Clinical trial NCT02616393
Conditions: Non-Small Cell Lung Cancer Leptomeningeal Metastases Brain Metastases
Sponsor: Kadmon Corporation, LLC
Start date: 2015-11-01; Completion date: 2018-04-03
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
A study to assess the activity of tesevatinib in subjects with non-small cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations who have disease progression with Brain Metastases (BM) or Leptomeningeal Metastases (LM) or who have either BM or LM at initial presentation (IP)

Detailed description:
This was a multicenter, phase 2, open-label study to assess the activity of tesevatinib, in subjects with non-small cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations, and brain metastases (BM) or leptomeningeal metastases (LM).

After completion of the screening assessments and confirmation of study eligibility, tesevatinib was orally administered to all subjects at a dose of 300 mg once daily (QD). Tumor response, both in the central nervous system (CNS) and outside the central nervous system (non-CNS), was assessed after the second cycle of treatment and then at the end of every two cycles of treatment thereafter. Subjects were treated with tesevatinib 300 mg QD until disease progression or the subject experienced unacceptable toxicity.

Subjects who discontinued tesevatinib therapy were followed for survival.

Subjects with NSCLC + EGFR mutations were assigned to one of three cohorts:

* Cohort A: Brain Metastases (BM). Subjects had progressed with BM.
* Cohort B: Leptomeningeal Metastases (LM). Subjects had initially presented or progressed with LM.
* Cohort C: Brain Metastases at Initial Presentation (BM-IP). Subjects had no prior systemic therapy.

Each of the three cohorts was to have 20 subjects, for a total of 60 subjects. All three cohorts were enrolled simultaneously.

The primary objectives were to include:

* Clinical activity of tesevatinib of subjects in Cohort A (BM) and Cohort C (BM-IP) as measured by Response Criteria in Solid Tumors (RECIST) version 1.1 which evaluated changes in BM size.
* Clinical activity of tesevatinib of subjects in Cohort B (LM) as measured by improvement in Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 symptoms and signs.

Efficacy assessments included response to treatment using RECIST criteria, progression-free survival (PFS), time to progression (TTP), overall survival (OS), and Quality of Life (QOL) questionnaires. Safety assessments included adverse event (AE) monitoring, electrocardiogram (ECG), Eastern Cooperative Oncology Group (ECOG) Performance Status, laboratory testing, physical examination, vital signs, and pregnancy testing. In addition, pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed.

An End of Treatment Visit occurred within 3 days after the subject's last dose of study drug. This could have occurred at the visit when disease progression was diagnosed. Subjects were continued to be followed for disease progression and survival.

A follow-up visit occurred 30 days (± 5 days) after the last dose of study drug. This visit may have occurred prior to 30 days if a new therapy was started within 30 days of last dose of study drug.

For long-term follow-up, after subjects withdrew from the active treatment portion of the study, they were contacted by telephone every 8 weeks to assess survival status and any subsequent anti-cancer treatment.

Arms: arm 1: Tesevatinib 300 mg orally (PO) once daily (QD) administered to subjects with NSCLC who had progressed with brain metastases (BM) arm 2: Tesevatinib 300 mg PO QD administered to subjects with NSCLC who had progressed with leptomeningeal metastases (LM) arm 3: Tesevatinib 300 mg PO QD administered NSCLC who presented initially with BM at initial presentation
Interventions: intervention 1: Tesevatinib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
e 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2, Multicenter Study of Tesevatinib in Subjects with Non-Small 
Cell Lung Cancer, EGFR Activating Mutation, Prior Treatment with a 
Tyrosine Kinase Inhibitor, and Brain Metastases or Leptomeningeal 
Metastases 
 
 
Protocol Number: 
KD019-206 
 
Study Drug: 
Tesevatinib (KD019) 
 
Sponsor: 
Kadmon Corporation, LLC 
 
450 East 29th Street 
 
New York, NY  10016 
 
Medical Monitor: 
Sanjay Aggarwal, MD 
 
Kadmon Corporation, LLC 
 
55 Cambridge Parkway 
 
Cambridge, MA  02142 
 
Date of Protocol: 
Original: 16 July 2015 
 
Amendment 1: 09 February 2016 
 
Amendment 2: 10 May 2016 
 
Amendment 3: 08 August 2017 
 
Amendment 4: 03October 2017 
 
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. 


Tesevatinib 
Protocol Number KD019-206 
Amendment 4 
 
1 
PROCEDURES IN CASE OF EMERGENCY 
Serious Adverse Events  
All serious adverse events (SAEs)* 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 15.3.1 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 subject 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 (AE) 
• 
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 (e.g. hospitalization for elective surgery, social and/or 
convenience admissions) 
**  A suspected unexpected serious adverse reaction (SUSAR) is any untoward and unintended responses 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 Section15.3.2 of 
this document; Suspected Unexpected Serious Adverse Reactions).  All suspected adverse reactions related to an investigational medicinal 
product which 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: 
 
APCER Life Sciences, LLC. 
Fax: 646-430-9549 
 
In the event of an issue with the fax line, forward the 
SAE/SUSAR via email to:  
 
ClinicalSAEReporting@kadmon.com 
 
Sanjay Aggarwal, MD 
Vice President Clinical Development, Medical Monitor 
 
Kadmon Corporation 
55 Cambridge Parkway 
Cambridge, MA 02142 
Mobile Phone: 857-253-8642 
E-mail:   sanjay.aggarwal@kadmon.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 the Food and Drug Administration (FDA) and ICH 
regulations. I further agree to report to Kadmon any adverse events (AEs) 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 MM YYYY) 
Name of Investigator (please print) 
 
 
 
 
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4 
SYNOPSIS 
Study title 
A Phase 2, Multicenter Study of Tesevatinib in Subjects with Non-Small Cell Lung Cancer, 
EGFR Activating Mutation, Prior Treatment with a Tyrosine Kinase Inhibitor, and Brain 
Metastases or Leptomeningeal Metastases 
Clinical phase 
Phase 2 
Number of study 
centers 
10-15 
Study background 
Tesevatinib (formerly known as KD019) is an orally administered tyrosine kinase 
inhibitor that has been documented to inhibit multiple molecular drivers of tumor 
growth, including epidermal growth factor receptor (EGFR), human epidermal growth 
factor receptor 2 (HER2), sarcoma (Src), and vascular endothelial growth factor 
receptor 2 (VEGFR2).   
Tesevatinib is a highly potent inhibitor of the EGFR activating mutations that, when 
present, drive the growth of non-small cell lung cancers (NSCLCs).  When measured in 
HCC827 cells, which are human lung cancer cells with an EGFR exon 19 deletion, the 
IC50 for inhibition of EGFR phosphorylation for tesevatinib (0.6 nM) was very similar 
to that for erlotinib (0.8 nM).  The IC50 for inhibition of proliferation in the same cell 
line was 3.5 nM for tesevatinib and 4.6 nM for erlotinib.  Thus tesevatinib and erlotinib 
have similar potency in vitro against a cell line with an activating EGFR mutation.   
Tesevatinib has been evaluated in two single-agent Phase 1 studies in subjects with 
advanced solid tumors (Studies XL647-001 and XL647-002), in two single-agent Phase 
2 studies in subjects with NSCLC (Studies XL647-201 and XL647-203), and in a Phase 
3 study (Study KD019-301) in NSCLC that only enrolled 8 patients.  Tesevatinib is also 
being evaluated in a Phase 1/2 study in subjects with HER2+ metastatic breast cancer, 
and in a Phase 1/2 study in subjects with autosomal dominant polycystic kidney disease 
(ADPKD).   
The single-agent tesevatinib Phase 1 study (XL647-002) concluded that the maximum 
tolerated dose (MTD) for daily dosing of tesevatinib was 300 mg daily because two 
subjects who received 350 mg daily had Grade 3 QT interval, corrected (QTc) 
prolongation (> 500 ms).  However, when these were later reviewed by a central 
cardiology review, they were both downgraded to Grade 2.  In one case, the site QTc 
reading was confounded by a new right bundle branch block and, in the other case, by 
bradycardia. Due to these complicating issues, the MTD for daily administration of 
tesevatinib was evaluated further in combination with trastuzumab in the ongoing study 
in patients with HER2+ breast cancer.  The MTD of 300 mg daily was recently 
confirmed in the breast cancer study.  This study and others have also determined that 
tesevatinib has a prolonged half-life of approximately 60 hours. 
The other single-agent tesevatinib Phase 1 study (XL647-001) evaluated a schedule of 
5 days of tesevatinib administered every 2 weeks.  This study initially used a powder-in-
capsule preparation of tesevatinib.  At 7 mg/kg, the only two subjects treated both had 
Grade 3 diarrhea.  In one subject (11032), the Grade 3 diarrhea occurred on Day 4 of the 
study and diarrhea resolved on Day 8.  In the other subject (11034), the Grade 3 
 
