central digital analysis will be used for any AE and 
SAE documentation. 
An increase in QTc(F) interval (by central digital analysis) to a value > 60 msec above baseline or 
to the level of ≥ 480 msec requires further monitoring and, after collection of a PK blood sample 
and discussion with the medical monitor on appropriate management, the subject may be dose 
reduced or removed from the study (see guidelines in Section 11.3.3). 
Abnormalities in the ECG that lead to a change in subject management (eg, requirement for 
additional medication or monitoring) or result in clinical signs and symptoms are considered 
clinically significant for the purposes of this study and will be recorded on the AE eCRF.  If ECG 
abnormalities meet criteria defining them as serious, they must be reported as SAE (see Section 
13.3.1). 
9.11 
Echocardiogram Assessments  
An echocardiogram will be performed at Screening, on Day 28 (Day 25 or 26 for Phase 2a 
subjects), at the Month 3 and 6 visits, and every 6 months thereafter and at the End-of-Study visit.  
                                                 
1 Adapted from:  Fridericia LS (1920). "The duration of systole in the electrocardiogram of normal subjects and of 
patients with heart disease." Acta Medica Scandinavica (53): 469–486. 


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The echocardiogram is to include measurement of ejection fraction and evaluation for pericardial 
effusion and cardiac valve function.  If pericardial effusion is diagnosed via echocardiogram, 
subject should be rechecked within 1–3 months to monitor for progression.   
9.12 
Ocular Evaluations 
Ocular evaluations will be performed on each enrolled subject.  Briefly, every 4 weeks, subjects 
will be asked if they have experienced any changes in vision, changes in color vision, or new loss 
of vision in any area.  Additionally, at Screening, subjects newly enrolled into the study will have 
an evaluation of best corrected visual acuity and will be evaluated with fundoscopic exam with 
non-dilated pupils, slit lamp photography of the iris, non-mydriatic photography of retina within 
the arcade, and optical coherence tomography (OCT) of the optic nerve head and macula.  All 
ocular assessments should also be conducted at Months 3, 6, 9, 12, 18 and 24 of the study. Subjects 
enrolled into the study prior to the requirement for these ocular tests will have the same ocular 
assessments performed at their next regularly scheduled study visit, and then will have the same 
ocular assessments performed when they reach any assessment times that they have not already 
past in the study (Months 3,6, 9, 12, 18, and 24). 
9.13 
Pharmacokinetic Assessments 
During the Phase 1b and Phase 2a 50 mg daily portions of the study, a blood sample will be 
collected predose and 1, 2, 4, 8, and 24 hours postdose for PK analyses on Day 1; predose and 1, 2, 
4, and 24 hours postdose on Day 14; and predose on Days 7, 21, and 28.  PK samples will be drawn 
predose at every monthly visit thereafter (up to and including the Month 6 visit) for subjects who 
continue dosing.   
In the Phase 2a portion of the study, 70 subjects (5 in each alternative dosing schedule and 15 
subjects in the 50 mg daily dosing schedule, and 50 subjects in the SILK cohort) will have blood 
samples drawn for PK analyses.   
For subjects receiving 150 mg of KD019 on Monday, Wednesday, and Friday:  
Samples will be collected on Study Day 1 (predose, 1, 2, 4, 8, and 24 hours postdose), 
predose on Days 3, 5, and 8, and on Day 12 (predose, 1, 2, 4, and 24 hours postdose).   
For subjects receiving 150 mg of KD019 on Monday and Thursday:  Samples will be 
collected on Study Day 1 (predose, and 1, 2, 4, 8, and 24 hours postdose); predose on Days 


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8, 11, and 18; and on Day 25 (predose, and 1, 2, 4, 8, and 24 hours postdose), predose at 
every monthly visit thereafter (up to and including the Month 6 visit) 
For subjects receiving 50 mg of KD019 daily:  Samples will be collected on Study Day 1 
(predose, 1, 2, 4, 8, and 24 hours postdose), Day 14 (predose, 1, 2, 4, and 24 hours 
postdose), and predose on Days 7, 21, and 28.  Additional samples will be collected predose 
at every monthly visit thereafter up to and including the Month 6 visit for those subjects 
who continue treatment (Follow-Up Treatment Period).   
For subjects receiving 50 mg of tesevatinib daily (the SILK cohort):  Samples will be 
collected on Study Day 1 (predose, 1, 2, 4, and 8 hours postdose), Day 14 (predose, 1, 2, 4, 
and 8 hours postdose), and predose on Days 7, 21, and 28.  Additional samples will be 
collected predose at every monthly visit thereafter up to and including the Month 6 visit. 
All subjects in the SILK cohort will have weekly blood draws during the Drug Holiday period and 
during the 4 weeks immediately following the Drug Holiday period.  These samples will be 
collected and analyzed for serum creatinine and cystatin C and plasma tesevatinib levels. 
In addition, a PK sample should be drawn any time the QTc(F) increases to > 60 msec above the 
highest average predose reading (average of baseline and screening) or to the level of ≥ 480 msec 
(based on the local ECG read). 
Tesevatinib concentration measurements will be conducted in all plasma samples collected under 
this protocol.  Efforts will be made to identify the specific structure of major tesevatinib 
metabolites present in all plasma samples collected from 1–24 hours after dosing on Days 1 and 14 
of the Phase 1b and Phase 2a 50 mg daily portions and on Days 1, 12, and 25 of the Phase 2a 
portion of the study.  
Plasma samples will be managed and stored by a central vendor. Detailed instructions for sample 
collection and preparation will be provided in a separate laboratory manual. 
9.14 
Magnetic Resonance Imaging for Exploratory Efficacy Assessments 
Magnetic resonance imaging (MRI) measurements will be used to explore the efficacy of 
tesevatinib.  Kidney volume will be determined by MRI at Screening (baseline measurement), at 
the Month 6 visit, and every 6 months thereafter.   


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The volumes of individual kidneys should be measured in T1-weighted images with use of a 
stereologic method and calculated from the set of contiguous images by summing the products of 
the area measurements and slice thickness.  htTKV is calculated using total kidney volume 
obtained from MRI divided by height in meters. 
9.15 
Iothalamate Testing 
In the Phase 2a portion of the study, optional iothalamate testing of renal clearance will be 
conducted at selected sites in 3–7 subjects at Screening.  A second test is to be performed as noted 
in Table 4-2 (Monday, Wednesday, Friday dosing) and Table 4-4 (Monday and Thursday dosing).  
Based upon the results of testing, a third timepoint may be performed within the first 2 months of 
study drug dosing and after consultation with the medical monitor.  Sites may use their site-specific 
protocol for testing. 
Plasma clearance of iothalamate will be measured after IV or SC injection of iothalamate.  
Iothalamate is a contrast agent widely utilized in renal clearance testing because, unlike creatinine, 
it is filtered at the glomerulus and not secreted in the proximal tubule.  Testing is performed by 
injection of iothalamate with serum samples obtained for iothalamate evaluation over 3 hours post 
iothalamate injection.  Thus, iothalamate renal clearance testing will provide an independent 
method for verification of renal function before and after tesevatinib administration.    


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10 
REMOVING SUBJECTS FROM STUDY 
Every reasonable effort will be made to keep the subject in the study; however, in the event that a 
subject is withdrawn from the study, every effort will be made by the investigator to complete and 
report the reasons for withdrawal as thoroughly as possible.  The reason for termination must be 
clearly documented on the appropriate page of the eCRF.  Study withdrawal should include the 
final assessments, as required by the protocol and every effort should be made to perform the study 
follow-up procedures (eg, laboratory tests, physical examination including an evaluation of 
toxicity/adverse events).  Refer to Table 4-1 through Table 4-4, Study Assessments.   
A termination eCRF must be completed for all enrolled subjects. 
10.1 
Subject Withdrawal (Stopping Rules) 
A subject’s participation in the study may be prematurely discontinued for any of the following 
reasons:  
1. Subject self-withdrawal.  
2. Request by a regulatory agency (eg, Institutional Review Board). 
3. Safety reasons, eg, adverse event including, but is not limited to, symptomatic pericardial 
effusion or cardiac tamponade.   
4. Subject experiences generalized impairment or mental incompetence that would result in 
the subject’s inability to continue in the study. 
5. If, in the investigator’s medical judgment, further participation would be injurious to the 
health and wellbeing of the subject, or is not in the best interest of the subject.  
6. Administrative reasons, such as subject non-compliance or protocol violation. 
7. Pregnancy 
8. An intercurrent event preventing the administration of tesevatinib for more than 28 days for 
those continuing on study after the initial 28-day treatment period (unless otherwise 
specified in the protocol). 
Subjects who are withdrawn from the study due to toxicity are to be followed until there is either: 
 Resolution or stabilization to baseline  
 The subject is lost to follow-up 
 The event is otherwise explained 


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If there is an ongoing toxicity associated with tesevatinib, subjects must be followed with 
appropriate medical management until resolution or stabilization. 
A reasonable effort should be made to contact any subject who is lost to follow-up during the 
course of the study in order to complete assessments and retrieve any outstanding data.  If a subject 
is unreachable by telephone after 3 attempts, the minimum of a registered letter should be sent 
requesting that the subject make contact with the investigator. 
Once a subject discontinues from the study for any reason, every effort will be made to collect all 
clinical and laboratory data as scheduled for the End-of-Treatment visit (see Section 9.7). 
10.2 
Study Discontinuation 
Kadmon Corporation has the right to terminate or to stop the study at any time.  Reasons for study 
discontinuation may include, but are not limited to the following:  
 The incidence or severity of AEs in this or other studies evaluating the drug indicates a 
potential health hazard to subjects.  
 Subject enrollment is unsatisfactory. 
 Drug supply issues. 
 Data recording is inaccurate or incomplete. 
 Excessive subject self-withdrawal. 
 Significant protocol deviations (eg, violation of eligibility criteria, dosing errors, missing 
data for study endpoint analysis). 
10.3 
Replacements 
During the Phase 1b portion of the study, if any subject does not complete 28 days of treatment 
(excluding discontinuation or decrease in dose due to an AE), they will be replaced.  A replacement 
subject will be obtained using the original eligibility criteria in the same dose cohort. Subjects 
discontinued from the Phase 2a portion of the study will not be replaced.   
The maximum number of replacement subjects will be 6 subjects.   


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11 
STUDY DRUG 
Tesevatinib will be provided in 50, 100, and 150 mg tablets.  Kadmon will provide each 
investigator with adequate supplies of tesevatinib.  Study drug must be stored at a controlled room 
temperature of 20°-25°C (66°-77°F). Brief excursions are permitted between 15°C and 30°C (59°F 
and 86°F). Drug must be inventoried according to applicable regulations. 
Subjects will be provided with an adequate supply of study drug and instructions for taking the 
study drug at home. Unused drug must be returned to the study site at each visit for accounting and 
reconciliation.  Tesevatinib tablets are white to off-white round tablets that contain 50% (w/w) API 
in the current lactose-based immediate release (IR) formulation.  Tesevatinib 50-, 100-, and 150-
mg tablets are packaged in 30-cc high-density polyethylene (HDPE) bottles capped with 28-mm, 
childproof caps.  The following information will be printed on the label for clinical lots of KD019: 
 
 
KD019 50-mg Tablets – 32 count 
 
Lot: xxxxx.xxx 
Direction:  Take as directed by physician. 
Store at controlled room temperature of 20°-25°C (66°-77°F). Brief excursions permitted 
between 15°C and 30°C (59°F and 86°F). 
Caution:  Federal law prohibits the transfer of this drug to any person other than the patient 
for whom it was prescribed. 
Caution:  New Drug – Limited by Federal Law to Investigational Use 21CFR312.6 (a).  
Keep out of the reach of children and pets. 
Kadmon Corporation, LLC   New York, NY 10016 USA 
 
KD019 Tablets 100-mg – 32 count 
Lot: xxxxx.xxx 
Direction:  Take as directed by physician. 
Store at controlled room temperature of 20°-25°C (66°-77°F). Brief excursions permitted 
between 15°C and 30°C (59°F and 86°F). 
Caution:  Federal law prohibits the transfer of this drug to any person other than the patient 
for whom it was prescribed. 
Caution:  New Drug – Limited by Federal Law to Investigational Use 21CFR312.6 (a).  
Keep out of the reach of children and pets. 
Kadmon Corporation, LLC   New York, NY 10016 USA 
 


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KD019 Tablets 150-mg – 32 count 
Lot: xxxxx.xxx 
Direction:  Take as directed by physician. 
Store at controlled room temperature of 20°-25°C (66°-77°F). Brief excursions permitted 
between 15°C and 30°C (59°F and 86°F). 
Caution:  Federal law prohibits the transfer of this drug to any person other than the patient 
for whom it was prescribed. 
Caution:  New Drug – Limited by Federal Law to Investigational Use 21CFR312.6 (a).  
Keep out of the reach of children and pets. 
Kadmon Corporation, LLC   New York, NY 10016 USA 
11.1 
Tesevatinib Administration 
In the Phase 1b portion of the study, tesevatinib will be administered orally at doses of 50, 100, 
and/or 150 mg once daily. In the Phase 2a portion of the study, tesevatinib will be administered on 
alternative schedules of 150 mg on Monday, Wednesday, and Friday of each week, 150 mg on 
Monday and Thursday of each week, or 50 mg once daily.  If subjects are able to be seen in clinic 
on the appropriate protocol specified study day, the schedule could also be Tuesday and Friday or 
Wednesday and Saturday.  However, the same schedule must be adhered to throughout the study.  
Study drug may be taken with or without food at approximately the same time every morning. 
Subjects should drink a full glass of water (approximately 8 ounces [240 mL]) immediately after 
study drug administration.  Grapefruit and similar (pomelo fruit, Seville, etc.) products should be 
avoided for the duration of study treatment. 
Subjects must be instructed not to make up missed doses unless the missed dose can be taken 
within 12 hours of the normal dosing time.  Subjects should not re-take study drug doses in the 
event of vomiting. 
Subjects will receive study drug for 28 days after the initiation of treatment (this will be 25 or 
26 days for subjects on the Monday/Thursday and Monday/Wednesday/Friday cohorts of the Phase 
2a portion of the study).  After the initial 28-day safety and tolerability assessment period, subjects 
will, at the investigator’s discretion, continue to receive study drug for a total of 24 months from 
the initiation of treatment or until the development of unacceptable toxicity, noncompliance, or 
withdrawal of consent by the subject, or investigator decision.   
In order to evaluate reversibility of creatinine increases, subjects on the Phase 1b portion of the 
study will have study drug held for a one-time drug holiday of at least 14 and up to 28 days with 