 
 
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diarrhea occurred on Day 7 and diarrhea resolved on Day 25. The next lowest dose, 4.68 
mg/kg, was determined to provide similar exposure to 350 mg given as formulated 
tablets, which was called the MTD for this schedule.  However, this study was 
performed from 2004-2007 when aggressively treating diarrhea due to EGFR inhibitors 
was not necessarily routine.  It is unknown whether 350 mg administered for 5 days 
every 2 weeks would be considered to be the MTD if subjects had aggressive diarrhea 
management.   
The first of the two single-agent Phase 2 studies in NSCLC (Study XL647-201) enrolled 
treatment naïve patients with advanced stage NSCLC who were Asian, female, or with 
minimal or no smoking history.  There were 41 subjects enrolled in an intermittent 
dosing schedule and 14 enrolled in a daily dosing schedule.  Subjects in the intermittent 
cohort received tesevatinib at a dose of 350 mg for 5 days every 2 weeks. Subjects in 
the daily dosing cohort received tesevatinib administered at a dose of 300 mg daily.  
Retrospective sequencing of tumor samples identified 14/41 subjects with EGFR 
mutations.  The confirmed partial response (PR) rate in subjects with EGFR mutations 
was 57% (8/14), and an additional 3 subjects with EGFR mutations had unconfirmed 
PRs. Response rates were similar in the daily and intermittent tesevatinib schedules.  
Patients with PRs were those whose tumors had Exon 19 deletions as well as those with 
the L858R mutation.  One subject in this study who is on the intermittent schedule has 
had a long-term response lasting nearly five years and is still receiving tesevatinib 
therapy. 
In the second single-agent tesevatinib study in NSCLC (Study XL647-203), tesevatinib 
was administered daily at a dose of 300 mg/day to 41 subjects with NSCLC who had 
disease progression after treatment with other EGFR inhibitors (erlotinib or gefitinib).  
The most frequently reported adverse events (AEs) were diarrhea, nausea, cough, dry 
skin, and electrocardiogram (ECG) QTc prolongation.  Two (2) of the 41 subjects 
experienced QTc(F) > 500 msec confirmed by a central cardiology review.  (All 
subjects in all tesevatinib studies with QTc prolongation have been asymptomatic.)  
Eleven subjects (11; 28%) required a dose reduction for toxicity, most commonly for 
diarrhea (27%) and rash (18%).  Whether EGFR-related diarrhea or rash were treated 
aggressively is not clear.  There were 12 subjects with documented T790M EGFR 
mutations, none of whom had a response to tesevatinib treatment. 
The Phase 3 study (KD019-301) was a double-blind, randomized, and controlled trial of 
KD019 vs erlotinib in subjects with Stage IIIB/IV non-small cell lung cancer who had 
progressed after first- or second-line chemotherapy.  The study was closed early due to 
slow enrollment after 8 subjects were entered. One subject who carried an EGFR 
activating mutation had a partial response to tesevatinib for eight cycles before 
progressing.   
A Phase 1b/2a study (KD019-204) of the combination of trastuzumab and tesevatinib is 
ongoing in subjects with HER2+ metastatic breast cancer.  The Phase 1 portion of the 
study used a 3+3 design that is commonly used in oncology studies.  The Phase 1 
portion of the study has determined that 300 mg daily of tesevatinib in combination with 
trastuzumab is the MTD dose, as the two subjects treated with 350 mg daily had Grade 
3 events considered to be at least possibly related to tesevatinib (one had Grade 3 
diarrhea not recovering to Grade 1 by seven days, and the other had Grade 3 QTc 
prolongation confirmed by central reading).   
 
 
 
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A Phase 1b/2a study (KD019-101) of tesevatinib in patients with ADPKD is ongoing.  
Subjects with ADPKD, in whom the drug will be administered chronically for years, did 
not tolerate the Grade 2 acneiform skin rash that occurred in 2/5 patients at 150 mg 
daily.  In addition there were 2/8 patients receiving tesevatinib at a dose of 100 mg daily 
who had asymptomatic prolongation of the QTc duration (one Grade 3 and one 
Grade 2).  Doses of 50 mg daily are being evaluated further. 
Study rationale 
Subjects with NSCLC with activating EGFR mutations have a high response rate to 
tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib or afatinib.  However, these 
are not curative therapies and tumors inevitably develop resistance.1,2 The central 
nervous system (CNS) is a sanctuary site, as gefitinib, erlotinib and afatinib penetrate 
poorly into the brain.  These drugs penetrate even more poorly into the cerebrospinal 
fluid (CSF), with CSF levels documented to be approximately 1% of plasma levels for 
gefitinib and afatinib and 2.5%–13% for erlotinib.3,4,5 Disease progression after initial 
gefitinib or erlotinib treatment involves the CNS in approximately 28% of patients, and 
includes leptomeningeal metastases (LM) in 8%.6 Progression with LM occurs more 
commonly in patients with previous brain metastases than in patients without previous 
brain metastases.6 Patients with brain metastases (BMs) generally present with 
neurologic symptoms, which can include headache, confusion, and seizures.  Patients 
with LM also present with neurologic symptoms, which often include headaches or 
cranial neuropathies or pain, but can be highly varied. 
Despite the frequency of progression in the CNS, there are no approved treatments for 
the treatment of BM or of LM in patients with NSCLC and activating EGFR mutations.  
Radiation therapy, either Whole-Brain Radiotherapy (WBRT) or stereotactic 
radiosurgery (SRS), is often used to control symptoms of BMs. However, these 
treatments are rarely curative, and are not without side effects. WBRT is associated with 
early occurring fatigue and all too often with neurocognitive decline.  In patients who 
received WBRT after SRS there is a significant decline of learning and memory 
function at 4 months compared to patients receiving only SRS.  SRS is associated with 
fewer side effects, but has a higher recurrence rate when used without WBRT as the 
entire brain is not irradiated.  There are few effective therapies to control LM. 
Intrathecal methotrexate is sometimes used, although response rates are low and time to 
disease progression is short. In patients with NSCLC with activating EGFR mutations, 
high doses of gefitinib or erlotinib have been used to treat patients with BM and LM 
with some degree of effectiveness.2,8,9 However, response rates are low and the time to 
disease progression is generally short with this treatment as well. 
Diagnosis of BM is generally obtained by magnetic resonance imaging (MRI) of the 
brain. The diagnosis of LM is more complex. Diagnosis of LM is most definitive when 
cytologic evaluation of CSF specimens detects malignant cells. However, single CSF 
analysis has a false negative rate of approximately 50%, and thus cytologic diagnosis of 
LM often requires several separate CSF samples.10  MRI findings (such as subarachnoid 
nodules, enhancement in basal cisterns, and enhancement/clumping of nerve roots) are 
diagnostic, but normal CNS imaging does not exclude a diagnosis of LM. Antibodies to 
EpCam, an epithelial cell adhesion molecule, have been utilized to identify rare tumor 
cells such as circulating tumor cells in the blood. The same approach to rare cell capture 
has been utilized in the analysis of tumor cells in CSF. In one study of patients with LM, 
cytology had a sensitivity of 67%, MRI had a sensitivity of 73%, and EpCam based 
 
 
 