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creatinine and cystatin C measurements before and immediately after the drug holiday, as well as a 
predose PK sample prior to restarting study drug.  This can be done 14 days after dose escalation to 
the MTD or any time after 6 months of KD019 administration. A drug holiday has also been added 
to the SILK cohort. 
All subjects also will be followed for a period of 30 days following their last dose of tesevatinib.  
11.2 
Dose Escalation and Entry of Subjects into the Next Cohort 
In the Phase 1b portion of the study, cohorts will be filled sequentially.  Once assigned to a cohort, 
each subject will continue to be treated at the same dose level and schedule throughout the course 
of the study.  For subjects dosed with 50 mg/day:  If the 100-mg cohort has been evaluated and the 
determination made that 100 mg/day is not the MTD, and study enrollment is opened at the 150 mg 
dose, then subjects initially treated in the 50 mg dose cohort will have the option of increasing their 
dose of tesevatinib to 100 mg/day after they have received a minimum of 6 months of treatment at 
the 50 mg/day dose. The participating study centers will be notified (eg, phone, e-mail, telefax) and 
confirmed in writing when accrual to a cohort has been closed.   
Accrual to the next cohort will not occur until the 28-day data from a previous cohort have been 
received and all safety data have been reviewed. 
At the end of each dosing cohort, a Data Safety Committee including an independent safety 
monitor with significant clinical expertise in polycystic kidney disease will review all safety data 
(PK, safety labs, ECGs, echocardiogram, and AEs).  An independent cardiologist will review all 
ECGs and echocardiograms.  Once all data has been reviewed it will be determined whether dose 
escalation may occur.  Dose escalation to the next higher dose will not begin until the safety data 
from the preceding dose cohort has been evaluated and deemed acceptable.  Specifically, the 
decision to progress to the next higher dose will be made after the safety data through a minimum 
of 28 days of follow-up are reviewed for at least 8 subjects in the preceding dose cohort and it is 
determined that it is safe to proceed to the next dose level. 
Dose escalation to the next planned tesevatinib dose will be reviewed and dose adjustments may be 
made if any of the following safety criteria are met: 
 ≥ 25% of subjects in a cohort experience a severe (or higher) related adverse event in the 
same organ or body system 


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 Any other related adverse event occurs in a subject that is deemed by the investigator to 
pose an unacceptable risk to other participants in the study such as symptoms of cardiac 
tamponade  
After the MTD for daily dosing was established, 24 additional subjects were enrolled in the Phase 
2a portion of the study and treated at 150 mg/day using alternate schedules of tesevatinib 
administration.  As the known toxicities of tesevatinib, including diarrhea and rash, may not be 
tolerable with daily dosing when used long-term in this subject population, alternative dosing 
schedules of either Monday, Wednesday, and Friday of each week or Monday and Thursday of 
each week were evaluated during this portion of the study.  Additionally, as the MTD for daily 
dosing has been determined to be 100 mg/day, subjects active in the Phase 1b portion had their 
dose either increased or decreased to this dose.  These subjects have continued on daily dosing in 
order to evaluate long-term tolerability of the daily dosing regimen. 
Drug holiday may start 14 days after dose escalation to the MTD or any time after 6 months of 
tesevatinib administration. 
11.3 
Warnings, Precautions, and Management 
Adverse events that have been associated with tesevatinib include the following:  diarrhea, skin 
rash, QTc(F) prolongation, hepatotoxicity, and pulmonary toxicity.  Study drug may be held for up 
to 28 days at the discretion of the investigator (unless otherwise specified below), except during the 
first 28 days of treatment in the Phase 1b portion of the study.   
11.3.1 
Diarrhea 
Diarrhea should be managed according to accepted practice (eg, with loperamide).  Subjects with 
severe diarrhea who are unresponsive to loperamide or who become dehydrated may require 
interruption of study drug until resolution to ≤ mild in intensity.  If subjects are in the monthly 
treatment period, drug may be held for up to 28 days.  If severe diarrhea occurs during the initial 
28-day treatment period on the Phase 1b portion of the study, subjects must be discontinued from 
the study.  In the event of severe or persistent diarrhea, nausea, anorexia, or vomiting associated 
with dehydration, study drug should be discontinued, and appropriate measures should be taken to 
rehydrate the subject intensively via intravenous administrations.  Subjects should be advised to 
contact the investigator immediately if they develop significant diarrhea; should this occur, an 
electrolyte panel, including magnesium and potassium, and ECG should be performed.  


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If unacceptable diarrhea recurs on reintroduction of tesevatinib at the same dose, then dose 
reduction of tesevatinib should be discussed with the medical monitor. 
11.3.2 
Skin Rash  
Skin rash should be managed according to locally accepted clinical recommendations.  Study drug 
may be held up to 28 days at the discretion of the investigator and after discussion with the medical 
monitor.  The following guidelines may be considered. 
11.3.2.1 
Suggestions for Rash Management  
[Lacouture 2011, Kiyohara 2013, http://www.psoriasis.org] 
 
Papulopustular (acneiform) rash: 
 
 Most common rash seen with EGFR inhibitors 
 Typically seen in the first few weeks of treatment 
 Usually peaks at Weeks 4–6 
 Then will decrease in severity at Weeks 6–8 
 Post-inflammatory skin changes can last for months, so prevention and reactive treatment 
are important 
Suggestions for preventative treatment: 
 
 Subject education prior to starting treatment on what to expect 
 Gentle cleansing of skin using mild soap products 
 Use of moisturizer twice daily making sure to include hands, feet and nails 
 Avoid sun when possible and use of sunscreen SPF 30 or higher (preferably titanium 
dioxide or zinc oxide) 
 Subjects should be advised to use UVA ocular protection (ie, sunglasses with UVA 
filtering) when outside 
 Hypoallergenic makeup when possible 
 


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Suggestions for treatment once a rash appears (see Appendix E for steroid potency chart): 
 Ongoing use of treatments from preventative treatments above 
 Mild (<10 % BSA involved, without pruritus or tenderness) 
 Topical steroids (refer to Appendix E for a steroid potency chart that categorizes brand- 
name topical steroid medications) 
o For face use medium potency 
o For body use strong potency 
o Note: As soon as rash improves the lowest strength steroid that controls 
rash should be used, especially on the face 
 Moderate (10%–30% BSA involved, ± pruritus/tenderness; limiting instrumental ADLs and 
causing psychosocial impact) 
 Topical steroids 
o For face use strong potency 
o For body use very strong potency 
o Note: As soon as rash improves the lowest strength steroid that controls rash 
should be used, especially on the face 
 Systemic treatment 
o Doxycycline 100 mg BID (less renal toxic than minocycline, but can cause 
photosensitivity) 
 Severe (> 30% BSA involved, limiting ADLs) 
 Refer to dermatology 
 Topical steroids 
o All areas very strong potency 
o Note: As soon as rash improves the lowest strength steroid that controls rash 
should be used, especially on the face 
 Systemic treatment 
o Doxycycline 100 mg BID 
o Oral steroids: prednisolone 10 mg QD for 1 week or equivalent 
Suggestions for once a rash reappears: 
 Over the course of treatment rash may come and go 
 Hydrocortisone 1% cream with moisturizer and sunscreen twice daily, in combination 
with doxycycline 100 mg BID 
 May need to follow guidelines above if rash worsens 


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If unacceptable rash recurs on reintroduction of tesevatinib at the same dose, then dose reduction 
of tesevatinib should be discussed with the medical monitor.  
11.3.3 
QT Interval Prolongation 
Acquired long QT syndrome can lead to life-threatening ventricular arrhythmias, particularly 
torsades de pointes. Risk factors for occurrence of arrhythmia include hypokalemia, 
hypomagnesemia, bradycardia, and concurrent use of multiple medications that prolong the 
QTc(F) interval. In vivo observations of QTc(F) prolongation in association with use of 
tesevatinib have been observed, including severe QTc(F) prolongation.  However, the lack of a 
clearly discernible pattern to such occurrence makes prediction of individual subject risk 
difficult. Therefore, the following are recommended: 
 Tesevatinib should be administered to subjects who have normal serum potassium and 
serum magnesium levels. 
 Tesevatinib should not be administered to subjects with pathologic bradycardia. 
 Medications with potential for QTc(F) prolongation should not be used concurrently or 
started within 24 hours of tesevatinib administration. 
Subjects should be carefully monitored for symptoms of arrhythmia (ie, dyspnea, chest pain or 
tightness, palpitations, dizziness) and for episodes of syncope.  An ECG should be obtained if 
these symptoms occur. In addition, serum potassium and magnesium must be maintained within 
the normal range (Strevel et al, 2007) and may require additional monitoring or adjustment if 
subjects develop diarrhea. 
11.3.3.1 
Response to QTc(F) Interval Prolongation 
The following guidelines should be used in the management of QTc(F) prolongation.  Subjects 
will have ECGs performed at times designated by the protocol (ECGs will be repeated 3 times 
consecutively within 30 minutes [must have an interval of at least 1–2 minutes between ECGs]).  
If the average QTc(F) interval increases to > 60 msec above the highest average predose value 
(average of Day 1 predose and screening values) or to the level of ≥ 480 msec according to local 
site analysis: 
 Hold study drug until central read is confirmed.  


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 Check electrolytes, especially magnesium and potassium; correct abnormalities as 
clinically indicated. 
 Obtain blood sample for PK analysis. 
 Manage as clinically indicated with cardiology consultation as needed. 
 Contact medical monitor to discuss additional monitoring. 
If results are confirmed by the central reader, the subject may be removed from the study after 
discussion with the medical monitor. If the subject continues in the study, discuss with the 
medical monitor appropriate management (including possibility of dose reduction) and ECG 
follow-up. 
11.3.4 
Elevated Amylase 
If subjects develop an elevated serum amylase during the study that is >1.5 ×ULN, then 
additional evaluations should be performed.  These should include evaluating serum lipase, 
amylase isoenzymes, and fasting triglycerides as well as obtaining history regarding symptoms 
of pancreatitis, symptoms of dry mouth, and use of alcohol.  The subject should have a drug 
holiday for 28 days, with amylase measured at the end of the drug holiday.  If the amylase is 
within normal range after the end of the drug holiday, tesevatinib may be restarted at a reduced 
dose, and amylase measured approximately 14 days later, and then at the start of each cycle of 
tesevatinib administration.  If results continue to be abnormal, the subject will be removed from 
study.   If an elevated serum amylase that is >1.5 ×ULN occurs a second time, the subject will be 
removed from the study. 
11.3.5 
Elevated Creatinine Phosphokinase 
If subjects develop an elevated serum CPK during the study that is >2.0 ×ULN, additional 
evaluations should be performed.  These should include evaluating serum CPK isoenzymes as 
well as obtaining history regarding muscle-related symptoms or strenuous or prolonged exercise. 
11.3.6 
Pulmonary Toxicity 
If subjects experience an acute onset of new and/or progressive, unexplained pulmonary 
symptoms such as dyspnea, cough, and fever, study drug should be held while subjects are 


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evaluated.  If interstitial lung disease (ILD) is diagnosed, study drug should be discontinued and 
treatment administered as necessary. 
11.3.7 
Hepatotoxicity 
Rare cases of hepatic failure have been reported. Confounding factors have included pre-existing 
liver disease or concomitant hepatotoxic medications.  Liver function test abnormalities 
(including elevated ALT, AST, and bilirubin) have been observed in clinical studies with 
tesevatinib.  Interruption of study drug should be considered in subjects developing liver function 
abnormality > 3x ULN 
Dose Modifications for Hyperbilirubinemia  
 
> ULN 2.5 × ULN 
2.5– <3 × ULN 
>3 × ULN 
 
KD019 Treat at same dose 
level 
1st Occurrence: 
Hold dose; reduce 1 dose 
level when recovered to 
mild intensity. 
1st Occurrence: 
Off Study 
 
 
2nd Occurrence:  
Off study 
 
 
 
 Dose Modifications for Transaminitis (AST/ALT)  
 
> ULN – 2.5 × ULN 
2.5– <3 × ULN 
>3  × ULN 
 
KD019 Treat at same dose 
level 
1st Occurrence: 
Hold dose; reduce 1 dose 
level when recovered or 
reduced to mild intensity. 
1st Occurrence: 
Hold dose and discuss 
management with Medical 
Monitor 
 
 
2nd Occurrence:  
Hold dose and discuss 
management with 
Medical Monitor 
2nd Occurrence:  
Off study 
 
 
11.3.8 
Pericardial Effusion 
Pericardial effusions have been seen in oncology studies with tesevatinib.  In addition, 1 subject 
with ADPKD receiving 50 mg tesevatinib daily developed a trace pericardial effusion. The 


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following guidelines should be followed in the event that a subject develops a pericardial 
effusion while receiving tesevatinib: 
For an asymptomatic pericardial effusion that is at least moderate in size, a follow-up 
echocardiogram should be performed within 1–3 months to monitor for progression.  Discuss 
results of the additional echocardiogram with the medical monitor to determine subject 
management. 
Subjects should be monitored for signs and symptoms of cardiac tamponade.  In addition to the 
monthly to bimonthly physical exam of blood pressure, pulse, respiration, weight, heart, and 
lung, physical exam should also asses for tachycardia, dyspnea, neck vein distension, and edema. 
11.3.9 
Adrenal Insufficiency 
One case of adrenal insufficiency has been reported in an oncology subject receiving tesevatinib.  
Subjects should be monitored for signs or symptoms of adrenal insufficiency and the medical 
monitor immediately notified if symptoms are observed. 
11.4 
Study Drug Accountability and Subject Treatment Compliance 
Drug accountability and subject treatment compliance will be assessed using drug dispensing and 
return records. The principal investigator is responsible for ensuring adequate accountability of 
all used and unused study drug. While the principal investigator may delegate components of 
drug accountability tasks to documented designee(s) (eg, pharmacist), the ultimate responsibility 
for drug control and accountability resides with the investigator.  This includes acknowledgment 
of receipt of each shipment of study drug (quantity and condition) and the maintenance of 
subject dispensing records and returned study product documentation.  Dispensing records will 
document quantities received from Kadmon and quantities dispensed to subjects, including lot 
number, date dispensed, subject identification number, subject initials, and the initials of the 
person dispensing study drug.  Reasons for deviation from the expected dispensing regimen also 
must be recorded.  


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At study initiation, the study monitor will evaluate and obtain a copy of each site’s written 
standard operating procedure for study drug disposal/destruction in order to ensure that it 
complies with the requirements of Kadmon.  
At the end of the study, following final drug inventory reconciliation by the monitor, the study 
site will dispose of and/or destroy any remaining unused study drug supplies, including empty 
containers, according to institutional procedures for destruction, reviewed and approved by 
Kadmon prior to material destruction. If the site cannot meet the requirements of Kadmon for 
disposal, arrangements will be made between the site and Kadmon or its representative, for 
destruction or return of unused study drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 


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12 
CONCOMITANT MEDICATION AND TREATMENT 
If the subject must use a concomitant medication during the study, it is the responsibility of the 
principal investigator to ensure that details regarding the medication are recorded on the eCRF. 
Subjects should avoid ingesting grapefruit, pomelo or Seville fruit (and juice) with tesevatinib or 
at any time during the study.  Subjects should not take medications that are associated with a risk 
of QTc(F) interval prolongation and/or torsades de pointes. Additionally, subjects are not 
permitted to take concomitant medications that inhibit (eg, ketoconazole, itraconazole, 
erythromycin, clarithromycin) or induce (eg, dexamethasone, phenytoin, carbamazepine, 
rifampicin, or phenobarbital) the CYP3A4 isozyme.  Tesevatinib is also highly protein bound, 
and other drugs that are also highly protein bound with the exception of warfarin (eg, diazepam, 
furosemide, dicloxacillin, propranolol, and phenytoin) should be avoided.  
Antiemetics and antidiarrheal medications should not be administered prophylactically before 
initial treatment with study drug. At the discretion of the investigator, treatment of symptoms 
with antiemetic and antidiarrheal medications may be undertaken per standard clinical practice. 
Since tesevatinib is a potent inhibitor of MATE transporter proteins, increased levels of 
concomitant medications that are secreted by the kidney proximal tubule cells into the renal 
tubule by MATE transporter proteins may occur.  Thus, subjects taking cephalexin, cimetidine, 
dofetilide, fexofenadine, metformin, procainamide, and pyrimethamine should be monitored 
carefully. 
12.1 
Additional Therapy  
A subject should not receive additional therapeutic treatment during the study period without the 
approval of the sponsor’s medical monitor. 
12.2 
Interaction of Tesevatinib with Other Medications 
12.2.1 
Tesevatinib 
Microsomal oxidation of tesevatinib involves CYP3A4; the percentage conversion of tesevatinib 
in human microsomes was low. This suggests a low potential for other drugs to significantly 
affect the biotransformation of tesevatinib in humans through interaction with CYP-mediated 
metabolic pathways. 


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P-glycoprotein (P-gp) is extensively expressed in multiple tissues and is involved in the transport 
of a vast variety of biological molecules.  It is not possible to screen for all drugs possibly 
influenced by p-glycoprotein but will monitor the main drugs such as colchicine, verapamil, 
tamoxifen, cyclosporine, and digoxin. 
12.2.2 
Management of Subjects Requiring Concomitant Medications Associated with 
QT Interval Prolongation 
Tesevatinib has been associated with prolongation of the QT interval. Subjects requiring 
treatment with drugs known to be associated with torsades de pointes or significant QT interval 
prolongation may not be enrolled into this study. This includes Class IA antiarrhythmics 
(eg, quinidine, procainamide); Class III antiarrhythmics (eg, amiodarone, sotalol, dofetilide); 
phenothiazine anti-psychotics: (eg, chlorpromazine, mesoridazine, pimozide, thioridazine); 
quinolone antibiotics: (eg, gatifloxacin, moxifloxacin, sparfloxacin); macrolide antibiotics 
(eg, erythromycin, clarithromycin, and troleandomycin) and other drugs that have a 
contraindication or boxed warning regarding QT prolongation in the prescribing information. 
Appendix B, Concomitant Medications Associated with a Risk of QTc(F) Interval Prolongation 
and/or Torsades de Pointes, contains a partial list of drugs associated with a risk of QT interval 
prolongation and/or torsades de pointes. 
Drugs associated with QT interval prolongation should be avoided in subjects receiving 
study drug. Should a subject develop a condition for which a medication known to affect QT 
interval is indicated, consideration should be given to the additive risk of QT interval 
prolongation versus the potential benefit of treatment with the required medication and/or study 
drug.  Contact the medical monitor prior to the administration of the concomitant medication. 
During the follow-up period, subjects who require short-term (2 to 3 weeks, not to exceed 
21 days) treatment with a concomitant medication associated with QT interval prolongation 
should have the study drug held until the concomitant treatment course is complete.  The 
decision about whether the subject can continue on study following this interruption will be 
determined by the medical monitor.  If the subject restarts study drug after discussion with the 
medical monitor, an ECG will be performed prior to restarting study drug. 
 


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13 
SAFETY 
13.1 
Safety Parameters 
The 5-point Clinical Symptom and Adverse Event Grading Scale will be used for grading 
toxicities (see Appendix C).  Subjects will be monitored throughout the treatment and follow-up 
period for occurrence of AEs (acute, delayed, and/or cumulative), as well as for changes in 
clinical status, vital sign measurements, and laboratory data.  Safety parameters to be 
measured/assessed include eligibility assessment, medical history, vital sign measurements, 
physical examinations, concomitant medications, hematology, serum chemistries, coagulation 
profiles, peripheral blood smears, renal function (creatinine clearance and cystatin C), urinalysis, 
pregnancy testing, ECGs, and echocardiograms.  
13.2 
Adverse Event Definition 
An adverse event (AE) is defined as any unintended or undesirable, noxious, or pathological 
change, compared to pre-existing conditions, experienced by a subject during a clinical study or 
the follow-up period, regardless of relationship to study drug.  Adverse events include: 
 Suspected adverse drug reactions 
 Reactions from drug overdose, abuse, withdrawal, sensitivity, or toxicity 
 Significant changes or abnormalities, when compared to baseline, in structure (sign), 
function (symptom), clinical laboratory results, ECG results, or physiological testing.  
This includes any worsening of a pre-existing condition temporally associated with the 
use of study drug 
 Pre- or post-treatment complications that occur as a result of protocol-mandated 
procedures 
 Pre-existing events, that increase in intensity/severity or change in nature 
 Other medical events, regardless of their relationship to the study drug, such as injury, 
surgery, accidents, extensions of symptoms, or apparently unrelated illnesses 
For the purpose of data collection, all untoward events that occur after informed consent through 
30 days after the last dose of tesevatinib must be recorded on eCRFs by the investigational site. 
This requirement includes AEs from unscheduled as well as scheduled visits.  
 


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An AE does not include:  
 
 Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); 
when the condition that leads to the procedure is an adverse event. 
 Pre-existing diseases, or conditions or laboratory abnormalities present or detected prior 
to the screening visit, those do not worsen. 
 Situations where an untoward medical occurrence has not occurred (eg, hospitalization 
for elective surgery, social, and/or convenience admissions). 
 Overdose of either KD019 or a concomitant medication without any signs or symptoms, 
unless the subject is hospitalized for observation. 
13.3 
Evaluating Adverse Events 
The investigator will determine the seriousness, intensity (severity), and causality (relationship) 
of an AE associated with the use of the study drug (ie, events where there is a reasonable 
possibility that the event may have been caused by the study drug) based on the following 
definitions: 
13.3.1 
Serious Adverse Events 
(Notify sponsor or designee within 24 hours of first awareness; document on eCRF) 
The SAE definition and reporting requirements are in accordance with the ICH Guideline for 
Clinical Safety Data Management, Definitions, and Standards for Expedited Reporting, 
Topic E2A. 
An SAE is any untoward medical occurrence that at any dose results in any of the following 
outcomes, regardless of relationship to study drug: 
 Death:  Any death that occurs while the subject is “on study” as well as any death that 
occurs within 30 days after the last dose of study drug.   
Note: Death is an outcome of an AE, and not an AE in itself.  The event(s) that 
caused death (eg, illness, accident) constitutes the SAE.   
 Life threatening:  Any adverse drug event that places the subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred (ie, this does not 
include a reaction that had it occurred in a more severe form, might have caused death).  


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 Inpatient hospitalization or prolongation of existing hospitalization: any AE 
requiring in-patient hospitalization.  A visit to the emergency room or hospital clinic 
would not be considered in-patient hospitalization; however, it could be considered 
serious if medical intervention was necessary in order to prevent a serious outcome. 
“In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. This may or may not be overnight. It does not 
include presentation to and care within an emergency department. 
In the absence of an AE, the investigator should not report hospitalization or prolongation 
of hospitalization.  Examples are the following: 
o 
Hospitalization or prolongation of hospitalization is needed for a 
procedure required by the protocol. 
o 
Hospitalization or prolongation of hospitalization is part of routine 
procedure followed by study center. 
o 
Hospitalization for survey visits or annual physicals. 
In addition, a hospitalization planned before the start of the study for a pre-existing 
condition which has not worsened would not be considered an SAE. Complications that 
occur during hospitalizations are AEs.  If a complication prolongs hospitalization, it is an 
SAE. 
 Persistent or significant disability/ incapacity:  Any substantial disruption of a 
person’s ability to conduct normal life functions.   
 Congenital anomaly/birth defect 
 Important medical event:  Any adverse event that may not result in death, that may not 
be immediately life threatening, or require hospitalization may be considered a SAE 
when, based upon appropriate medical judgment, it may jeopardize the subject and may 
require medical or surgical intervention to prevent an SAE outcome.   


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13.3.2 
Unexpected Adverse Events  
(Notify sponsor or designee by the next business day; document on eCRF) 
An unexpected AE is any adverse drug event that is not identified in nature, severity, or 
frequency in the current protocol, IB or in other reports or information provided to the 
investigator.  This refers to any AE that has not been previously observed, (eg, included in the 
IB), rather than from the perspective of such an event not being anticipated from the 
pharmacological properties of the product.  For example: hepatic necrosis would be unexpected 
(by virtue of greater severity) if the Investigator brochure only referred to elevated hepatic 
enzymes or hepatitis. Unexpected adverse events may or may not be serious. 
13.3.3 
Non-Serious Adverse Events  
(Document on eCRF) 
All other AEs, not fulfilling the previous definitions, are classified as non-serious. 
13.3.4 
Protocol-Related Adverse Events 
AEs that are not related to KD019 may be considered by the investigator or the medical monitor 
to be related to the conduct of the clinical study.  That is, the event may be related to the fact that 
a subject is participating in the study.  For example, a protocol-related AE may be an event that 
occurs during a washout period or that is related to a procedure required by the protocol. 
13.3.5 
Relationship/Causality to Study Drug 
The investigator will assess the relationship of the event to study drug as (1) not related; (2) 
unlikely related; (3) possibly related; (4) probably related; or (5) definitely related. 
In assigning the causal relationship, the following should also be considered:   
 Temporal relationship – Did the effect occur in a reasonable temporal association with 
administration of KD019? 
 Pattern consistent with known drug effect – Is the effect an expected consequence of 
KD019 administration based upon the known biologic effects, toxicologic data, and prior 
experience with KD019 or closely related drugs? 
 Other potential etiologies – Is there another more likely cause of the adverse effect? 


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 Challenge – Did the adverse event recur or worsen upon re-exposure to KD019 or upon 
an increase in the dose?  (Note: Intentional re-challenge for the purpose of assessing 
causal relationship of an adverse event to the study drug should NOT be performed.) 
 De-challenge – Did the adverse event resolve or diminish upon cessation of KD019 
treatment or reduction in dose? 
13.3.6 
Recording Adverse Events 
All AEs (including SAEs) are to be accurately recorded on the Adverse Event page of the 
subject’s eCRF and not as remarks elsewhere on the eCRF.  The following aspects of the AE 
must be recorded: 
 The onset date and time (when applicable) of the AE 
 Intensity/severity (per the Clinical Symptom and Adverse Event Grading Scale, 
Appendix C)  
 The resolution date and time of the AE, when applicable 
 A description of the AE 
 Any factors considered as possibly promoting the occurrence of the AE 
 Concomitant medication/therapy including name, dose, dose frequency, indication, and 
dates of use  
 An assessment of the relationship/causality by the investigator; a decisive factor in the 
documentation is the temporal relationship between the AE and study drug. 
13.3.7 
Adverse Event Monitoring and Follow-Up 
The investigator will follow all subjects who experience adverse events until the event has 
resolved or has stabilized (ie, the subject has returned to the baseline state or the investigator 
does not expect any further improvement or worsening of the subject’s condition).  The 
appropriate follow-up visits must be scheduled and the specific tests repeated or performed as 
necessary.  Where a diagnosis is possible, it is preferable to report this diagnosis rather than a 
series of terms (signs/symptoms) relating to the diagnosis.  
 


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13.3.8 
Laboratory and ECG Abnormalities 
Note: For the purposes of this study, ECG abnormalities will be handled in the same manner as 
laboratory abnormalities. 
Non-Clinically Significant (NCS) Laboratory Abnormalities 
All laboratory results must be filed in the subject’s medical record and be monitored. The 
investigator must review laboratory results in a timely manner demonstrated by signature/date 
and assignment of clinical significance assessment.  Non-clinically-significant laboratory 
abnormalities, ie, minor deviations from the normal range, are expected and it is likely that no 
medical intervention will be required.  Such results will not be considered to be adverse events. 
Clinically Significant (CS) Laboratory Abnormalities 
CS laboratory abnormalities will be graded using the CTCAE.  
All severe and life-threatening laboratory result abnormalities and any laboratory abnormality 
that is considered to be clinically significant by the investigator will be recorded on the AE 
eCRF.  An abnormal test result will be considered an AE if:  
 It is not associated with an already reported AE, diagnosis or pre-existing condition 
 There is a change in concomitant medication or intervention as needed, in direct response 
to the laboratory result 
 The investigator exercises his/her discretion to make significance determinations for any 
subject laboratory result or result that requires intervention 
All such lab abnormalities will be repeated and assessed by the investigator, or licensed (MD), as 
soon as possible for “seriousness” and if they meet the regulatory definition of “serious”, they 
will be reported as SAEs following regulatory and protocol requirements.  Repeat laboratory 
tests may be run in order to monitor the result.  
Serious Laboratory Abnormalities 
Any lab abnormality meeting the regulatory definition of “serious” must be recorded on both the 
adverse event eCRF/record and the Serious Adverse Event Form.  If a subject experiences a 
serious toxicity or dies, the FDA will be notified within 24 hours, as required.   


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13.3.9 
Pregnancy 
If any subject or the partner of a subject becomes pregnant following the first dose of tesevatinib, 
the subject will be taken off study. If any subject or a partner of a subject becomes pregnant, the 
subject and/or their partner will be followed regularly until birth or termination of the pregnancy. 
The pregnancy must be immediately reported to the sponsor. Forms for reporting pregnancies 
will be provided to the study sites upon request. The anticipated date of birth or termination of 
the pregnancy should be provided at the time of the initial report.  The outcome of a pregnancy 
(for a subject or for the partner of a subject) must be reported to the medical monitor as soon as it 
is known. If the pregnancy ends for any reason before the anticipated date initially reported, the 
investigator must notify the Kadmon medical monitor as soon as possible. 
If the outcome of the pregnancy meets any criterion for classification as a SAE (including 
stillbirth, neonatal death, spontaneous abortion, or congenital anomaly – including that in an 
aborted fetus) the investigator must follow the procedures for reporting SAEs. Any neonatal 
death occurring  30 days after birth will be reported as a SAE. 
13.3.10 
Serious Adverse Event Reporting 
Governing Regulatory Requirements 
Compliance with this request for prompt reporting is essential in that the sponsor is responsible 
for informing the US Food and Drug Administration (FDA) and other regulatory authorities as 
well as all other participating investigators of the event.  
Under FDA ruling (US Code of Federal Regulations, Title 21 CFR Part 312.32) and the ICH 
Guidelines for Clinical Safety Data Management Definitions and Standards for Expedited 
Reporting, the sponsor is required to submit written documentation, in the form of a safety 
report, detailing: 
 Any event associated with the use of the drug, that is both serious and unexpected, or  
 Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity  
Written submission must be made by the sponsor to the FDA and the IRBs as soon as possible 
and in no event later than 15 calendar days after the sponsor’s initial notification of the event.  
The sponsor shall also inform all investigators. 