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identification of CSF tumor cells had a sensitivity of 100%.11 Cell-free DNA is present 
in patients with activating EGFR mutations and BM, and can be utilized to evaluate the 
EGFR mutations that are present.12 Evaluation of cell-free DNA in the CSF may provide 
a method independent of cytological analysis for evaluation of the course of patients 
with LM. 
Approximately 50% of erlotinib-resistant, EGFR-mutant patients harbor a T790M 
EGFR mutation, which gefitinib, erlotinib, and afatinib do not inhibit.1,2 IC50s for one 
cell line with the T790M EGFR mutation were 10.4 µM for gefitinib, 16.1 µM for 
erlotinib, and 0.9 µM for tesevatinib.13 Despite having an IC50 against cells with the 
T790M EGFR mutation that is much lower than that for gefitinib or erlotinib, 
tesevatinib was not effective in treating NSCLC patients with the T790M EGFR 
mutation in the XL647-203 study.14 However, patients with BM and LM occurring 
while receiving erlotinib therapy have been documented to have a much lower 
frequency (10%) of T790M mutation in the CNS than is the case for patients with 
progression in non-CNS locations (38%).15 This presumably occurs because erlotinib 
and afatinib and gefitinib penetrate poorly into the CNS, and thus tumor cells in the 
CNS can grow in the presence of the low levels of TKI that are present. 
Tesevatinib effectively penetrates into the brain, with levels in mice and rats with intact 
blood-brain barriers (BBB) the same or higher than plasma levels. Tesevatinib has 
levels in the choroid plexus and meninges in rats that are 10 times the plasma levels, 
suggesting that tesevatinib may penetrate well into CSF and may be an effective 
treatment for leptomeningeal metastases adhering to the inner surface of meninges.   
Preliminary data from the initial patients enrolled in this study demonstrate that 
tesevatinib can achieve brain and leptomeningeal exposures with clinically significant 
effects.  Radiological data are available from one of the 6 initial patients enrolled in the 
study.  A 36 year old female patient was enrolled with symptoms of Grade 1 headache, 
anal numbness, and intermittent left leg weakness.  She had a right parietal brain 
metastasis and leptomeningeal metastases diagnosed both by CSF cytology and by MRI.  
By study day 14 the headache, anal numbness, and intermittent left leg weakness were 
no longer present.  On MRI at study day 41 there was a 57% decrease in size of the right 
parietal brain metastasis and no evidence of leptomeningeal metastases. 
Thus, there is good biologic rational to evaluate tesevatinib in subjects with NSCLC and 
EGFR activating mutations who have disease progression with BM or LM, or who have 
BM or LM at initial presentation. This study will enroll subjects with BM or LM 
occurring while being treated with erlotinib or afatinib or gefitinib, or with BM or LM 
at initial presentation. 
Study objectives 
Cohort A 
Primary objective 
• 
To evaluate the clinical activity of tesevatinib in subjects with non-small cell 
lung cancer (NSCLC), activating EGFR mutations, and brain metastases (BM) 
as measured by Response Evaluation Criteria In Solid Tumors (RECIST) 
version 1.1 evaluated changes in BM size. 
Secondary objectives 
 
 
 
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• 
To evaluate changes in Quality of Life (QOL) in subjects receiving tesevatinib 
for BM. 
• 
To determine the median progression-free survival (PFS), rate of CNS non-
progression at 3 and 6 months, non-CNS time to progression (TTP), and CNS 
TTP. 
• 
To determine the median overall survival (OS). 
Exploratory objective 
• 
To evaluate the correlation between EGFR DNA mutations seen in plasma cell 
free DNA at screening with response. 
Cohort B  
Primary objective  
• 
To evaluate the clinical activity of tesevatinib in subjects with NSCLC, activating 
EGFR mutations, and leptomeningeal metastases (LM) as measured by 
improvement in Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03 symptoms and signs. 
Secondary objectives 
• 
To evaluate the activity of tesevatinib in subjects with NSCLC, EGFR activating 
mutations and LM as measured by decreases in NSCLC cells in the CSF using 
standard cytology. 
• 
To evaluate the activity of tesevatinib in subjects with NSCLC, EGFR activating 
mutations and LM as measured by improvement in CNS MRI findings . 
• 
To evaluate the pharmacokinetics (PK) of tesevatinib in CSF versus plasma 
• 
To evaluate changes in QOL in subjects receiving tesevatinib for LM. 
• 
To determine the median PFS, rate of CNS non-progression at 3 and 6 months, 
non-CNS TTP, and CNS TTP.  
• 
To determine the median OS. 
Exploratory objective 
• 
To evaluate the correlation between EGFR DNA mutations seen in plasma cell 
free DNA at screening with response. 
• 
To evaluate the activity of tesevatinib in subjects with NSCLC, EGFR activating 
mutations and LM as measured by decreases in NSCLC cells in the CSF using 
rare cell capture techniques. 
• 
To evaluate the activity of tesevatinib in subjects with NSCLC, EGFR activating 
mutations and LM measured by decreases in CSF cell-free DNA. 
• 
To utilize CSF cell-free DNA to detect activating EGFR mutations in patients 
receiving tesevatinib for LM. 
Cohort C 
Primary objective 
• 
To evaluate the clinical activity of tesevatinib in subjects with NSCLC, activating 
EGFR mutations, and BM at initial presentation as measured by RECIST 1.1 
evaluated changes in BM size. 
 
 
 
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Secondary objectives 
• 
To evaluate changes in QOL in subjects receiving tesevatinib for BM. 
• 
To determine the median PFS, rate of CNS non-progression at 3 and 6 months, 
non-CNS TTP, and CNS TTP in subjects with NSCLC, activating EGFR 
mutations, and BM at initial presentation. 
• 
To determine the median OS. 
Exploratory objectives 
• 
To evaluate the correlation between EGFR DNA mutations seen in plasma cell 
free DNA at screening with response. 
 
Study design 
This is a multicenter, Phase 2 study to assess the activity of tesevatinib in subjects with 
NSCLC and activating EGFR mutations and BM or LM. 
Screening and Study Treatment 
After completion of the screening assessments and confirmation of study eligibility, 
tesevatinib will be orally administered to all subjects at a dose of 300 mg once daily. 
Tumor response, both in the CNS and outside the CNS, will be assessed after the second 
cycle of treatment and then at the end of every two cycles of treatment thereafter.  Subjects 
will usually receive treatment with tesevatinib only until disease progression occurs, 
however treatment beyond progression is permissible in certain circumstances (See 
Duration of Treatment). 
Measuring response in LM is complex.10 Subjects with LM entering the study will be 
required to have MRI evidence of LM or cytological evidence of LM or both.  Thus in 
subjects with LM, response will be measured by symptom improvement, disappearance of 
signs of LM on MRI and/or by improvement in cytological results.  
Subjects will undergo safety evaluations, including physical examination, vital sign 
measurements, hematology, serum chemistry, urinalysis and ECG.  MRI/computed 
tomography (CT) will be performed to evaluate peripheral tumor lesions.  MRI will be 
performed to evaluate both BM and LM tumor involvement.  For subjects with LM in 
Cohort B, lumbar puncture (LP) will be performed to evaluate CSF levels of tesevatinib, 
CSF malignant cell numbers by standard cytology and by rare cell capture techniques, CSF 
cell-free DNA, and detection of activating EGFR mutations in CSF cell-free DNA. 
End of Treatment Visit 
An End-of-Treatment visit is to occur within 3 days after the subject’s last dose of study 
drug.  This may occur at the visit at which disease progression is diagnosed. The subject 
will continue to be followed in the study for disease progression and survival. 
Follow-Up Period 
A follow-up visit will occur 30 days (±5 days) after the last dose of study drug. Subjects 
will undergo PEs; vital sign measurements; hematology, serum chemistry, and urinalysis, 
all performed prior to the start of any new therapy.  This visit may occur prior to 30 days 
if a new therapy is started within 30 days of last dose of study drug. 
Long-Term Follow-Up 
 
 
 
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After withdrawal from the active treatment portion of the study, subjects will be contacted 
by telephone every 8 weeks to assess survival status and any subsequent anti-cancer 
treatment. 
Study 
population/Number of 
subjects 
Up to 20 subjects with NSCLC who have progressed with BM will be enrolled in Cohort 
A.  Up to 20 subjects who have initial presentation or progressed with LM will be enrolled 
in Cohort B.  Up to 20 subjects with NSCLC and BM and no prior systemic therapy will be 
enrolled in Cohort C.  Cohort A, Cohort B, and Cohort C will be open for enrollment 
simultaneously; when one cohort has completed enrollment the other cohorts will remain 
open for enrollment until enrollment in those cohorts are also complete. 
Diagnosis and main 
criteria for inclusion 
Cohort A – Brain Metastases 
Inclusion criteria:  
Subjects will be included if they meet the following criteria: 
1. Age ≥ 18 years old. 
2. History of NSCLC with EGFR mutation (either exon 19 deletion or L858R 
mutation or an EGFR activating mutation that has had a clinical response to 
erlotinib, afatinib, or gefitinib in the patient being enrolled). 
3. Occurrence or progression of BM while receiving first line therapy (either erlotinib 
or afatinib or gefitinib) for at least 14 days.  Patients may have received osimertinib 
(or other agents inhibiting the T790M EGFR mutation) as second line therapy. If 
BM progression occurs after osimertinib, patient will be eligible. 
4. At least one measurable BM by RECIST 1.1 criteria (≥ 10mm in longest diameter).  
Target lesions must not have received stereotactic radiotherapy (SRS). If subject 
had prior WBRT, progression in any measurable BM lesion must have occurred at 
least 3 months after the end of WBRT.  Subjects with asymptomatic brain 
metastases may be enrolled without prior radiation therapy to the brain. Subjects 
with minimally symptomatic brain metastases may be enrolled without prior 
radiation therapy to the brain if they do not require immediate surgical or radiation 
therapy in the opinion of the treating investigator and in the opinion of a radiation 
therapy or neurosurgical consultant. 
5. Subjects in Cohort A may have asymptomatic LM detected by MRI.  (Subjects with 
symptoms or signs attributed to LM will be enrolled in Cohort B whether or not 
they have brain metastases) 
6. No clinically significant progression outside of the CNS on most recent EGFR 
inhibitor therapy. 
7. Eastern Cooperative Oncology Group (ECOG) Score ≤ 2. 
8. 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.   
9. Adequate organ and bone marrow functions as follows: 
a. 
Serum creatinine ≤ 1.5 mg/dL 
b. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (except in patients 
diagnosed with Gilbert’s disease where bilirubin must be ≤ 3 × ULN). 
c. 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3× 
 
 
 
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the ULN 
d. White blood count (WBC) > 3000/mm3 
e. 
Absolute neutrophil count ≥ 1500/mm3 
f. 
Platelet count > 100,000/mm3 
g. Hemoglobin > 8 g/dL  
10. Serum potassium and magnesium levels above the lower limit of normal (LLN). 
11. No coexisting medical problems of sufficient severity to limit compliance with the 
study. 
12. Willing and able to sign written informed consent and be able to comply with the 
study protocol for the duration of the study. 
13. 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. 
a. 
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.  
b. 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 3 months after their last dose of study drug.  Effective birth 
control includes (a) intrauterine device (IUD) plus one barrier method; (b) on 
stable doses of hormonal contraception for at least 3 months (e.g., oral, 
injectable, implant, transdermal) plus one barrier method; (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 
c. 
For male patients who are sexually active and who are partners of 
premenopausal women: agreement to use two forms of contraception as in 
criterion 13 above during the treatment period and for at least 3 months after 
the last dose of study drug. 
Exclusion criteria: 
Subjects will be excluded if they meet any of the following criteria: 
1. First day of dosing with tesevatinib is less than 2 weeks from the last treatment of 
cytotoxic chemotherapy, biological therapy, or immunotherapy and less than 6 
weeks for nitrosoureas and mitomycin C. Surgical procedures must have been 
performed at least 2 weeks prior to the start of study treatment.  Subjects must have 
recovered from the reversible effects of prior lung cancer treatments, including 
surgery and radiation therapy (excluding alopecia). 
2. First day of dosing with tesevatinib is less than 4 weeks from the last radiotherapy 
of the brain or spinal cord/cauda equina. 
3. First day of dosing with tesevatinib is less than 2 weeks from treatment with 
another investigational agent. 
4. Treatment with erlotinib must be discontinued at least 3 days prior to first dose of 
tesevatinib and treatment with afatinib or other tyrosine kinase inhibitor must be 
discontinued at least 3 days prior to first dose of tesevatinib.   
 
 
 
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5. Any concurrent therapy for BM other than the specified treatment in this study.  
6. Taking any medication known to moderately or severely inhibit the CYP3A4 
isozyme or any drugs that are CYP3A4 inducers (including anti-epileptic agents 
such as phenytoin).  A stable regimen (≥ 4 weeks) of antidepressants of the 
selective serotonin reuptake inhibitor (SSRI) class is allowed (common SSRIs 
include escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and 
fluoxetine). 
7. Taking any drugs associated with torsades de pointes or known to moderately or 
severely prolong the QTc(F) interval. 
8. Has evidence of active heart disease such as myocardial infarction within the 
3 months prior to study entry; symptomatic coronary insufficiency congestive heart 
failure; moderate or severe pulmonary dysfunction. 
9. History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic 
sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR 
interval only), or congenital long QT syndrome. Subjects with a history of atrial 
arrhythmias should be discussed with the medical monitor. 
10. Has an active infectious process. 
11. Female subject who is pregnant or lactating. 
12. Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular 
foreign body. 
13. Has marked prolongation of QTc(F) interval at screening or Cycle 1 Day 1 (QTc[F] 
interval > 470 msec) using the Fridericia method of correction for heart rate. 
14. Gastrointestinal (GI) condition that interferes with drug absorption. 
15. Non-malignant neurological disease that would interfere with evaluation of 
symptoms or signs of brain metastases. 
 
Cohort B – Leptomeningeal Metastases 
Inclusion criteria: 
Subjects will be included if they meet the following criteria: 
1. Age ≥ 18 years old.  
2. History of NSCLC with EGFR mutation (either exon 19 deletion or L858R 
mutation or, if previously treated, history of an activating EGFR mutation that has 
had a clinical response to erlotinib, afatinib, or gefitinib in the patient being 
enrolled). 
3. Presentation with LM at initial presentation with no prior systemic treatment, or 
occurrence or progression of LM while receiving first line therapy (either erlotinib 
or afatinib or gefitinib) for at least 14 days. Patients may have received osimertinib 
(or other agents inhibiting the T790M EGFR mutation) as second line therapy. If 
LM progression occurs after osimertinib, patient will be eligible. 
4. Presence of at least one CTCAE 4.03 symptom/sign of at least Grade 1 attributed 
by the investigator to leptomeningeal metastases 
5. Diagnosis of LM by: 
a) Cytological evidence in CSF sample of LM due to NSCLC, and/or 
b) Findings on gadolinium-enhanced MRI  
 
 
 
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6. No clinically significant progression outside of the CNS on most recent EGFR 
inhibitor therapy. 
7. Concomitant brain metastases and brain metastases previously treated with 
radiation therapy are allowed. (Subjects with symptoms or signs attributed to LM 
will be enrolled in Cohort B whether or not they have brain metastases) 
8. ECOG Score ≤2. 
9. 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. 
10. Adequate organ and bone marrow functions as follows: 
a) Serum creatinine ≤ 1.5 mg/dL 
b) Total bilirubin ≤ 1.5 × ULN (except in patients diagnosed with Gilbert’s 
disease where bilirubin must be ≤ 3 × ULN). 
c) ALT and AST ≤ 3× the (ULN 
d) WBC > 3000/mm3 
e) Absolute neutrophil count ≥ 1500/mm3 
f) 
Platelet count > 100,000/mm3 
g) Hemoglobin > 8 g/dL 
11. Serum potassium and magnesium levels above the LLN. 
12. No coexisting medical problems of sufficient severity to limit compliance with the 
study. 
13. Willing and able to sign written informed consent and be able to comply with the 
study protocol for the duration of the study. 
14. 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. 
a. 
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.  
b. 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 3 months after their last dose of study drug.  Effective birth 
control includes (a) intrauterine device (IUD) plus one barrier method; (b) on 
stable doses of hormonal contraception for at least 3 months (e.g., oral, 
injectable, implant, transdermal) plus one barrier method; (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 
c. 
For male patients who are sexually active and who are partners of 
premenopausal women: agreement to use two forms of contraception as in 
criterion 14 above during the treatment period and for at least 3 months after 
the last dose of study drug 
 
 
 
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Exclusion criteria: 
Subjects will be excluded if they meet any of the following criteria: 
1. First day of dosing with tesevatinib is less than 2 weeks from the last treatment of 
cytotoxic chemotherapy, biological therapy, or immunotherapy, and less than 6 
weeks for nitrosoureas and mitomycin C.  Surgical procedures must have been 
performed at least 2 weeks prior to the start of study treatment. Subjects must have 
recovered from the reversible effects of prior lung cancer treatments, including 
surgery and radiation therapy (excluding alopecia). 
2. First day of dosing with tesevatinib is less than 4 weeks from the last radiotherapy 
of the brain or spinal cord/cauda equina. 
3. First day of dosing with tesevatinib is less than 2 weeks from treatment with 
another investigational agent. 
4. Treatment with erlotinib must be discontinued at least 3 days prior to first dose of 
tesevatinib and treatment with afatinib or other tyrosine kinase inhibitor must be 
discontinued at least 3 days prior to first dose of tesevatinib. 
5. Any concurrent therapy for LM other than the specified treatment in this study.  
6. Taking any medication known to moderately or severely inhibit the CYP3A4 
isozyme or any drugs that are CYP3A4 inducers (including anti-epileptic agents 
such as phenytoin).  A stable regimen (≥ 4 weeks) of antidepressants of the SSRI 
class is allowed (common SSRIs include escitalopram oxalate, citalopram, 
fluvoxamine, paroxetine, sertraline, and fluoxetine). 
7. Taking any drugs associated with torsades de pointes or known to moderately or 
severely prolong the QTc(F) interval. 
8. Has evidence of active heart disease such as myocardial infarction within the 
3 months prior to study entry; symptomatic coronary insufficiency congestive heart 
failure; moderate or severe pulmonary dysfunction. 
9. History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic 
sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR 
interval only), or congenital long QT syndrome.  Subjects with a history of atrial 
arrhythmias should be discussed with the medical monitor. 
10. Has an active infectious process. 
11. Female subject who is pregnant or lactating. 
12. Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular 
foreign body. 
13. Has marked prolongation of QTc(F) interval at screening or Cycle 1 Day 1 (QTc[F] 
interval > 470 msec) using the Fridericia method of correction for heart rate. 
14. GI condition that interferes with drug absorption. 
15. Non-malignant neurological disease that would interfere with evaluation of 
symptoms or signs of leptomeningeal metastases. 
16. Contraindications to lumbar puncture: 
a) International normalized ratio (INR) > 1.5 
b) Platelets < 50 × 109/L (Note that platelets are required to be ≥100× 109/L at 
 
 
 
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screening) 
c) Therapeutic anticoagulant treatment that can’t be held for 24 hours.  Low dose 
low molecular weight heparin given for deep vein thrombosis (DVT) 
prophylaxis is allowed. 
d) CNS lesions considered to be at risk for cerebral herniation, 
myelocompression, or conus/cauda compression.   
 