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In addition, the sponsor is further required to report, by either telephone or facsimile 
transmission or in writing to the FDA the occurrence of any unexpected fatal or life-threatening 
event associated with the use of the drug and no later than 7 calendar days after notification of 
the event.  
Time-Frame for Reporting 
Any death, pregnancy, or SAE experienced by a patient from the time of informed consent until 
30 days after receiving the last dose of study drug, regardless of relationship to study drug, or 
any death that occurs more than 30 days after receiving study drug, and is believed to be study 
drug-related, must be promptly reported (within 24 hours of the investigator becoming aware of 
the event) by fax to the sponsor (or designee). 
 
In the event of an issue with the fax line, forward the SAE form via email to 
INCDrugSafety@INCResearch.com. 
The investigator will be able to contact the safety Medical Monitor at all times: 
        
 
Information to be Provided by the Investigator 
SAEs must be recorded on the SAE eCRF page. This requirement includes all SAEs that occur 
after informed consent and through 30 days after last dose of study treatment, and in addition, 
any SAE that are assessed as possibly related to study treatment by the investigator, even if the 
SAE occurs more than 30 days after the last dose of study treatment. 
The minimum information required for SAE reporting includes identity of investigator, site 
number, subject number, an event description, SAE term(s), onset date, the reason why the event 
is considered to be serious (ie, the seriousness criteria) and the investigator’s assessment of the 


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relationship of the event to study treatment (not related, unlikely related, possibly related, 
probably related, or definitely related). Additional SAE information including medications or 
other therapeutic measures used to treat the event, action taken with the study treatment due to 
the event, and the outcome/resolution of the event will be recorded on the SAE form. Forms for 
reporting SAEs will be provided to the study sites. 
In all cases, the investigator should continue to monitor the clinical situation and report all 
material facts relating to the progression or outcome of the SAE. Furthermore, the investigator 
may be required to provide supplementary information as requested by the Kadmon Drug Safety 
personnel or designee. 
When reporting SAEs, the following additional points should be noted: 
 When the diagnosis of an SAE is known or suspected, the investigator should report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms. Signs 
and symptoms may then be described in the event description. For example, dyspnea 
should not be used as an SAE term if the diagnosis which caused the dyspnea is known to 
be malignant pleural effusion.  
 Death should not be reported as an SAE, but as an outcome of a specific SAE. The cause 
of death is the SAE.  In the exceptional case where the events leading to death are 
unknown, then death may be used as an event term. If an autopsy was performed, the 
autopsy report should be provided.  
 While most hospitalizations necessitate reporting of an SAE, some hospitalizations do not 
require SAE reporting, as follows:  
 Elective or previously scheduled surgery, (eg, a previously scheduled ventral 
hernia repair) 
 Procedures for pre-existing conditions that have not worsened after initiation of 
treatment 
 Pre-specified study hospitalizations for observation 
 Events that result in hospital stays of less than 24 hours and that do not require 
admission, (eg, an emergency room visit for hematuria that results in a diagnosis 
of cystitis and discharge to home on oral antibiotics) 
 SAEs must, however, be reported for any surgical or procedural complication resulting in 
prolongation of the hospitalization. 


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13.3.11 
Regulatory Reporting 
Kadmon Drug Safety (or designee) will process and evaluate all SAEs as soon as the reports are 
received.  For each SAE received, Kadmon will make a determination as to whether the criteria 
for expedited reporting have been met. 
Kadmon (or designee) will submit SAEs that meet the criteria for expedited reporting to the 
Regulatory Authorities in accordance with local regulations governing safety reporting.  
Reporting of SAEs by the investigator to his or her IRB will be done in accordance with the 
standard operating procedures and policies of the IRB. Adequate documentation must be 
maintained showing that the IRB was properly notified. 
13.3.12 
Follow-up Information on a Serious Adverse Event 
Appropriate diagnostic tests should be performed and therapeutic measures, if indicated, should 
be instituted.  Appropriate consultation and follow-up evaluations should be carried out until the 
event has returned to baseline or is otherwise explained by the investigator.   
Follow-up data concerning the SAE (eg, diagnostic test reports, physician's summaries, etc.) also 
must be submitted to Kadmon, as they become available, by telefax or email transmission, until 
resolution of the SAE. 
13.4 
Other Safety Considerations 
13.4.1 
Medication Errors 
Any medication error that results in an AE, even if it does not meet the definition of serious, 
requires reporting within 24 hours to the medical monitor.  An overdose of tesevatinib without 
any associated signs or symptoms, unless the subject is hospitalized for observation, will not 
constitute an AE but will be recorded as a protocol deviation.  
13.4.2 
Follow-Up of Serious Adverse Events 
Any SAE that led to treatment discontinuation (including clinically significant abnormal 
laboratory values that meet these criteria) and is ongoing 30 days after last dose of study 
treatment must be followed until the event has resolved or has stabilized (ie, the subject has 
returned to the baseline state, or the investigator does not expect any further improvement or 
worsening of the subject’s condition).  This follow-up guidance also applies to SAEs that occur 
more than 30 days after last dose of study treatment.  


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13.5 
Safety Monitoring 
To minimize the possibility of exposing study subjects to unusual risk, at the end of each dosing 
cohort, the safety information from this study will be reviewed by an independent Data Safety 
Committee, including an independent safety monitor with clinical expertise in PKD and an 
independent cardiologist. Safety data will be reviewed, and a recommendation will be made to 
the study sponsor as to whether it is safe to proceed to the next dosing cohort. 
 


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14 
STATISTICAL CONSIDERATIONS 
All descriptive and inferential statistical analyses will be performed using the most recently 
released and available SAS statistical software, unless otherwise noted. For categorical variables, 
the number and percent of each category within a parameter will be calculated for non-missing 
data. For continuous variables, the mean, median, and standard deviation, as well as the 
minimum and maximum values, will be presented.  
Statistical significance will be declared when the two-tailed p-value is found to be less than or 
equal to 0.05, unless otherwise noted. Missing data will not be imputed unless otherwise stated. 
All clinical data captured will be provided in data listings.  
14.1 
General Design  
In the Phase 1b portion of the study, subjects received 50, 100, or 150 mg of tesevatinib for 
28 days or until the development of unacceptable toxicity, noncompliance, withdrawal of consent 
by the subject, or investigator decision.  After the MTD for daily dosing had been established 
according to criteria in the protocol (100 mg QD), 24 additional subjects were enrolled in the 
Phase 2a portion of the study and treated using two alternative dosing schedules of 150 mg of 
tesevatinib on Monday, Wednesday, and Friday of each week and 150 mg on Monday and 
Thursday of each week.  While the MTD dose of 100 mg/day was based on criteria defined in 
the protocol, the occurrence of moderate QTc prolongation in 2 subjects dosed at that level led to 
a decision to further evaluate the dose of 50 mg/day.   
Modeling of ADPKD subpopulations for a randomized Phase 3 clinical study has been 
performed.  Enrollment criteria being considered for Phase 3 are ADPKD subjects with baseline 
eGFR ≥ 35 mL/min/1.73 m2 and ≤ 80 mL/min/1.73 m2, and htTKV ≥ 1000 mL.  In order to 
study the safety profile in this specific ADPKD subpopulation, up to 50 additional subjects with 
PKD and baseline eGFR ≥ 35 mL/min/1.73 m2, and ≤ 80 mL/min/1.73 m2, and htTKV ≥ 1000 
mL will be enrolled (SILK Cohort).  Each of the up to 50 subjects to be enrolled will be required 
to complete either PK testing as described for other Phase 2a subjects in this protocol or 
iothalamate testing.  In addition, all 50 subjects will undergo a mandatory 28-day drug holiday 
after completing the first month of treatment with tesevatinib.  During this drug holiday, and 4 
weeks after, subjects will return to the clinic weekly for creatinine and tesevatinib plasma 


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measurements.  All subjects will resume tesevatinib treatment at the Month 2 study visit 
following completion of the 28-day drug holiday. 
14.2 
Sample Size Justification  
Eight subjects per cohort is a standard and reasonable sample size for determination of safety in 
this Phase 1b portion of the study.  Given the frequency and timing of the most common AEs in 
prior clinical studies of tesevatinib, 8 treated subjects per dose is sufficient to describe the safety 
profile of tesevatinib in this subject population.  These subjects who receive 50 mg daily of 
tesevatinib will provide 75% likelihood of having at least 1 AE if the true incidence of an AE is 
5%.   
In the Phase 2a cohort, the 65 subjects in the 50 mg QD dose group will allow an 80% 
confidence interval of approximately ± 0.64 mL/min about an expected mean 6-month change 
from baseline of -2.5 mL/min when the standard deviation is 4.0 mL/min.  
14.3 
Statistical Considerations  
14.3.1 
Study Populations  
Adult subjects with ADPKD will be enrolled.  The safety population will consist of all subjects 
who receive at least 1 dose of tesevatinib.  An evaluable subject will be defined as one who has 
completed 28 days (for subjects in the Phase 2a portion of the study this will be 25 or 26 days in 
the Monday/Thursday and Monday/Wednesday/Friday cohorts, and 28 days in the 50 mg daily 
dosing cohort).  Phase 1b unevaluable subjects (subjects who are not evaluable for toxicity) will 
be replaced. Subjects who do not complete the study, for whatever reason, will have all available 
data up until the time of termination related to the reason they were terminated included in the 
analysis.  Completion of the study for subjects enrolled in the Phase 1b portion will be defined as 
uninterrupted completion of the first 28 days of study drug administration, and completion of the 
study for subjects entered in the Phase 2a portion of the study will be defined as completion of 
the Month 6 MRI. 
For the Phase 2a cohort, all subjects treated will be included in the analyses based on their 
available data. 


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14.3.2 
Subject Accountability, Demographics, and Baseline Characteristics  
Subject disposition will be tabulated by dose cohort. Similarly, subject demographic information 
and baseline characteristics including PKD traits will be displayed by treatment. Any 
discrepancy between treatment assigned and treatment received will be accounted for in these 
displays. Data for screen failures, pertaining to why they failed to qualify to enroll will also be 
collected. 
Similar analyses will be presented for the Phase 2a cohort. 
14.3.3 
Tesevatinib Exposure  
The amount of tesevatinib administered by visit and overall (total dose) will be tabulated and 
presented by subject in data listings for all cohorts.  In addition, delays and all other alterations in 
tesevatinib administration will be presented.  
14.3.4 
Concomitant Medications  
Concomitant medications will be coded using WHO Drug Dictionary (WHO-DD March 2013, 
Type B2 or later) and the data will be summarized by dose cohort and presented in tables and 
listings.  
14.3.4.1 
Interim Analyses 
On Study Day 1, subjects will receive their first daily dose of tesevatinib.  During the Phase 1b 
portion of the study, all subjects within a dosing cohort must complete 28 days of follow-up and 
the safety data reviewed before subjects from a subsequent dose cohort receive tesevatinib at the 
next higher dose.  Subjects in Cohort 1 will receive the starting dose 50 mg tesevatinib (Dose 
Level 1).  After all subjects in Cohort 1 complete a minimum of 28 days of follow-up and the 
safety data have been reviewed, dose escalation involving new subjects can begin with Cohort 2 
subjects receiving 100 mg tesevatinib daily (Dose Level 2).  Similarly, after all subjects in 
Cohort 2 complete a minimum of 28 days of follow-up and safety data review, dose escalation 
involving new subjects can precede with Cohort 3 receiving 150 mg tesevatinib daily (Dose 
Level 3).  
14.3.5 
Pharmacokinetics 
Plasma concentrations of tesevatinib from subjects will be analyzed using validated assays at a 
central laboratory, and PK parameters will be estimated using standard PK methodology. Plasma 


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tesevatinib concentrations and PK parameters will be summarized using descriptive statistics.    
Efforts will be made to identify the specific structure of major tesevatinib metabolites present in 
all plasma samples collected from 1–24 hours after dosing on Days 1 and 14 in Phase 1b and on 
Days 1 and 12 (Monday, Wednesday, and Friday dosing) and Days 1 and 25 (Monday and 
Thursday dosing) in Phase 2a. 
14.3.6 
Efficacy/Activity 
Descriptive statistics, including confidence intervals for GFR, will be presented over time for the 
Phase 2a cohort.  In addition, identical statistics for the change and percent change from baseline 
GFR over time will be presented with the 6-month change from baseline being of particular 
interest. 
Similar descriptive statistics will be presented for the reciprocal of serum creatinine endpoints. 
14.3.7 
MRI 
Exploratory efficacy analysis will include MRI measurements of kidney volume.  htTKV will be 
calculated using total kidney volume obtained from MRI divided by height in meters.  Kidney 
volume will be determined by MRI at Screening (baseline measurement), and every 6 months 
thereafter.  These results, including change and percent change from baseline, will be 
summarized descriptively, including confidence intervals.  Log transformation may be needed if 
these data are found not to be normally distributed.  A separate set of analyses will be presented 
for the Phase 2a cohort. 
14.3.8 
Safety Data  
Safety analyses will be performed on all subjects who receive any quantity of study drug.  AEs 
that are unrelated to treatment and that occur more than 30 days after the administration of the 
last dose of treatment will not be reported or analyzed. Safety evaluation will be performed based 
on the actual study treatment a subject has received.  A separate set of safety analyses will be 
presented for the Phase 2a cohort. 
Safety observations and measurements include AEs, safety laboratory tests, vital sign 
measurements, physical examinations, pregnancy status, echocardiograms, ECG assessments, 
and pharmacokinetic data.  