Cohort C – Brain Metastases at Initial Presentation 
Inclusion criteria:  
Subjects will be included if they meet the following criteria: 
1. Age ≥ 18 years old. 
2. NSCLC with EGFR activating mutation. 
3. No prior systemic treatment for NSCLC.  Treatment with systemic steroids is not 
considered systemic treatment for NSCLC.   
4. No prior radiation therapy to the CNS (brain or spinal cord) 
5. At least one measurable BM by RECIST 1.1 criteria (≥ 10mm in longest diameter) 
in  a subject with asymptomatic or minimally symptomatic brain metastases who 
does not require immediate surgical or radiation therapy in the opinion of the 
treating investigator and in the opinion of a radiation therapy or neurosurgical 
consultant.  
6. Subjects in Cohort C may have asymptomatic LM detected by MRI.   
7. ECOG Score ≤2. 
8. 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.   
9. Adequate organ and bone marrow functions as follows: 
e) Serum creatinine ≤ 1.5 mg/dL 
f) 
Total bilirubin ≤ 1.5 × ULN (except in patients diagnosed with Gilbert’s 
disease where bilirubin must be ≤ 3 × ULN). 
g) ALT and AST ≤ 3× the ULN 
h) WBC > 3000/mm3 
i) 
Absolute neutrophil count ≥ 1500/mm3 
j) 
Platelet count > 100,000/mm3 
k) Hemoglobin > 8 g/dL  
10. Serum potassium and magnesium levels above the LLN. 
11. No coexisting medical problems of sufficient severity to limit compliance with the 
study. 
12. Willing and able to sign written informed consent and be able to comply with the 
study protocol for the duration of the study. 
13. Female subjects of childbearing potential have a negative pregnancy test at 
screening. Females of childbearing potential are defined as sexually mature women 
 
 
 
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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. 
a. 
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.  
b. 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 3 months after their last dose of study drug.  Effective birth 
control includes (a) intrauterine device (IUD) plus one barrier method; (b) on 
stable doses of hormonal contraception for at least 3 months (e.g., oral, 
injectable, implant, transdermal) plus one barrier method; (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 
c. 
For male patients who are sexually active and who are partners of 
premenopausal women: agreement to use two forms of contraception as in 
criterion 13 above during the treatment period and for at least 3 months after 
the last dose of study drug 
Exclusion criteria: 
Subjects will be excluded if they meet any of the following criteria: 
1. Surgical procedures that were performed less than 2 weeks prior to the start of 
study treatment.   
2. Any concurrent therapy for BM other than the specified treatment in this study.  
3. Taking any medication known to moderately or severely inhibit the CYP3A4 
isozyme or any drugs that are CYP3A4 inducers (including anti-epileptic agents 
such as phenytoin).  A stable regimen (≥ 4 weeks) of antidepressants of the SSRI 
class is allowed (common SSRIs include escitalopram oxalate, citalopram, 
fluvoxamine, paroxetine, sertraline, and fluoxetine). 
4. Taking any drugs associated with torsades de pointes or known to moderately or 
severely prolong the QTc(F) interval. 
5. Has evidence of active heart disease such as myocardial infarction within the 
3 months prior to study entry; symptomatic coronary insufficiency congestive heart 
failure; moderate or severe pulmonary dysfunction. 
6. History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic 
sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR 
interval only), or congenital long QT syndrome. Subjects with a history of atrial 
arrhythmias should be discussed with the medical monitor. 
7. Has an active infectious process. 
8. Female subject who is pregnant or lactating. 
9. Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular 
foreign body. 
10. Has marked prolongation of QTc(F) interval at screening or Cycle 1 Day 1 (QTc[F] 
interval > 470 msec) using the Fridericia method of correction for heart rate. 
11. GI condition that interferes with drug absorption. 
12. Non-malignant neurological disease that would interfere with evaluation of 
 
 
 
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symptoms or signs of brain metastases. 
Dosage and 
administration 
Tesevatinib will be administered at the dose of 300 mg once daily. Tesevatinib will be 
used in dosage strength of 100-mg, and 150-mg tablets. Patient diaries will be utilized to 
evaluate compliance. One cycle will be defined as 28 days of treatment. 
Tesevatinib should be taken in the morning (unless there is a subject-specific rationale 
to take it regularly at a different time of day) and can be administered without regard to 
food intake.  
Duration of treatment/ 
Discontinuation 
Duration of treatment:  Subjects will be treated with study drug until disease progression or 
unacceptable toxicity occurs.  However, subjects with limited peripheral disease 
progression (oligoprogressive disease) may receive local ablative (radiation therapy or 
surgery) while study drug is withheld for up to 28 days, and then be continued on 
tesevatinib. 
Discontinuation:  Subjects who discontinue tesevatinib treatment will be followed for 
survival.   
Concomitant 
medications 
Concomitant treatment and medication information will be collected from the time the 
subject signs the informed consent form until 30 days after their last dose of study drug 
or until the subject starts a new treatment, and is to be reported on the appropriate case 
report form (eCRF). The generic name of the drug (or trade name for combination 
drugs) must be specified along with the reason for use, and duration of treatment. 
Additionally, all diagnostic, therapeutic, or surgical procedures, whether relating to 
malignancy or not, should be recorded in the eCRF including the date, indication, 
description of the procedure(s), and any clinical finding. Any medication that is 
considered necessary for the subject’s welfare may be given at the discretion of the 
investigator. Ancillary treatments will be given as medically indicated. The reason for 
administration must be recorded on the eCRF. Any changes in documented, permitted 
concomitant treatment already being taken at the beginning of the clinical study must be 
recorded in the eCRF, noting the type of medication, the duration, and indication.  
Concurrent treatment with bisphosphonates or denosumab is allowed, if started prior to the 
start of tesevatinib administration. 
Prohibited treatments 
• 
Other investigational drugs 
• 
Concurrent anti-tumor therapies such as chemotherapy, gene therapy, 
biologics, tyrosine kinases inhibitors, radiation therapy, or other 
immunotherapy 
• 
Medications associated with torsades de pointes or known to moderately or 
severely prolong the QTc(F) interval, including anti-arrhythmic medications 
within 2 weeks prior to Day 1 of treatment in the study.   
• 
Tesevatinib is largely metabolized by CYP3A4. Therefore, taking any 
medication known to moderately or severely inhibit the CYP3A4 isozyme or 
any drugs that are CYP3A4 inducers (including anti-epileptic agents such as 
phenytoin).  A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class 
is allowed (common SSRIs include escitalopram oxalate, citalopram, 
fluvoxamine, paroxetine, sertraline, and fluoxetine). 
 