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Adverse events will be summarized both overall and by dose cohort and tabulated by severity 
and relationship to tesevatinib (causality).  The original terms used by investigators to identify 
adverse events in the eCRFs will be mapped into preferred terms using MedDRA® (Version 18.1 
or higher). Adverse events will then be grouped by MedDRA® preferred terms into frequency 
tables according to body system.  The number and percentage of subjects experiencing adverse 
events will be tabulated by body system and preferred term both overall and by dose cohort.  
When an adverse event occurs more than once, the maximum severity and causality will be 
counted.  Additionally, serious adverse events, adverse events that are related to tesevatinib, and 
adverse events that are unrelated to tesevatinib will be summarized separately.  Concurrent 
illnesses will be listed and examined as possible confounders in the treatment relationship. 
Finally, any other potentially related adverse events will be analyzed and discussed, as necessary.  
Concurrent medications/therapies will also be listed. 
A listing of all AEs and SAEs by subject will also be provided. The duration of AEs will be 
determined and included in listings, along with action taken and outcome.  Incidence of 
laboratory abnormalities will be summarized. The worst on-study grade after the first dose of 
study drug will be summarized. The incidence of NCI-CTCAE Grade ≥ 3 (Version 4.03) 
laboratory abnormalities under treatment and shifts in toxicity grading from baseline to highest 
grade post-baseline will be displayed. Results for variables that are not part of the NCI CTCAE 
(Version 4.03) will be presented in the listings as below, within, and above the normal limits of 
the local laboratory.  Pregnancy test results will be summarized by time point and dose cohort. 
Iothalamate testing will be evaluated as data are received to ensure that testing is consistent with 
no effect on renal function. 
Vital sign measurements will be summarized at each scheduled time point using descriptive 
statistics.  Physical examination results will be summarized by scheduled time point. Physical 
examination results will also be presented in the subject data listings. Physical findings including 
height and weight will be presented for each subject by visit and dose cohort.  
Digital ECG results and wave intervals measurements will be summarized and reported by 
subject visit and dose cohort and/or as appropriate. QTc(F) prolongation results will be 


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summarized separately. Covariate analyses will be employed as necessary (eg, QTc[F] interval 
vs. plasma drug concentration). 
Echocardiogram results will be summarized and reported by subject visit and dose cohort and/or 
as appropriate. 


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15 
DATA QUALITY ASSURANCE 
All data will be entered in a validated electronic data capture system using single data entry. 
Standard procedures (including following data review guidelines, manual clinical review based 
on subject profiles, computerized validation to produce queries, and maintenance of an audit file 
which includes all database modifications) will be followed to ensure accurate data. Clinical 
personnel will review all data listings for outliers, data inconsistencies, and spelling errors. 
During the course of the study, a study monitor (CRA) will make site visits to review protocol 
compliance, compare eCRFs against individual subject’s medical records, assess drug 
accountability, and ensure that the study is being conducted according to pertinent regulatory 
requirements. 
Electronic CRF entries will be verified with source documentation. The review of medical 
records will be performed in a manner to ensure that subject confidentiality is maintained.  
Checking the eCRFs for completeness, clarity and cross checking with source documents is 
required to monitor the progress of the study. Direct access to source data is also required for 
inspections and audits, and will be carried out giving due consideration to data protection and 
medical confidentiality. Each investigator will have assured Kadmon of full access to complete 
source data for study participants and associated necessary support at all times. 
In addition to routine monitoring procedures, audits of clinical research activities in accordance 
with SOPs may be performed to evaluate compliance with the principles of GCP.  A regulatory 
authority may also wish to conduct an inspection (during the study or even after its completion).  
If a regulatory authority requests an inspection, the investigator must immediately inform 
Kadmon that this request has been made. 
Study conduct may be assessed during the course of the study by a Clinical Quality Assurance 
representative(s) to ensure that the study is conducted in compliance with the protocol.  This 
designee, as well as the CRA, will be permitted to inspect the study documents (study protocol, 
eCRFs, investigational product accountability, original study-relevant medical records).  All 
subject data will be treated confidentially.  In the course of the clinical study, access will be 
available to Kadmon or designee (eg, CRO) to view the eCRFs after completion of the individual 


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sections of the study. Furthermore, the study protocol, each step of the data-recording procedure 
and the handling of the data as well as the study report may be subject to independent review by 
a Quality Assurance representative.  Clinical site and study audits will be conducted as necessary 
to assure the validity of the study data. 


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16 
ETHICAL ASPECTS 
16.1 
Local Regulations 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
ICH E6 Tripartite Guideline and in a manner consistent with the most recent version of the 
Declaration of Helsinki. The investigator will ensure that the conduct of the study complies with 
the basic principles of GCP as outlined in the current version of 21 CFR, subpart D, Part 312, 
“Responsibilities of Sponsors and Investigators”, Part 50, “Protection of Human Subjects”, and 
Part 56, “Institutional Review Boards”. 
16.2 
Informed Consent 
A properly executed, written informed consent document, in compliance with 21 CFR, Part 50 
and the International Conference on Harmonization (ICH) guidelines, will be obtained from each 
subject before the subject is entered into the study and before any study screening procedure is 
performed that involves risk.  Attention will be directed to the basic elements required for 
incorporation into the informed consent under US Federal Regulations for Protection of Human 
Subjects (21 CFR 50.25[a]) and (21 CFR 50.25[b]), as necessary.  Sample ICFs will be supplied 
to each site. Kadmon or its designee must review any proposed deviations from the sample ICF. 
The final IRB-approved document must be provided to Kadmon for regulatory purposes. 
It is the responsibility of the investigator, or a person designated by the investigator, to obtain 
written informed consent from each subject (or the subject’s legally authorized representative) 
participating in this study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study. In the case where the subject is unable to read, an impartial 
witness should be present during the entire informed consent discussion. After the subject has 
orally consented to participation in the study, the witness’ signature on the form will attest that 
the information in the consent form was accurately explained and understood. A copy of the ICF 
must be provided to the subject or to the subject’s legally authorized representative. If applicable, 
it will be provided in a certified translation of the local language.  The site will retain the original 
signed/dated consent form and any associated HIPAA authorization for all consented subject 
candidates. 


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The eCRF for this study contains a section for documenting informed subject consent, and this 
must be completed appropriately. Signed ICFs must remain in each subject’s study file and must 
be available for verification by study monitors at any time. If new safety information results in 
significant changes in the risk/benefit assessment, the consent form should be reviewed and 
updated as necessary. All subjects (including those already being treated) should be informed of 
the new information, should be given a copy of the revised form, and should give their written 
consent to continue in the study. 
16.3 
Institutional Review Board 
This study is being conducted in compliance with the protocol, the ICH GCP Guidelines, and the 
applicable regulatory requirements under a United States IND application. This protocol (and 
any modifications) and appropriate consent procedures must be reviewed and approved by an 
IRB. This board must operate in accordance with the current federal or local regulations. The 
investigator will send a letter or certificate of IRB approval to Kadmon (or designee) before 
subject enrollment and whenever subsequent modifications to the protocol are made. 
16.4 
Future Use of Subject Samples 
Not all of the tissue and blood components obtained during this study may be required for the 
tests that are part of the clinical study. Following the conclusion of the study, the samples may be 
used for additional research. These samples will be held for a maximum of 5 years. This may 
include pharmacogenomics profiling analyzing CYP enzyme polymorphisms.  This will be of 
particular interest given the use of tesevatinib in a new patient population who may experience 
toxicity not previously seen in earlier studies, and may help identify those at risk for toxicity at 
various doses. This research will help to understand disease subtypes, drug response and toxicity, 
and possibly identify new drug targets or biomarkers that predict subject response to treatment. 
The use of the samples for internal research will be done according to the guidelines defined by 
the FDA guidance for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that 
are Not Individual Identifiable (issued 25 April 25 2006) and the EMEA Reflection Paper on 
Pharmacogenetic Samples, Testing and Data Handling (EMEA/CHMP/PGxWP/201914/2006). If 
a subject requests destruction of their tissue and blood samples and the samples have not yet 
been de-identified, Kadmon will destroy the samples as described in this FDA guidance. 
Kadmon will notify the investigator in writing that the samples have been destroyed. 


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17 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between a 
Kadmon representative and the investigator. Protocol modifications will be prepared, reviewed, 
and approved by Kadmon representatives. 
All protocol modifications must be submitted to the IRB for information and approval in 
accordance with local requirements, and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects, or when the change involves only logistical or administrative 
aspects of the study (eg, change in monitor, change of telephone number) or to eliminate an 
immediate hazard to study subjects. In these circumstances, immediate approval of the chairman 
of the IRB must be sought, and the investigator should inform Kadmon, and the full IRB within 
5 business days after the emergency occurs. 
  


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18 
CONDITIONS FOR TERMINATING THE STUDY 
Kadmon has the right to terminate the study at any time. In terminating the study, Kadmon and 
the investigator will ensure that adequate consideration is given to the protection of the subjects’ 
interests. 
The following data and materials are required by Kadmon before a study can be considered to be 
complete or terminated: 
 Laboratory findings, clinical data, and all special test results from Screening through the 
end of the study, including the follow-up period for all enrolled subjects. 
 Case Report Forms/Records.  Electronic case report forms (eCRFs) will be used in this 
study.  Records (including correction forms) for all enrolled subjects will be properly 
completed by appropriate study personnel, and signed and dated by the principal 
investigator, as required. 
 Principal investigator sign-off of all required eCRF forms. 
 Completed Drug Accountability Records, Drug Inventory Log, and Inventory of 
Returned Drug forms or documentation of destruction, as appropriate. 
 Return of all unused study drug to Kadmon unless an alternate disposition method is 
agreed upon at study initiation by Kadmon and investigational site(s). 
 Copies of protocol amendments and other documents, and IRB approval/notification, as 
applicable. 
 A summary of the study prepared by the principal investigator (IRB summary closure 
letter is an acceptable equivalent).  
 
 


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19 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
19.1 
Investigator’s Files and Retention of Documents 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into two separate categories as follows: (1) investigator’s study file and (2) subject 
clinical source documents. 
The investigator’s study file will contain the protocol and protocol amendments, eCRFs, query 
forms, IRB and governmental approval with correspondence, sample informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
Subject clinical source documents (usually predefined by the project to record key efficacy and 
safety parameters independent of the eCRFs) may include subject hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, X-ray, 
pathology and special assessment reports, signed ICFs, consultant letters, email communication 
and subject screening and enrollment logs. The investigator must keep these two categories of 
documents on file for at least 2 years following the marketing application approval date for the 
study treatment and for the indication being investigated or for 2 years after the investigation is 
discontinued and the FDA is notified. After that period of time, the documents may be destroyed 
subject to local regulations with prior written permission from Kadmon. If the investigator wants 
to assign the study records to another party or move them to another location, Kadmon must be 
notified in advance. 
If the investigator cannot guarantee the archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Kadmon to 
store these in a sealed container outside of the study site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside of the study site. 


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19.2 
Source Documents and Background Data 
Investigators must maintain adequate and accurate source documents on which the eCRFs for 
each subject are based. They are separate and distinct from the eCRFs. 
 
These records include detailed notes on: 
 
 Medical history 
 Date and time of informed consent with HIPAA authorization either contained in the ICF 
or presented to the subject candidate as a standalone document 
 Description of the complete consenting process 
 The basic identifying information that linked the subject’s medical record with the eCRFs 
 The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject 
 The medical condition of the subject during their involvement in the study 
 All adverse events 
 The subject’s exposure to the study medication 
 The subject’s exposure to any concomitant therapy 
 All relevant observations and data on the condition of the subject throughout the study 
 Justification for all entries in the subject’s eCRF 
 Radiology images (hard copy and digital), and reports if required 
 Death information and any available autopsy data 
A subject log of all potentially eligible subjects considered, but not consented, for obvious 
deviations from the entry criteria, will be kept at each site. The log will contain subjects’ initials, 
diagnosis, eligibility, or, if not eligible, reason for not consenting.  All consented subjects will be 
logged, regardless of whether they ultimately enroll.  
Upon request, the investigator will supply Kadmon with any required background data from the 
study documentation or clinic records. This is particularly important when eCRFs are illegible or 
when errors in data transcription are suspected. In case of special problems or governmental 
queries or requests for audit inspections, it is also necessary to have access to the complete study 
records, provided that subject confidentiality is protected. 


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19.3 
Audits and Inspections 
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the Kadmon Quality Assurance Unit (or 
designee), or to health authority inspectors after appropriate notification. The verification of the 
eCRF data must be by direct inspection of source documents. 
19.4 
Electronic Case Report Forms 
Clinical study data for this study will be captured on electronic case report forms (eCRF) 
designed for computer processing and analysis.  This computerized system will be validated and 
compliant with 21 CFR Part 11. Corrections to data will be made according to 21 CFR Part 11, 
Electronic Records; Electronic Signatures. If corrections are made after review and sign-off by 
the investigator, he/she must be aware of the changes and provide written acknowledgement. 
There will also be an electronic audit trail.  The investigator agrees to provide all information 
requested on the eCRF in an accurate manner according to instructions provided.  The 
investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to Kadmon in the eCRF and in all required reports. 
An eCRF is required to be submitted for every subject who receives any amount of study drug.  
This includes submission of retrievable data on subjects who withdraw before completion of the 
study.  Prior to submission, eCRFs must be reviewed for completeness and accuracy, and signed 
and dated where indicated by the principal investigator or authorized delegate from the study 
staff.  If a subject stops treatment or terminates from the study, the dates and reasons must be 
noted on the eCRF. 
 
 


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20 
MONITORING THE STUDY 
All aspects of the study will be carefully monitored by Kadmon or authorized representatives 
according to GCP and standard operating procedures (SOPs) for compliance with applicable 
government regulations. 
It is understood that the responsible Kadmon study monitor (or designee) will contact and visit 
the investigator regularly and will be allowed on request to inspect the various records of the 
study (eCRFs and other pertinent data) provided that subject confidentiality is maintained in 
accordance with local requirements.  The principal investigator (or a designee) and key study 
personnel must be available to assist the monitor during these visits.  The investigator (or 
designee) must agree to cooperate with the monitor to ensure that any problems detected during 
the course of these monitoring visits are resolved. 
It will be the monitor’s responsibility to inspect the eCRFs in comparison to source documents at 
regular intervals throughout the study according to the monitoring plan, to verify the adherence 
to the protocol and the completeness, consistency, and accuracy of the data being entered on 
them and clarifying any data queries. The monitor should have access to laboratory test reports 
and other subject records needed to verify the entries on the eCRF.  The completed and corrected 
eCRFs/CRFs for completed visits will either be collected by the monitor at the end of the study 
or obtained electronically for data processing. The investigator is responsible for the timely 
completion of eCRFs by assigned study staff.  The eCRFs are expected to be completed within 
seven (7) days of the subject’s visit.  A copy of the eCRFs will be retained by the investigator 
who must ensure that it is stored in a secure place with other study documents, such as the 
protocol, the Investigator’s Brochure, and any protocol amendments. 
Upon completion of the study, the monitor will make a final assessment of the conduct of the 
study and inventory all clinical supplies to be returned to Kadmon. 
 
 


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21 
CONFIDENTIALITY OF STUDY DOCUMENTS AND SUBJECT RECORDS 
The investigator must ensure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On eCRFs or other documents submitted to Kadmon 
and the IRB, subjects should be identified by an identification code and/or initials and not by 
their names. The investigator should keep a subject enrollment log. The investigator should 
maintain documents not for submission to Kadmon (eg, subjects’ written consent forms) in strict 
confidence. 
Authorized regulatory officials and Kadmon personnel (or their representatives) will be allowed 
full access to inspect and copy the records.  All study drug, subject bodily fluids and tissue, 
and/or other materials collected shall be used solely in accordance with this protocol, unless 
otherwise agreed to in writing by Kadmon. 
The principal investigator also agrees that all information received from Kadmon, including but 
not limited to the Investigator’s Brochure, this protocol, eCRFs, the investigational new drug, 
and any other study information remain the sole and exclusive property of Kadmon during the 
conduct of the study and thereafter.  This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from the Sponsor. The principal investigator further agrees to take 
all reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
 


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22 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. The investigator 
agrees to submit all manuscripts or abstracts to Kadmon for review at least 30 days before 
submission. This allows Kadmon to protect proprietary information and to provide comments 
based on information from other studies that may not yet be available to the investigator. 
In the event that Kadmon coordinates a publication or presentation of study results from all study 
sites, the participation of investigator or other representatives of study site as a named author 
shall be determined in accordance with Kadmon policy and generally accepted standards for 
authorship. 