 
 
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• 
Steroid medications are allowed 
• 
Use of proton pump inhibitors, H2 antagonists, and antacids is allowed, with 
restrictions 
• 
Tesevatinib is a MATE inhibitor.  MATE transporter substrates and/or 
inhibitors should be used with caution 
Safety assessments 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE; Version 4.03 - www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-
%20DMCC.pdf) will be used for grading toxicities.  Safety assessments will include 
adverse events (AEs), serious adverse events (SAEs), physical examinations (PEs), vital 
sign measurements, clinical safety laboratory evaluations (hematology, serum 
chemistry, and urinalysis), ECOG scores, and ECGs. 
The AE reporting period for a subject enrolled in the study begins when the subject 
provides informed consent and is continued through 30 days after the last dose of study 
drug or until start of new treatment. All AEs that occur in enrolled subjects during the 
AE reporting period specified in the protocol must be recorded, regardless of the 
relationship of the AE to study drug. Any known untoward event that occurs beyond the 
AE reporting period that the investigator assesses as possibly related to tesevatinib 
should be reported to Kadmon. 
Vital sign measurements, including sitting blood pressure, pulse rate, respiratory rate, 
and temperature will be monitored throughout the study. 
If ≥ Grade 3 CTCAE AEs occur that are determined to be at least possibly related to 
study drug (with the exception of asymptomatic Grade 3 elevations of amylase or lipase, 
Grade 3 elevation of alkaline phosphatase in a subject known to have bone metastases, 
Grade 3 elevation of glucose in a subject receiving systemic corticosteroids, Grade 3 
creatine phosphokinase [CPK] elevation in the absence of muscle symptoms, or Grade 3 
sodium values ≥126 mmol/L in a subject with diarrhea), tesevatinib will be withheld 
until all drug-related toxicities have resolved to ≤ Grade 1. 
If the QTc(F) interval increases to the level of ≥ 500 msec study drug should be 
withheld and appropriate investigations undertaken. 
Pharmacokinetic 
Evaluation 
For patients in Cohort B, PK samples will be drawn to evaluate tesevatinib 
pharmacokinetics.  A plasma sample for tesevatinib PK analysis will be obtained at predose 
on Day 14 of Cycle 1 and at predose on Day 1 of Cycle 3.  A plasma sample also will be 
obtained on Cycle 1 Day 14 and on Cycle 3 Day 1, within 4–8 hours after tesevatinib 
administration (i.e., at approximately the same time the CSF PK sample is obtained). 
CSF PK samples will be obtained on Cycle 1 Day 14 and on Cycle 3 Day 1, within 4–8 
hours after tesevatinib administration.  
For all cohorts, additional samples for the preparation of plasma will be collected for 
tesevatinib analyses if the QTc(F) interval increases to the level of ≥ 500 msec (sample to 
be drawn as soon as possible after ECG performed). 
Pharmacodynamic 
Evaluation 
For all subjects, a plasma cell free DNA sample will be obtained at screening in order to 
correlate response with EGFR DNA mutations seen in plasma cell free DNA at screening. 
For subjects with LM (Cohort B), NSCLC cells in the CSF will be evaluated by both 
 
 
 
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standard cytology and by a central rare cell detection methodology at Screening, on Day 14 
of Cycle 1, and on Day 1 of Cycle 3. Samples will be evaluated for EGFR mutations (both 
the EGFR mutation or mutations known to be present in the tumor of a particular subject by 
prior investigation as well as for the T790M mutation and other EGFR mutations) as well 
as by immunochemistry for EGFR expression and phosphorylation. 
Efficacy 
For subjects with BM (Cohort A and Cohort C) efficacy will be evaluated by RECIST 
1.1 criteria separately for non-CNS tumor lesions and for BMs at screening, at Cycle 2 
Day 1 (for BM), at Cycle 3, and then every 2 cycles (approximately 8 weeks) thereafter 
until disease progression. 
For subjects with LM (Cohort B), symptoms attributed to leptomeningeal disease will 
be evaluated at screening, Cycle 1 Day 1, at Cycle 1 Day 14, at Cycle 2 Day 1, at Cycle 
3, and then every 2 cycles (approximately 8 weeks) thereafter until disease progression.  
CTCAE v4.03 (www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-
%20DMCC.pdf ) will be utilized for the evaluation of symptoms and signs attributed to 
leptomeningeal disease. Symptom improvement is defined as a decrease in 1 grade in at 
least one CTCAE v4.03 symptom or sign attributed to leptomeningeal metastases 
without worsening of other symptoms or signs that are attributed to leptomeningeal 
metastases.  Symptom progression is defined as an increase of 1 grade in at least one 
CTCAE v4.03 symptom or the appearance of new symptoms or signs of LM.  
Symptoms or signs attributed to leptomeningeal metastases will be followed as one 
component of the efficacy evaluation for Cohort B. 
In addition to bone scan at screening, scans of the thorax and abdomen will be 
performed at screening, at Cycle 3, and then every two cycles thereafter until disease 
progression.  Radiological disease assessments by brain MRI will be performed at 
screening, at Cycle 2 Day 1, at Cycle 3 Day 1, and then every two cycles until disease 
progression. Response for peripheral disease and for BM will be evaluated according to 
RECIST, Version 1.1.  Response will be recorded separately for non-CNS disease, for BM, 
and for LM.  All CT and MRI scans will be collected for central review.  All clinical 
decisions during the study will be based on local site radiology assessments, which will also 
be used for the primary efficacy analysis. 
For subjects with LM (Cohort B), NSCLC cells in the CSF will be evaluated during the 
study (screening, Day 14 of Cycle 1, and on Day 1 of Cycle 3) for malignant cells both 
by standard cytological analysis and by a rare cell detection methodology.  CSF 
obtained at the same time points will be evaluated for protein and glucose levels. 
Response will be based on standard cytological analysis if cytology was positive at 
screening.  Response categories will be complete response (CR) (no malignant cells, 
which must be present on 2 consecutive CSF evaluations to support response of CR), 
and non-PR, non-progressive disease (PD) (continued presence of malignant cells).  PD 
will not be defined by CSF cytology. 
For subjects with LM (Cohort B), CSF for isolation of cell-free DNA will be collected 
at screening, Day 14 of Cycle 1, and on Day 1 of Cycle 3.  Evaluation for EGFR 
mutations will be performed.  Quantitation of EGFR mutations in cell-free DNA will be 
utilized for an exploratory efficacy analysis. 
LM will also be evaluated by serial MRI of the brain.  For patients with positive 
findings of LM on MRI at screening, response categories will be CR (no evidence of 
 
 
 
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LM on MRI), or non-PR, non-PD (continued presence of evidence of LM on MRI).  PD 
for LM will not be defined by MRI. 
The response efficacy endpoints will be evaluated separately for peripheral disease, for 
BM, and for LM, and a summary response will also be derived (See Table 14-1).  For 
LM, if positive CSF cytology and MRI diagnostic findings were both present at 
screening, CR requires the absence of LM by both modalities.  Best overall response, 
duration of response, and duration of stable disease will be reported, based on the 
examples in Table 14-1. PFS, rate of CNS non-progression at 3 and 6 months, non-CNS 
TTP, and CNS TTP, and OS also will be assessed.  
Subjects with limited CNS or extra-CNS disease progression (oligoprogressive disease) 
may receive local ablative therapy (radiation therapy or surgery) and then be continued 
on tesevatinib.  This practice is consistent with data indicating that some patients with 
NSCLC on TKI therapy who have oligoprogressive disease appear to have significant 
periods of additional disease control with this approach.16 Any such patients will be 
considered to have disease progression for analyses of PFS and for analyses of 
progression in the relevant (CNS or extra-CNS) compartment at the time of detection of 
oligoprogressive disease.  
Subjects with scans that are on the “borderline” of disease progression (e.g. 21% 
increase in sum of target lesion diameters or equivocal findings on CSF cytology or 
MRI) but for whom the investigator determines a clinical benefit may occur in the 
study.  These subjects will be allowed to continue in the study after discussion with the 
medical monitor.  If improvement is documented at the next subsequent staging time 
point (e.g. 17% increase in sum of target lesion diameters or stable CNS symptoms), the 
subject will continue on study.  If worsening is documented (e.g. 30% increase in sum 
of target lesion diameters or worsening of CNS symptoms), the subject should be 
discontinued from the study, and the progression date should be the original date on 
which “borderline” disease progression was first documented.  If stable, then they will 
be followed until improvement or worsening occurs. 
Quality of Life 
QOL will be evaluated via the EORTC QLQ-C30 and EORTC QLQ-BN20 questionnaires 
administered at Screening, on Day 1 of Cycle 3, and on Day 1 of odd-numbered cycles 
thereafter. 
Statistical methods 
For Cohort A, assuming that 20% of subjects with BM have RECIST 1.1 response (CR or 
PR), the study has an approximately 80% chance of having at least 3 subjects with RECIST 
1.1 response, and an over 90% chance of at least 2 subjects having a response.  All subjects 
who take at least one dose of study drug will be evaluable for safety and efficacy 
assessments. 
For Cohort B, assuming that 20% of subjects with LM have improvement in at least one 
symptom or sign attributed to leptomeningeal metastases, the study has an approximately 
80% chance of having at least 3 subjects with improvement in at least one symptom or sign 
attributed to leptomeningeal metastases and an over 90% chance of at least 2 subjects 
having improvement.  All subjects who take at least one dose of study drug will be 
evaluable for safety and efficacy assessments.   
For Cohort C, assuming that 20% of subjects with BM have RECIST 1.1 response (CR 
or PR), the study has an approximately 80% chance of having at least 3 subjects with 
 
 
 
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Amendment 4 
 
RECIST 1.1 response, and an over 90% chance of at least 2 subjects having a response.  
All subjects who take at least one dose of study drug will be evaluable for safety and 
efficacy assessments. 
Treatment-emergent AEs will be summarized using the Medical Dictionary for 
Regulatory Activities (MedDRA®) (Version 18.1 or higher) System Organ Class (SOC) 
and preferred term, classified from verbatim terms. The incidence and percentage of 
subjects with at least one occurrence of a preferred term will be included, according to 
the most severe grade using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE; Version 4.03). The number of events per 
preferred term will also be summarized.  Causality (relationship to study treatment) will 
be summarized separately. 
AEs, SAEs, related AEs, related SAEs, ≥ Grade 3 AEs, related ≥ Grade 3 AEs, and AEs 
leading to withdrawal, dose modification, or treatment discontinuation will be 
summarized by cohort and tesevatinib overall according to SOC and preferred terms.  
AEs will also be summarized in listings. Duration of AEs will be determined and 
included in listings, along with action taken and outcome. 
Descriptive statistics including 95% confidence intervals for improvement in symptoms 
attributed to leptomeningeal metastases, clearing of NSCLC cells in the CSF, and 
clearing of CNS MRI findings will be presented.  Exploratory evaluation of efficacy 
results by EGFR mutation will be performed. 
In addition, identical statistics for the change and percent change from Cycle 1 Day 1 
tumor measurements will be presented. These analyses will be done after each two 
cycles of therapy, and will include peripheral (non-CNS) tumors as well as brain 
metastases. Summary statistics will be produced for PFS and OS. The percentage of 
subjects without disease progression after 3 and 6 months of dosing will also be 
presented separately by local and central radiograph results.  
Laboratory results will be classified according to NCI-CTCAE Version 4.03 and 
summarized by cohort. Laboratory results not corresponding to a coded term will not be 
graded. 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 ≥ Grade 3 
laboratory abnormalities under treatment and shifts in toxicity grading from Cycle 1 
Day 1 to highest grade post-Cycle 1 Day 1 will be displayed. Results for variables that 
are not coded will be presented in the listings as below, within, and above the normal 
limits of the local laboratory.  
Vital sign measurements will be summarized at each scheduled time point using 
descriptive statistics.  ECOG performance status results will be summarized by 
scheduled time point. Additional statistical details will be provided in a prospective 
statistical plan. 
Tesevatinib concentrations in the plasma and CSF will be summarized at each 
scheduled collection time point using descriptive statistics, and displayed graphically. 
 
 
 
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Page 22 of 129 
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Tesevatinib 
Protocol Number KD019-206 
Amendment 4 
 
Table 4-1: 
Study Assessments for Cohort A – Brain Metastases and Cohort C - Brain Metastases at Initial Presentation 
Timepoint  
(Study Day) 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7+ 
EOS Txk 
30-Day 
FU l 
(± 5d) 
LTFU 
UNSm 
-29 to -1 Day 1 
Day 7 
(± 3d) 
Day 14 
(± 3d) 
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1  
(± 3d) 
Day 1  (± 
3d) 
Day 1  
(± 3d) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Score 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Safety Labsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy Testd 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-Lead ECGe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Tumor Assessmentf 
X 
 
 
 
Xf 
X 
 
X 
 
X 
X 
 
 
 
Bone scang 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tesevatinib 
Administrationh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Plasma Cell-free DNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
QOL questionnairesi 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
Concomitant Medications 
To be collected from the time of informed consent through 30 days after last dose of study drug. 
AE Monitoringj 
To be collected from the time of informed consent through 30 days after last dose of study drug. 
Collect/Dispense Study 
Drug 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect/Dispense Study 
Drug Diary 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Follow-Up Phone Contact 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
 
d = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = end of study; FU = follow-up; LTFU = long-term follow-up; MRI = magnetic resonance imaging; 
PK = pharmacokinetic; QOL = quality of life; UNS = unscheduled; Tx = treatment 
 
a: 
At screening, PE to include height and weight. Complete PE including weight is required at all visits except for Days 7 and 14 of Cycle 1, when an abbreviated PE is acceptable (to be 
completed in a targeted manner covering related body systems). 
b: 
Vital sign measurements (blood pressure, heart rate, respiratory rate, and temperature) to be obtained after the subject has been sitting for 5 minutes.  On Cycle 1, Day 1, and Cycle 1, 
Day 14 vital signs are to be measured predose and 1 and 4 hours postdose. 
 
 
  
Kadmon Corporation 
 
 
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Tesevatinib 
Protocol Number KD019-206 
Amendment 4 
 
c: 
Safety labs = hematology and clinical chemistry and urinalysis.  Note that Cycle 1 Day 1 labs need not be repeated if screening visit occurred within 4 days prior to Day 1 visit.  Safety 
labs will also be done at C2D15, C3D15, C4D15, C5D15, and C6D15; they are to be done locally and will include serum chemistry only.  There will be a 3 day window for the D15 
chemistry labs.  Cystatin C does not need to be included in the chemistry labs done on C2D15, C3D15, C4D15, C5D15, and C6D15. 
d: 
Pregnancy tests will be done using urine samples in women of childbearing potential.  Subject must have a negative urine pregnancy test documented within the 24-hour period prior to 
the first dose of study drug.  Confirm with serum testing if urine sample is positive.. 
e: 
Supine 12-Lead ECGs will be performed at screening; Days 1, 7 and 14 of Cycle 1; on Day 1 of Cycles 2 and Day 1 of each Cycle including at End of Study Drug Treatment visit 
Assessment to be performed at predose, and once within 4 – 8 hours postdose for Days 1, 7 and 14 of Cycle 1.  At each timepoint, repeat ECG three times consecutively within 
30 minutes (must have an interval of at least 1–2 minutes between ECGs).  
f: 
Tumor assessment is to be performed at screening, at C2D1, on C3D1, and after every 2 cycles (beginning on Day 1 of Cycle 3 [± 7 days]).  Tumor assessment should include brain 
MRI.  Peripheral (non-CNS) tumor may be assessed with either CT or MRI, but method of assessment should be the same throughout the study.  Tumor assessment on C2D1 will be 
limited to brain MRI. 
g: 
Bone scans are to be performed at screening and then as clinically indicated.   
h: 
Tesevatinib will be administered at the dose of 300 mg once daily.   
i: 
EORTC QLQ-C30 and EORTC QLQ-BN20 questionnaires administered at screening, on Day 1 of Cycle 3, and on Day 1 of odd-numbered cycles thereafter and EOS 
j: 
AEs are to be collected from the time of informed consent through 30 days after last dose of study drug.   
k: 
The End-of-Study Drug Treatment visit is to occur within 3 days after the subject’s last dose of study drug.  This may occur at the visit at which disease progression is diagnosed. 
Tumor assessment does not need to be performed if it was performed in the previous 8 weeks.   
l: 
The 30-Day Follow-Up visit should occur 30 days (±5 days) after the subjects’ last dose of tesevatinib, but prior to starting on a new therapy.  This may occur prior to 30 days if the 
new therapy is started within 30 days of last dose of study drug.   
m: For unscheduled visits, study assessments are at the investigator’s discretion. 
n: 
Subjects are to be contacted by telephone every 8 weeks to assess survival status and any subsequent anti-cancer treatment. 
 