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23 
REFERENCES 
American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines. 
http://www.asco.org/ascov2/Practice+&+Guidelines/Guidelines/Clinical+Practice+Guidelines.  
Accessed 26 April 2011. 
Belibi FA, Reif G, Wallace DP, Yamaguchi T, Olsen L, Li H, et al. Cyclic AMP promotes 
growth and secretion in human polycystic kidney epithelial cells. Kidney Int. 2004 
Sep;66(3):964-73. 
Chapman AB. Approaches to testing new treatments in autosomal dominant polycystic kidney 
disease: insights from the CRISP and HALT-PKD studies. Clin J Am Soc Nephrol. 2008 
Jul;3(4):1197-204. 
Grantham JJ, Torres VE, Chapman AB, Guay-Woodford LM, Bae KT, King BF Jr, et al. 
Volume progression in polycystic kidney disease. N Engl J Med. 2006 May 18; 354(20):2122-
30. 
Grantham JJ. Clinical practice Autosomal dominant polycystic kidney disease. N Engl J Med. 
2008 Oct 2; 359(14):1477-85. 
Guay-Woodford LM, Muecher G, Hopkins SD, Avner ED, Germino GG, Guillot AP, et al. The 
severe perinatal form of autosomal recessive polycystic kidney disease maps to chromosome 
6p21.1-p12: implications for genetic counseling. Am J Hum Genet. 1995 May;56(5):1101-7. 
Hammond TG, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Redfern WS, et al. Methods of 
collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical 
industry: results of an international survey. Cardiovasc Res. 2001;49(4):741-50. 
Kiyohara Y, Yamazaki N, Kishi A, et al.  Erlotinib-related skin toxicities: Treatment strategies in 
patients with metastatic non-small cell lung cancer. J Am Acad Dermatol 2013; 69(3):463–472. 
Lacouture ME, Anadkat MJ, Bensadoum RJ, et al. Clinical practice guidelines for the prevention 
and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer. 2011; 
19:1079–1095. 


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Onuchic LF, Furu L, Nagasawa Y, Hou X, Eggermann T, Ren Z, et al. GGPKHD1, the 
polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple 
immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am J 
Hum Genet. 2002 May;70(5):1305-17.  
Torres VE. Treatment strategies and clinical trial design in ADPKD. Adv Chronic Kidney Dis. 
2010 Mar; 17 (2):190-204. 
Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007 
Apr 14;369(9569):1287-301. 
Wilson PD.  Polycystic Kidney Disease. N Engl J Med. 2004; 350(2):151-164. 
 
 


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Appendix A: Equations to Predict Glomerular Filtration Rate (MDRD-4, CKD-EPI2012cys, 
and CKD-EPI2012Scr-cys)  
 
4-Variable Modification of Diet in Renal Disease (MDRD-4) Equation 
High Level Formula for Black or African-American Males: 
Estimated GFR = 175 × (Creatinine -1.154) × (Age -0.203) × 1.212 
High Level Formula for Males NOT Black or African-American (any other option): 
Estimated GFR = 175 × (Creatinine -1.154) × (Age -0.203) 
High Level Formula for Black or African-American Females: 
Estimated GFR = 175 × (Creatinine -1.154) × (Age -0.203) × 1.212 × 0.742 
High Level Formula for Females NOT Black or African-American (any other option): 
Estimated GFR = 175 × (Creatinine -1.154) × (Age -0.203) × 0.742 
 
 
CKD-EPI2012cys Equation to Predict Glomerular Filtration Rate (GFR) 
 
Gender 
Scys 
(mg/L) 
Equation 
female 
≤ 0.8 
133 × (Scys/0.8)
-0.499 × 0.996
age (× 0.932) 
 
> 0.8 
133 × (Scys/0.8)
-1.328 × 0.996
age (× 0.932) 
male 
≤ 0.8 
133 × (Scys/0.8)
-0.499 × 0.996
age 
 
> 0.8 
133 × (Scys/0.8)
-1.328 × 0.996
age 
Note: Age is shown as years. 
Scr = serum creatinine; Scys = serum cystatin C; CKD-EPI2012cys = cystatin C-based CKD-EPI equation developed in 2012 
 
 


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CKD-EPI2012Scr-cys Equation to Predict Glomerular Filtration Rate (GFR) 
 
Gender 
Scr 
(mg/dL) 
Scys 
(mg/L) 
Equation 
female 
≤ 0.7 
≤ 0.8 
130 × (Scr/0.7)
-0.248 × (Scys/0.8)
-0.375 × 0.995
age (× 1.08, if black) 
 
 
> 0.8 
130 × (Scr/0.7)
-0.248 × (Scys/0.8)
-0.711 × 0.995
age (× 1.08, if black) 
 
> 0.7 
≤ 0.8 
130 × (Scr/0.7)
-0.601 × (Scys/0.8)
-0.375 × 0.995
age (× 1.08, if black) 
 
 
> 0.8 
130 × (Scr/0.7)
-0.601 × (Scys/0.8)
-0.711 × 0.995
age (× 1.08, if black) 
male 
≤ 0.9 
≤ 0.8 
135 × (Scr/0.9)
-0.207 × (Scys/0.8)
-0.375 × 0.995
age (× 1.08, if black) 
 
 
> 0.8 
135 × (Scr/0.9)
-0.207 × (Scys/0.8)
-0.711 × 0.995
age (× 1.08, if black) 
 
> 0.9 
≤ 0.8 
135 × (Scr/0.9)
-0.601 × (Scys/0.8)
-0.375 × 0.995
age (× 1.08, if black) 
 
 
> 0.8 
135 × (Scr/0.9)-0.601 × (Scys/0.8)-0.711 × 0.995age (× 1.08, if black) 
Note: Age is shown as years. 
Scr = serum creatinine; Scys = serum cystatin C; CKD-EPI2012Scr-cys = serum creatinine- and cystatin C-based CKD-EPI 
equation  
 
 
 
 
 
CKD-EPI2012cys and CKD-EPI2012Scr-cys Equations abstracted from:  Zhu Y, Ye X, Zhu B, Pei X, Wei 
L, et al. Comparisons between the 2012 New CKD-EPI (Chronic Kidney Disease Epidemiology 
Collaboration) Equations and Other Four Approved Equations. PLoS ONE. 2014. 9(1): e84688.   
doi:10.1371/journal.pone.0084688 
 
 
 


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Appendix B: Concomitant Medications Associated With a Risk of QTc(F) Interval 
Prolongation and/or Torsades de Pointes  
Use of these drugs should be avoided in subjects who are receiving KD019. Subjects who require 
treatment with these drugs should have KD019 held for up to 21 days while receiving the 
treatment and should be closely monitored for QTc(F) prolongation and potential AEs. This list 
is not comprehensive and all concomitant medications should be evaluated for potential 
contribution to QTc(F) prolongation.  Refer to the following web site whenever a potential 
concomitant medication is needed for additional listings and information: 
 https://crediblemeds.org/index.php?rf=US 
Drug Type 
Drug Name 
Anti-anginal 
bepridil 
Anti-arrhythmic 
amiodarone, disopyramide, dofetilide, ibutilide, 
procainamide, quinidine, sotalol 
Antibiotic 
clarithromycin, erythromycin, azithromycin, sparfloxacin, 
gatifloxacin, moxifloxacin, troleandomycin 
Anti-cancer 
arsenic trioxide 
Anti-infective/pneumocystis pneumonia 
pentamidine 
Anti-malarial 
chloroquine, halofantrine 
Anti-nausea 
domperidone, droperidol 
Anti-psychotic 
haloperidol, mesoridazine, thioridazine 
Anti-psychotic/anti-emetic 
chlorpromazine 
Anti-psychotic/Tourette’s tics 
pimozide 
GI stimulant/heartburn 
cisapride 
Opiate agonist/pain control/narcotic dependence 
levomethadyl, methadone 
Reference:  http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm 
 
 


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Amendment Number 13 
 
 
 
 
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Appendix C: Clinical Symptom and Adverse Event Grading Scale 
 
CLINICAL ADVERSE EVENT GRADING SCALE 
Severity 
Grade 
Definition 
Mild 
1 
Awareness of symptom, but easily tolerated.  Usually transient 
requiring no special treatment; does not interfere with usual status or 
activities 
 
Moderate 
2 
May be ameliorated by simple therapeutic measures; may interfere with 
usual activities 
 
Severe 
3 
Incapacitating; unable to perform usual activities 
 
Life-threatening 
4 
Requires immediate intervention; need for emergency treatment 
 
Death 
5 
Resulting in the subsequent death of the subject 
 
 
 
 


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Appendix D: QTc(F) Calculation 
 
The formula is: QTc(F) = QT/(RR1/3) 
 
 Manually and carefully measure the QT msec (use the longest) 
 The "RR interval in seconds" = dividing 60/heart rate 
 Power of 1/3 = 0.34 
 Take the RR and elevate it to the power of 0.34 
 Divide the QT by that number 
 
Example: 
 
For a QT of 400 msec and a heart rate of 80 bpm 
 
RR interval = 60/heart rate = 60/80 = 0.75 
 
0.750.34 = 0.9 
 
400/0.9 = QTc(F) = 444 msec 
 
The QTc(F) for a QT of 400 msec and a heart rate of 80 bpm is 444. 
 
 
 


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Appendix E: Topical Steroid Potency Chart 
The following potency chart categorizes brand- name topical steroid medications along with the 
name of the corresponding generic drug. The medications are listed in order of their potency. 
Please note that the percentage of ingredient in the medication does not necessarily correlate with 
the strength of the steroid. The list may not be comprehensive. 
Brand Name 
Generic Name 
Class 1 – Superpotent 
Clobex Lotion/Spray/Shampoo, 0.05% 
 
Clobetasol propionate 
Cormax Cream/Solution, 0.05% 
Clobetasol propionate 
Diprolene Ointment, 0.05% 
Augmented betamethasone 
Olux E Foam, 0.05% 
Clobetasol propionate 
Olux Foam, 0.05% 
Clobetasol propionate 
Temovate Cream/Ointment/Solution, 0.05% 
Clobetasol propionate 
Ultravate Cream/Ointment, 0.05% 
Halobetasol propionate 
Vanos Cream, 0.1% 
Fluocinonide 
Cordran Tape, 0.05% 
Flurandrenolide 
Class 2 - Potent 
Diprolene Cream AF, 0.05% 
Augmented betamethasone 
Elocon Ointment, 0.1% 
Mometasone furoate 
Florone Ointment, 0.05% 
Diflorasone diacetate 
Halog Ointment/Cream, 0.1% 
Halcinonide 
Lidex Cream/Gel/Ointment, 0.05% 
Fluocinonide 
Psorcon E Cream, 0.05% 
Diflorasone diacetate 
Topicort Cream/Ointment, 0.25% 
Desoximetasone 
Topicort Gel, 0.05% 
Desoximetasone 
Class 3 – Upper Mid-Strength 
Cutivate Ointment, 0.005% 
Fluticasone propionate 
Lidex-E Cream, 0.05% 
Fluocinonide 
Luxiq Foam, 0.12% 
Betamethasone valerate 
Topicort LP Cream, 0.05% 
Desoximetasone 
Class 4 – Mid-Strength  


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Brand Name 
Generic Name 
Cordran Ointment, 0.05% 
Flurandrenolide 
Elocon Cream/Lotion, 0.1% 
Mometasone furoate 
Kenalog Cream/Spray, 0.1% 
Triamcinolone acetonide 
Synalar Ointment, 0.025% 
Fluocinolone acetonide 
Westcort Ointment, 0.2% 
Hydrocortisone Valerate 
Class 5 - Lower Mid-Strength 
Capex Shampoo, 0.01% 
Fluocinolone acetonide 
Cordran Cream/Lotion, 0.05% 
Flurandrenolide 
Cutivate Cream/Lotion, 0.05% 
Fluticasone propionate 
Dermatop Cream, 0.1% 
Prednicarbate 
DesOwen Lotion, 0.05% 
Desonide 
Locoid Cream/Lotion/Ointment/ 
Solution, 0.1% 
Hydrocortisone butyrate 
Pandel Cream, 0.1% 
Hydrocortisone probutate 
Synalar Cream, 0.025/ 
Fluocinolone acetonide 
Westcort Cream, 0.2% 
Hydrocortisone valerate 
Class 6 – Mild 
Aclovate Cream/Ointment, 0.05% 
Alclometasone dipropionate 
Derma-Smoothe/FS Oil, 0.01% 
Fluocinolone acetonide 
Desonate Gel, 0.05% 
Desonide 
Synalar Solution, 0.01% 
Fluocinolone acetonide 
Verdeso Foam, 0.05% 
Desonide 
Class 7 - Least Potent  
Cetacort Lotion, 0.5%/1% 
Hydrocortisone 
Cortaid Cream/Spray/Ointment, 1% 
Hydrocortisone 
Hytone Cream/Lotion, 1%/2.5% 
Hydrocortisone 
Micort-HC Cream, 2%/2.5% 
Hydrocortisone 
Nutracort Lotion, 1%/2.5% 
Hydrocortisone 
Synacort Cream, 1%/2.5% 
Hydrocortisone 
Abstracted from:  National Psoriasis Foundation. Topical treatments for Psoriasis. 2013. 
http://www.psoriasis.org/document.doc?id=164 (accessed 24 February 2014). 
 

SAP_001.pdf: 
Kadmon Corporation 
KD019-101
     
     Statistical Analysis Plan 
SAP Version 1.0: 10-September-2020 
      Page 1 of 24 
STATISTICAL ANALYSIS PLAN 
A Phase 1b/2a, Safety, Pharmacokinetic and Dose-Escalation 
Study of KD019 in Subjects with Autosomal Dominant 
Polycystic Kidney Disease 
Protocol Number: KD019-101 
Statistical Analysis Plan Version: 
Date of Statistical Analysis Plan: 
Version 1.0 
xx-Jun-2020
NCT01559363


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SIGNATURE PAGE 
 
 
 
 
 
 
 
 
 
 
 
 
 


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DOCUMENT HISTORY 
Version 
Author 
Description 
1.0  
 
10-Sep-2021 
New Document 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1 
INTRODUCTION .............................................................................................. 8 
2 
STUDY SUMMARY ........................................................................................... 9 
2.1 
Study Objectives ............................................................................................ 9 
2.1.1 
Primary Objectives.................................................................................. 9 
2.1.2 
Secondary Objectives.............................................................................. 9 
2.1.3 
Post-hoc Objectives: ............................................................................. 10 
2.2 
Study Design ................................................................................................ 10 
2.2.1 
KD019-101 ........................................................................................... 10 
2.3 
Visit Schedule and Study Assessment ......................................................... 11 
3 
STATISTICAL METHODS ............................................................................ 11 
3.1 
General Methods .......................................................................................... 11 
3.1.1 
Computing Environment ....................................................................... 11 
3.1.2 
Sample Size Justification and power calculations: ............................... 11 
3.1.3 
General Considerations ......................................................................... 12 
3.1.4 
Study Day.............................................................................................. 12 
3.1.5 
Baseline ................................................................................................. 13 
3.1.6 
Handling of Incomplete or Missing Data .............................................. 13 
3.2 
Analysis Populations .................................................................................... 14 
3.3 
Subject Disposition and Evaluability ........................................................... 15 
3.4 
Protocol Deviations ...................................................................................... 15 
3.5 
Demographics and Baseline Characteristics ................................................ 15 


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3.5.1 
Demographics ....................................................................................... 15 
3.5.2 
Medical History .................................................................................... 15 
3.6 
Prior and Concomitant Medications ............................................................. 16 
3.7 
Primary Endpoint Analysis .......................................................................... 16 
3.7.1 
Secondary Endpoint Analyses .............................................................. 18 
3.7.2 
Post-hoc Endpoint Analysis .................................................................. 18 
3.8 
Safety Analysis ............................................................................................. 19 
3.8.1 
Adverse Events ..................................................................................... 19 
3.8.2 
Clinical Laboratory Evaluation ............................................................. 19 
3.8.3 
Vital Signs ............................................................................................. 20 
3.8.4 
ECG....................................................................................................... 20 
3.9 
Pharmacokinetic Analysis Plan .................................................................... 20 
4 
LIST OF TABLES, FIGURES, AND LISTINGS ..................................... 21-24 
  
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Full Term 
ADI 
Actual dose intensity 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ATC 
American Therapeutic Chemical (Classification) 
BID 
Twice daily 
C1D1 
Cycle 1 Day 1 
CI 
Confidence interval 
CM 
Concomitant medication 
CNI 
Calcineurin inhibitor 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of response 
ECG  
Electrocardiogram 
EOT 
End of treatment 
HCT 
Hematopoietic cell transplantation 
FVC 
Forced vital capacity 
ICH 
International Conference on Harmonisation  
LR 
Lack of response 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-treat 
KPS 
Karnofsky Performance Scale 
NE 
Not evaluable 
ORR 
Overall response rate 
OS 
Overall survival 
OS-9 
Overall survival at 9 months 
PD 
Pharmacodynamics 
PDI 
Planned dose intensity 
PFS 
progression-free survival 
PFS-6 
progression-free survival at 6 months 
PK 
Pharmacokinetics 
PR 
Partial response 
PT 
Preferred Term 
RANO 
Response Assessment in Neuro-Oncology criteria 
RDI 
Relative dose intensity 
RV 
Residual volume 
QD 
Once daily 
ORR 
Overall response rate 


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Abbreviation 
Full Term 
QTcF 
Corrected QT interval using Fridericia's formula 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC  
System Organ Class 
STB 
Stable 
TEAE 
Treatment-emergent adverse event 
 
 
 


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1 INTRODUCTION 
Tesevatinib (formerly named KD019) was originally developed for a solid tumor 
indication, and is currently being investigated for the treatment of cancer. In 
nonclinical studies, tesevatinib selectively inhibited key kinases and validated targets 
in animal models of polycystic kidney disease (PKD). In addition, it has shown either 
no or extremely weak inhibitory activity of other kinases that should reduce off-target 
effects. Tesevatinib has also been shown to be a potent inhibitor of receptor and 
cytoplasmic tyrosine kinases (TKs). The product was specifically optimized to 
simultaneously inhibit EGFR, human epidermal growth factor receptor 2 (HER2), 
Src, vascular endothelial growth factor receptor 2 (VEGFR2/ KDR), and ephrin 
receptor B4 (EphB4) tyrosine kinases with high potency, and demonstrated excellent 
activity in target-specific cellular functional assays. In nonclinical animal models, 
tesevatinib had acceptable oral bioavailability and has shown sustained inhibition of 
its targets in vivo following a single oral dose. 
In Phase 1 and 2 clinical studies conducted in healthy subjects and subjects with solid 
tumors, over 300 subjects have been treated to date; at least 185 of these have been 
treated at levels ≥ 300 mg daily. At least 53 subjects have received tesevatinib for ≥ 6 
months, and safety and tolerability were acceptable. Tesevatinib is also in 
development for the treatment of breast cancer and non-small cell lung cancer 
(NSCLC). 
In summary, both the nonclinical results in PKD models and the clinical safety results 
in human oncology studies suggest that tesevatinib could be a promising therapeutic 
in autosomal dominant polycystic kidney disease (ADPKD). 
Evaluation of the safety and tolerability data from the subjects in KD019-101 led to 
the conclusion that tesevatinib 50 mg daily was the dose and schedule most 
appropriate for use in a randomized study. 
 
 
 
 
 
 


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This Statistical Analysis Plan (SAP) describes detailed statistical procedures to be 
used for study KD019-101 
. KD019-101 is specified in the protocol 
(Amendment No. 13, 06-Oct-2016): A Phase 2, Multicenter Study of Tesevatinib 
Monotherapy in Patients with Recurrent Glioblastoma. 
 
 
 
 
The SAP was written in accordance with the recommendations outlined in the 
International Conference on Harmonisation (ICH) E9 Guideline entitled “Guidance 
for Industry: Statistical Principles for Clinical Trials” and the most recent ICH-E3 
Guideline, entitled “Guidance for Industry: Structure and Content of Clinical Study 
Reports.”  
2 STUDY SUMMARY 
2.1 Study Objectives  
2.1.1 Primary Objectives 
2.1.1.1 KD019-101: 
• Phase 1b: To determine the safety, plasma pharmacokinetics (PK), and 
maximum tolerated dose (MTD) of tesevatinib when administered to subjects 
with ADPKD. 
• Phase 2a: To evaluate the annualized change in glomerular filtration rate 
(GFR) in subjects with ADPKD when treated with tesevatinib. 
 
2.1.2 Secondary Objectives  
2.1.2.1 KD019-101: 
• To evaluate subjects treated with tesevatinib with regard to annualized percent 
change from baseline in total kidney volume (TKV) 
• To evaluate subjects treated with tesevatinib with regard to annualized change 
from baseline in the reciprocal of serum creatinine 


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• To evaluate subjects treated with tesevatinib with regard to safety profile 
• To evaluate subjects treated with tesevatinib with regard to serum creatinine 
profiles 
• To evaluate subjects treated with tesevatinib with regard to PK and tolerability 
of 2 alternative dosing schedules (dosing on Monday, Wednesday, and Friday 
of each week, and dosing on Monday and Thursday of each week) 
 
2.1.3 Post-hoc Objectives:  
• To evaluate the slope of the change in the annualized estimated GFR 
 
2.2 Study Design 
2.2.1 KD019-101 
This is a Phase 1b/2a, multicenter, open-label, dose-escalation, safety, MTD, and PK 
study in subjects with ADPKD. The Phase 1b portion of the study has been 
completed and the MTD for daily dosing was determined to be 100 mg daily. In this 
portion of the study, subjects received 50, 100, or 150 mg of tesevatinib orally once 
daily for 28 days or until the development of unacceptable toxicity, noncompliance, 
or withdrawal of consent by the subject, or investigator decision. After the initial 28-
day safety and tolerability assessment period, subjects may have, at the discretion of 
the investigator, continued to receive study drug for a total of 24 months from the 
initiation of treatment. 
For those subjects who had received a minimum of 6 months of treatment at the 50 
mg/day dose, dose escalation to 100 mg/day was allowed after the 100 mg/day was 
evaluated for safety.  
In order to study the safety profile in this specific ADPKD subpopulation, up to 50 
additional subjects with PKD and baseline eGFR ≥ 35 mL/min/1.73 m2 and ≤ 80 
mL/min/1.73 m2, and htTKV ≥ 1000 mL will be enrolled (SILK Cohort). Up to 50 
subjects will be enrolled and required to complete PK testing as described for other 
Phase 2a subjects in this protocol or iothalamate testing. 


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2.3 Visit Schedule and Study Assessment 
The flow chart of visit schedule and study assessments is given in Table 4-1 of the 
KD019-101 Protocol 
. 
3 STATISTICAL METHODS  
3.1 General Methods 
3.1.1 Computing Environment 
All statistical programming and data analyses will be performed using SAS 
Version 9.4 on Windows platform. 
3.1.2 Sample Size Justification and power calculations: 
Eight subjects per cohort is a standard and reasonable sample size for determination 
of safety in this Phase 1b portion of the study. Given the frequency and timing of the 
most common AEs in prior clinical studies of tesevatinib, 8 treated subjects per dose 
is sufficient to describe the safety profile of tesevatinib in this subject population. 
These subjects who receive 50 mg daily of tesevatinib will provide 75% likelihood of 
having at least 1 AE if the true incidence of an AE is 5%. 
 


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In the Phase 2a cohort, the 65 subjects in the 50 mg QD dose group will allow an 
80% confidence interval of approximately ± 0.64 mL/min about an expected mean 6-
month change from baseline of -2.5 mL/min when the standard deviation is 4.0 
mL/min. 
3.1.3 General Considerations  
General considerations for descriptive statistics and presentation for continuous and 
categorical data are given below.  
3.1.3.1 Continuous variables 
Continuous data will be described using descriptive statistics: number of observations 
(n), mean, standard deviation, median, minimum, and maximum.   
Means, medians, standard deviations, and confidence intervals (CIs) will be reported 
to one decimal place more than the data reported on the case report form (CRF) or by 
the vendor. Minimum and maximum will be reported to the same number of decimal 
places displayed on the CRF or by the vendor. P-values will be reported to 4 decimal 
places. 
3.1.3.2 Binary Endpoint and Other Categorical Variables 
For endpoints with two possible outcomes such as alive/otherwise or 
response/otherwise within specific periods, the 95% confidence interval will be 
calculated with Clopper-Pearson method for survival rates or response rates.   For 
other categorical variables, the counts and percent of each category within a 
parameter will be calculated for observed data only. The denominator for all 
percentages, unless otherwise specified, will be the number of subjects in the cohort 
or in the specified analysis population. 
3.1.4 Study Day 
The Study Day for all assessments prior to the first study drug administration is 
calculated as the difference between the date of the event or measurement (e.g., 
adverse event [AE] onset date, assessment date, sample collection date) and the start 
date of study treatment. The day before the start of study treatment is Study Day -1. 
The Study Day for all post-assessments after the first study drug administration is 
calculated as the difference between the date of the event or measurement (e.g., AE 


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onset date, assessment date, sample collection date) and the start date of study 
treatment plus one day. The first day of study treatment is Study Day 1. 
3.1.5 Baseline 
Baseline value is defined as the valid and last non-missing value obtained within 
28 days prior to subject receiving the first study medication, unless otherwise stated 
under the related assessment section. Baseline can be the day before the first study 
medication or on the same day as the first study medication if a pre-dose assessment 
is available. Subjects without data on a parameter before the first study medication 
will have a missing baseline for this parameter.  
3.1.6 Handling of Incomplete or Missing Data 
Missing data will not be imputed in general and will be reported as missing in all 
listings. For categorical variables, patients with missing data are not included in 
calculations of percentages unless otherwise specified.  
3.1.6.1 Missing start and end dates for AE and concomitant medication (CM)  
The assumption will be the worst or most conservative judgment when imputing AE 
and CM start and end dates. The purpose of imputing a start date is to help define 
whether the AE/CM started while taking study drug. 
For a partial or missing start date: 
• If the day is missing, the first day of the month will be imputed. If the missing 
day is the same as the month of first dose of study drug, then the first dose 
date will be imputed. 
• If the day and month are missing, the first day of January will be imputed. If 
the year is the same as the first dose date, then the first dose date will be 
imputed. 
• If the day is completely missing, the first dose date will be imputed. If the end 
date suggests it could have started prior to this, the first day of January of the 
same year as the end date will be imputed. 
• When imputing a start date, the start date will ensure that the new imputed 
date is sensible, i.e., is prior to the end date of the AE or CM. 
For a partial or missing end date: 
• If the day is missing, the last day of the month or the last assessment date, 
whichever is earlier, will be imputed. 
• If the day and month are missing, the 31st of December or the last assessment 
date, whichever is earlier, will be imputed 


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• If the date is completely missing, there will be a need to look at whether the 
AE/CM is still ongoing before imputing a date. If the ongoing flag is missing, 
then it will be assumed that AE is still present, or CM is still being taken (i.e., 
do not impute a date). If the AE/CM has stopped, then the last assessment date 
will be imputed. 
These data imputations are for categorization purpose only and will not be used in the 
listings. 
If the assessment of the relationship of the AE to tesevatinib is missing, then it will be 
assumed that the AE is related to tesevatinib and the AE considered as such in the 
frequency tables of possibly related AEs. No imputation should be done at the data 
level. 
3.1.6.2 Missing event dates  
Event date will be imputed only when day is missing, and the purpose of imputing an 
event date is to most conservatively calculate time to event.  
If the day is missing, the first (mid, last) day of the month will be imputed for 
undesired (neutral, desired) event. If the missing day is the same as the month of first 
dose of study drug, then the first dose date will be imputed for undesired event. 
These data imputations are for time to event calculation only and will not be used in 
the listings. 
3.2 Analysis Populations 
The following populations will be analyzed: 
Modified Intent-to-treat (mITT) Population: The primary population for efficacy 
analyses will be a Modified Intent-to-treat (mITT) Population. For KD019-101 it is 
defined as all subjects who completed 28 days (for subjects in the Phase 2a portion of 
the study this will be 25 or 26 days in the Monday/Thursday and 
Monday/Wednesday/Friday cohorts, and 28 days in the 50 mg daily dosing cohort).  
 
 
 
The mITT Population will be used for tables of demography, baseline characteristics, 
and efficacy. 
 


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Safety Population: The Safety Population is defined as all subjects who receive at 
least 1 dose of tesevatinib. 
3.3 Subject Disposition and Evaluability 
Subjects who failed screening (i.e., subjects who signed the informed consent were 
screened but never started the study treatment, and their basic demographics and any 
AE after signing the informed consent may have been collected in the CRF) will be 
excluded from any populations defined in Section 3.2. Therefore, these subjects will 
be excluded from any summary tables or listings.  
The number of subjects discontinuing from the study and the primary reason for 
discontinuation will be summarized.  
3.4 Protocol Deviations 
All protocol deviations will be identified and classified as major or minor before 
clinical database lock and all major protocol deviations will be presented in a listing. 
Major Deviation: Protocol deviation that may impact the accuracy, and/or reliability 
of the study data or that may impact subject rights, safety or well-being. 
Minor Deviation: Protocol deviation that does not impact the accuracy, and/or 
reliability of the study data or subject rights, safety or well-being. 
3.5 Demographics and Baseline Characteristics 
3.5.1 Demographics 
Subject demographics and baseline characteristics will be summarized for the mITT 
Population by cohort and study. Descriptive statistics will be provided for age, height, 
and weight.  
3.5.2 Medical History 
Medical history will be summarized by primary System Organ Class (SOC) and 
Preferred Term (PT). Medical history will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) Version 18.1 (or higher) terminology.   


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3.6 Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary. Prior medications are defined as those medications that began and 
stopped before the start of study treatment. Concomitant medications are defined as 
medications taken after the start of study treatment and during the study period, 
including those began before but ongoing at the start of study treatment. If a 
medication start date is partially or fully missing and it is unclear as to whether the 
medication is prior or concomitant, it will be assumed that the medication is 
concomitant. 
Number and percentage of incidence of prior and CM will be summarized according 
to study, cohort, Anatomical Therapeutic Class (ATC) and preferred drug name. 
3.7 Primary Endpoint Analysis 
The primary endpoint for the Phase 1b portion of KD019-101 is safety and 
tolerability. This will be covered in Section 3.9. 
 
 The primary endpoint is annualized 
change in glomerular filtration rate (GFR) in subjects with ADPKD when treated with 
tesevatinib. The annualized change in GFR will be calculated as the percent change 
from baseline divided by total duration in days times 365.25.  
This analysis will be done using the mITT population. Descriptive statistics will be 
provided for each cohort 
. The annualized GFR will 
be calculated for the 6, 12, 18 and 24 months timepoints.  
GFR will be estimated using three equations; MDRD-4, CKD-EPI2012cys, and CKD-
EPI2012Scr-cys.  
4-Variable Modification of Diet in Renal Disease (MDRD-4) Equation 
High Level Formula for Black or African-American Males: 
Estimated GFR = 175 × (Scr-1.154) × (Age-0.203) × 1.212 
High Level Formula for Males NOT Black or African-American (any other 
option): 
Estimated GFR = 175 × (Scr-1.154) × (Age-0.203) 
High Level Formula for Black or African-American Females: 


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Estimated GFR = 175 × (Scr-1.154) × (Age-0.203) × 1.212 × 0.742 
High Level Formula for Females NOT Black or African-American (any other 
option): 
Estimated GFR = 175 × (Scr-1.154) × (Age-0.203) × 0.742 
    Note: Age is shown in years. Scr = serum creatinine 
CKD-EPI2012cys Equation to Predict Glomerular Filtration Rate (GFR) 
Gender 
Scys (mg/L) 
Equation 
Female 
≤ 0.8 
133 × (Scys/0.8)-0.499 × 0.996age (× 0.932) 
 
> 0.8 
133 × (Scys/0.8)-1.328 × 0.996age (× 0.932) 
Male 
≤ 0.8 
133 × (Scys/0.8)-0.499 × 0.996age 
 
> 0.8 
133 × (Scys/0.8)-1.328 × 0.996age 
    Note: Age is shown in years. Scys= serum cystatin 
 
 
CKD-EPI2012Scr-cys Equation to Predict Glomerular Filtration Rate (GFR) 
Gender Scr (mg/L) Scys (mg/L) 
Equation 
Female 
≤ 0.7 
≤ 0.8 
130× (Scr/0.7)-0.248× (Scys/0.8)-0.375× 0.995age (× 1.08, if black) 
 
 
> 0.8 
130× (Scr/0.7)-0.248× (Scys/0.8)-0.711× 0.995age (× 1.08, if black) 
 
> 0.7 
≤ 0.8 
130× (Scr/0.7)-0.601× (Scys/0.8)-0.375× 0.995age (× 1.08, if black) 
 
 
> 0.8 
130× (Scr/0.7)-0.601× (Scys/0.8)-0.711× 0.995age (× 1.08, if black) 
Male 
≤ 0.7 
≤ 0.8 
130× (Scr/0.9)-0.207× (Scys/0.8)-0.375× 0.995age (× 1.08, if black) 
 
 
> 0.8 
130× (Scr/0.9)-0.207× (Scys/0.8)-0.711× 0.995age (× 1.08, if black) 


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> 0.7 
≤ 0.8 
130× (Scr/0.9)-0.601× (Scys/0.8)-0.375× 0.995age (× 1.08, if black) 
 
 
> 0.8 
130× (Scr/0.9)-0.601× (Scys/0.8)-0.711× 0.995age (× 1.08, if black) 
    Note: Age is shown in years. Scys= serum cystatin, Scr = serum creatinine 
3.7.1 Secondary Endpoint Analyses  
3.7.1.1 Total Kidney Volume 
The annualized percent change from height adjusted baseline in total kidney volume 
(hTKV) will be summarized by cohort and study using the mITT population. hTKV 
will be determined by MRI at screening (baseline measurement), at the 6-month visit, 
and every 6 months thereafter. Descriptive statistics will be provided for each 
timepoint and cohort 
.  The annualized percent 
change from baseline will be calculated as the percent change from baseline divided 
by total duration in days times 365.25.  
3.7.1.2 Serum Creatinine 
The annualized percent change from baseline in the reciprocal of serum creatinine 
will be summarized by cohort using the mITT population. Descriptive statistics will 
be provided for each cohort 
. The change from 
baseline in the reciprocal of serum creatinine will be calculated using the first and last 
timepoint for each subject. The annualized percent change from baseline will be 
calculated as the percent change from baseline divided by total duration in days times 
365.25.  
3.7.2 Post-hoc Endpoint Analysis 
3.7.2.1 Slope of the change in eGFR 
The slope of the change in the estimated GFR was derived from the individual slopes 
for each patient using the MDRD-4 equation. Descriptive statistics will be provided 
for each cohort 
. The change from baseline in the 
estimated GFR will be calculated two ways. The first using the first and last timepoint 
for each subject and the second using all of the available timepoints.  
 


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3.8 Safety Analysis 
Safety assessments will include AEs, serious adverse events (SAEs), vital sign 
measurements, clinical laboratory evaluations (hematology and chemistry), and 
electrocardiograms (ECGs). Unscheduled visits for safety assessments will not be 
presented in summary tables but will be in listings. All safety analyses will be 
performed using the safety population for all cohorts and both studies.  
3.8.1 Adverse Events 
AEs will be coded using the MedDRA dictionary (Version 20.1 or higher). 
Treatment-emergent AEs (TEAEs) are any AE occurring or worsening in severity 
after the first administration of study medication. All AEs (including SAEs) will be 
graded using the 5-point Common Terminology Criteria for Adverse Events 
(CTCAE) V5.0 scale (mild, moderate, severe, life-threatening, or death). Causality 
with KD019 will be classified as: definitely related; probably related; possibly 
related; unlikely related; unrelated; or not related. 
The number and percentage of patients who experienced at least one TEAE as well as 
the number and percentage of patients who experienced AEs of each specific SOC 
and PT will be presented. For the presentation of AE incidences, the SOCs and the 
PTs within each SOC will be presented by decreasing total frequency. Tabulation by 
maximum severity and relationship to tesevatinib will also be included by treatment 
group. 
The TEAEs, Grade ≥ 3 TEAEs, SAEs, and TEAEs leading to dose 
modification/discontinuation will be summarized by treatment arm, SOC, and PT. 
These analyses will be repeated for events considered related (definitely 
related/probably related/possibly related) to tesevatinib.  
Subject listings will be provided for SAEs, AEs resulting in study drug 
discontinuation and deaths. 
Adverse events will also be presented in listings. Time to onset and duration of AEs 
will be included in listings, along with action taken and outcome. 
3.8.2 Clinical Laboratory Evaluation 
The summary statistics (including number, mean, standard deviation, median, 
minimum and maximum) of all laboratory variables and changes from baseline will 


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be calculated for each visit or study assessment by treatment group. For parameters of 
white blood cell counts, neutrophils (absolute count), lymphocytes (absolute count), 
monocytes (absolute count), hemoglobin, platelets, ALP, ALT, aspartate 
aminotransaminase, total bilirubin, plots of mean/mean changes from baseline with 
the corresponding standard error will be displayed. 
For shift tables, laboratory results will be classified using the CTCAE Version 5.0. 
All graded laboratory parameters will be summarized separately for hematology and 
biochemistry. Corresponding shift tables comparing baseline to the worst 
post-baseline grade within the treatment period will be provided. 
3.8.3 Vital Signs 
Descriptive statistics for vital signs (weight, temperature, blood pressure, pulse rate, 
and respiratory rate) values and the change from baseline will be presented for each 
scheduled assessment time point.  
3.8.4 ECG 
Descriptive statistics for ECG parameters (i.e., PR interval, QRS interval, and QTcF 
interval) at each time point with triplicate ECGs will be presented for the values and 
change from baseline scores. (QTcF is the QT interval using Fridericia’s correction 
which is calculated by QTcF = QT/RR1/3.)  
The number and percentage of subjects with observed QTcF values that satisfy the 
following conditions will be presented by treatment group and study visit and 
categorized as: ≤ 450 ms; > 450 to 480 ms; > 480 to 500 ms; and > 500 ms. 
The number and percentage of subjects having change from baseline QTcF values 
that satisfy the following conditions will be presented by treatment group and study 
visit and categorized as: ≤ 0 ms; > 0 to ≤ 30 ms; > 30 to ≤ 60 ms; and > 60 ms. 
3.9 Pharmacokinetic Analysis Plan 
PK serum concentration and all biomarkers will be summarized at each collection 
time-point by cohort for KD019-101.  
   
 
 


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4 LIST OF TABLES, FIGURES, AND LISTINGS 
In all tables, figures and listing, results will be presented by treatment cohorts and overall, unless be otherwise specified. 
Table/Listing/Figure 
Title 
Demographics and Baseline 
Characteristics 
  
Tables (14.1.Y.Z) 
Table 14.1.1 Screen Failure 
  
Table 14.1.2 Patient Disposition 
  
Table 14.1.3 Summary of Demographics and Baseline Characteristics 
  
Table 14.1.4 Summary of Major Protocol Deviations  
  
Table 14.1.5 Summary of Medical History 
Treatment Exposure and 
Concomitant Medication 
  
Tables (14.2.Y.Z) 
Table 14.2.1 Summary of Treatment Compliance and Exposure 
  
Table 14.2.2.a Summary of Prior Medications 
  
Table 14.2.2.b Summary of Concomitant Medications 
Efficacy 
  
Tables (14.3.Y.Z) 
Table 14.3.1 Annualized Change in Estimated Glomerular Filtration Rate 
  
Table 14.3.2 Annualized Percent Change from Baseline in Height Adjusted Total Kidney Volume 
  
Table 14.3.3 Annualized Percent Change from Baseline in Reciprocal of Serum Creatinine 


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Table 14.3.3.1 Annualized Percent Change from Baseline in Reciprocal of Serum Creatinine for Study 101 
Safety 
  
Tables (14.4.Y.Z) 
Table 14.4.1 Summary of AEs 
  
Table 14.4.1.1 Summary of AEs for Study 101 
  
 
  
Table 14.4.2 Summary of TEAEs 
  
Table 14.4.2.1 Summary of TEAEs for Study 101 
  
 
  
Table 14.4.3 Summary of TEAEs Related to KD019  
  
Table 14.4.3.1 Summary of TEAEs Related to KD019 for Study 101 
  
 
  
Table 14.4.4 AEs by Preferred Term and Maximum Severity 
  
Table 14.4.4.1 AEs by Preferred Term and Maximum Severity for Study 101 
  
 
  
Table 14.4.5 AEs by Preferred Term and Strongest Relationship 
  
Table 14.4.5.1 AEs by Preferred Term and Strongest Relationship for Study 101 
  
 
  
Table 14.4.6 Summary of Grade >=3 TEAEs by System Organ Class and Preferred Term 
  
Table 14.4.6.1 Summary of Grade >=3 TEAEs by System Organ Class and Preferred Term for Study 101 
  
 
  
Table 14.4.7 Summary of Grade >=3 TEAEs Related to KD019 by System Organ Class and Preferred Term 


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Table 14.4.8 Summary of Serious Adverse Events  
  
Table 14.4.9 Summary of Serious Adverse Events Related to KD019 
  
Table 14.4.10 Summary of TEAEs leading to Dose Modification 
  
Table 14.4.11 Summary of TEAEs Related to KD019 leading to Dose Modification 
  
Table 14.4.12 Summary of TEAEs leading to Dose Discontinuation 
  
Table 14.4.13 Summary of TEAEs Related to KD019 leading to Dose Discontinuation 
  
Table 14.4.14 Summary of Clinical Laboratory: Hematology 
  
Table 14.4.15 Summary of Clinical Laboratory: Chemistry 
  
Table 14.4.16 Summary of Clinical Laboratory: Any Other Clinical Labs 
  
Table 14.4.17 Shifts from Baseline for Hematology Assessment 
  
Table 14.4.18 Shifts from Baseline for Chemistry Assessment 
  
Table 14.4.19 Summary of Vital Sign Results and Change from Baseline 
  
Table 14.4.20 Summary of 12-Lead ECG and Change from Baseline  
  
Table 14.4.21 Summary of QTcF Interval Results 
  
Table 14.4.22 Overall Summary of AEs 
  
Table 14.4.23 Overall Summary of AEs for Study 101 
  
 
  
  
Listings (16.2.Y.Z) 
Listing 16.2.1 Disposition of Subjects  
  
Listing 16.2.2 Protocol Deviations 
  
Listing 16.2.3 Patients Excluded From Efficacy Analysis 
  
Listing 16.2.4 Patient Demographics 
  
Listing 16.2.5 Dose Changes 
  
Listing 16.2.6.1 Estimated Glomerular Filtration Rate 


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Listing 16.2.6.2 Height Adjusted Total Kidney Volume 
  
Listing 16.2.7.1 Adverse Events 
  
Listing 16.2.7.2 Adverse Events leading to Study Drug Discontinuation 
  
Listing 16.2.7.3 Adverse Events leading to Death 
  
Listing 16.2.7.4 Serious Adverse Events 
  
Listing 16.2.8.1 Clinical Laboratory: Hematology 
  
Listing 16.2.8.2 Clinical Laboratory: Chemistry 
  
Listing 16.2.8.3 Clinical Laboratory: Any Other Clinical Labs 
  
Listing 16.2.8.4 Vital Signs  
  
Listing 16.2.8.5 12-Lead ECG  
Efficacy  
  
Figures (14.3.Y.Z) 
Figure 14.3.1 Annualized Change in Estimated Glomerular Filtration Rate 
  
Figure 14.3.2 Annualized Percent Change from Baseline Height Adjusted Total Kidney Volume