 
  
Kadmon Corporation 
 
 
Page 24 of 129 
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Tesevatinib 
Protocol Number KD019-206 
Amendment 4 
 
Table 4-2: 
Study Assessments for Cohort B – Leptomeningeal Metastases 
Timepoint  
(Study Day) 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7+ 
EOS Txn 
30-Day 
FU o 
(± 5d) 
LTFU 
UNSp 
-29 to -1 Day 1 
Day 7 
(± 3d) 
Day 14 
(± 3d) 
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1  
(± 3d) 
Day 1  (± 
3d) 
Day 1  
(± 3d) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Score 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Safety Labsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy Testd 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-Lead ECGe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Tumor Assessmentf 
X 
 
 
 
Xf 
X 
 
X 
 
X 
X 
 
 
 
Evaluation of LM 
Symptoms 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
 
Bone scang 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tesevatinib 
Administrationh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Plasma PK Samplingi 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Plasma Cell-free DNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSF PK Samplingj 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
CSF Cytology and Cell-free 
DNAk 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
QOL questionnairesl 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
Concomitant Medications 
To be collected from the time of informed consent through 30 days after last dose of study drug. 
AE Monitoringm 
To be collected from the time of informed consent through 30 days after last dose of study drug. 
Collect/Dispense Study 
Drug 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect/Dispense Study 
Drug Diary 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Follow-Up Phone Contact 
 
 
 
 
 
 
 
 
 
 
 
 
Xq 
 
 
 
 
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Page 25 of 129 
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Final 01 August 2017 
 
 


Tesevatinib 
Protocol Number KD019-206 
Amendment 4 
 
CSF = cerebrospinal fluid; CT = computed tomography; d = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = end of study; FU = follow-up; LTFU = 
long-term follow-up; MRI = magnetic resonance imaging; PK = pharmacokinetic; QOL = quality of life; UNS = unscheduled; Tx = treatment 
 
a: 
At screening, PE to include height and weight. Complete PE including weight is required at all visits except for Days 7 and 14 of Cycle 1, when an abbreviated PE is acceptable (to be 
completed in a targeted manner covering related body systems). 
b: 
Vital sign measurements (blood pressure, heart rate, respiratory rate, and temperature) to be obtained after the subject has been sitting for 5 minutes..  On Cycle 1, Day 1, and Cycle 1, 
Day 14 vital signs are to be measured predose and 1 and 4 hours postdose. 
c: 
Safety labs = hematology and clinical chemistry and urinalysis.  Note that Cycle 1 Day 1 labs need not be repeated if screening visit occurred within 4 days prior to Day 1 visit.  Safety 
labs will also be done at C2D15, C3D15, C4D15, C5D15, and C6D15; they are to be done locally and will include serum chemistry only.  There will be a 3 day window for the D15 
chemistry labs.  Cystatin C does not need to be included in the chemistry labs done on C2D15, C3D15, C4D15, C5D15, and C6D15. 
d: 
Pregnancy tests will be done using urine samples in women of childbearing potential.  Subject must have a negative urine pregnancy test documented within the 24-hour period prior to 
the first dose of study drug.  Confirm with serum testing if urine sample is positive. 
e: 
Supine 12-Lead ECGs will be performed at screening; Days 1, 7 and 14 of Cycle 1; on Day 1 of Cycles 2 and Day 1 of each Cycle including at End of Study Drug Treatment visit 
Assessment to be performed at predose and once within 4 – 8 hours postdose for Days 1, 7, and 14 of Cycle 1.  At each timepoint, repeat ECG three times consecutively within 
30 minutes (must have an interval of at least 1–2 minutes between ECGs).  
f: 
Tumor assessment is to be performed at screening, C2D1, C3D1, and after every 2 cycles (beginning on Day 1 of Cycle 3 [± 7 days]).  Tumor assessment should include brain MRI.  
Peripheral (non-CNS) tumor may be assessed with either CT or MRI, but method of assessment should be the same throughout the study.  Tumor assessment on C2D1 will be limited to 
brain MRI. 
g: 
Bone scans are to be performed at screening and then as clinically indicated.  
h: 
Tesevatinib will be administered at the dose of 300 mg once daily.    
i: 
A plasma sample for tesevatinib PK analysis will be obtained at predose on Day 14 of Cycle 1 and at predose on Day 1 of Cycle 3.  A tesevatinib plasma sample also will be obtained 
on Cycle 1 Day 14, and Cycle 3 Day 1, within 4–8 hours after tesevatinib administration (at approximately the same time the CSF PK sample is obtained). Additional samples for the 
preparation of plasma will be collected for tesevatinib analyses if the QTc(F) interval increases to ≥ 500 msec (sample to be drawn as soon as possible after ECG performed). 
j: 
CSF PK samples will be obtained on Cycle 1 Day 14 and on Cycle 3 Day 1 at 4-8 hours after administration of the tesevatinib dose that day.   
k: 
NSCLC cells in the CSF will be evaluated at screening, on day 14 of Cycle 1, and on Cycle 3 Day 1 and will be evaluated for EGFR mutations (both the EGFR mutation or mutations 
known to be present in the tumor of a particular patient by prior investigation as well as for the T790M mutation) as well as by immunochemistry for EGFR expression and 
phosphorylation.  Samples will be drawn both for standard cytological analysis as well as for a rare cell detection methodology.  CSF for cell-free DNA isolation will be obtained at the 
same times (screening, on day 14 of Cycle 1 and on Cycle 3 Day1) and will be evaluated for EGFR mutations and the amount of cell-free DNA present.  In cases where CSF is limiting, 
samples will first be sent for CSF cytology, glucose, and protein, second for CSF tesevatinib PK, third for rare cell detection, and last for cell-free DNA. 
l: 
EORTC QLQ-C30 and EORTC QLQ-BN20 questionnaires administered at screening, on Day 1 of Cycle 3, and on Day 1 of odd-numbered cycles thereafter and EOS. 
m: AEs are to be collected from the time of informed consent through 30 days after last dose of study drug.   
n: 
The End-of-Study Drug Treatment visit is to occur within 3 days after the subject’s last dose of study drug. This may occur at the visit at which disease progression is diagnosed. Tumor 
assessment does not need to be performed if it was performed in the previous 8 weeks. 
o: 
The 30-Day Follow-Up visit should occur 30 days (±5 days) after the subjects’ last dose of tesevatinib, but prior to starting on a new therapy.  This may occur prior to 30 days if the 
new therapy is started within 30 days of last dose of study drug.   
p: 
For unscheduled visits, study assessments are at the investigator’s discretion. 
q: 
Subjects are to be contacted by telephone every 8 weeks to assess survival status and any subsequent anti-cancer treatment. 
 
 
 
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Page 26 of 129 
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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
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 .............................................................. 33 
5.1 
Tesevatinib...................................................................................................................... 33 
5.1.1 
Tesevatinib Nonclinical Toxicology ................................................................................. 33 
5.1.2 
Clinical Experience with Tesevatinib ............................................................................... 33 
5.2 
Safety Profile of Tesevatinib ......................................................................................... 35 
5.2.1 
Tesevatinib ........................................................................................................................ 35 
5.3 
Rationale ......................................................................................................................... 39 
5.3.1 
Study Rationale ................................................................................................................. 39 
5.3.2 
Rationale for Dosage Selection ......................................................................................... 41 
5.4 
Compliance Statement ................................................................................................... 41 
5.4.1 
Good Clinical Practice ...................................................................................................... 42 
6 
STUDY OBJECTIVES ....................................................................................... 43 
7 
STUDY DESIGN ................................................................................................. 45 
7.1 
Study Sites ...................................................................................................................... 45 
7.2 
Overview of Study Design ............................................................................................. 45 
7.3 
Randomization and Blinding ........................................................................................ 45 
8 
STUDY POPULATION ..................................................................................... 46 
8.1 
Target Population .......................................................................................................... 46 
8.2 
Inclusion Criteria – Cohort A ....................................................................................... 46 
8.3 
Exclusion Criteria – Cohort A ...................................................................................... 48 
8.4 
Inclusion Criteria – Cohort B ....................................................................................... 49 
8.5 
Exclusion Criteria – Cohort B ...................................................................................... 51 
8.6 
Inclusion Criteria – Cohort C ....................................................................................... 52 
8.7 
Exclusion Criteria – Cohort C ...................................................................................... 54 
9 
STUDY ASSESSMENTS AND PROCEDURES ............................................. 56 
9.1 
Procedures to be Performed ......................................................................................... 56 
9.1.1 
Informed Consent ............................................................................................................. 56 
9.1.2 
Demographics and Medical History ................................................................................. 56 
9.1.3 
Complete and Symptom-Directed Physical Examinations ............................................... 56 
9.1.4 
Vital Sign Measurements .................................................................................................. 56 
9.1.5 
ECOG Performance Status ............................................................................................... 57 
9.1.6 
Hematology, Serum Chemistries, and Urinalysis ............................................................. 57 
9.1.7 
Pregnancy Test .................................................................................................................. 58 
9.1.8 
12-Lead Electrocardiogram (ECG) ................................................................................... 58 
9.1.9 
Bone Imaging .................................................................................................................... 60 
9.1.10 
Lumbar Puncture (LP) – Cohort B Only ........................................................................... 60 
9.1.11 
Pharmacokinetics – Cohort B Only .................................................................................. 60 
9.1.12 
Tesevatinib Administration ............................................................................................... 60 
9.1.13 
Tumor Assessments .......................................................................................................... 61 
 
 
 
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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
9.1.14 
Quality of Life Questionnaires.......................................................................................... 61 
9.1.15 
Study Diary ....................................................................................................................... 61 
9.1.16 
Prior and Concomitant Medications ................................................................................. 61 
9.1.17 
Adverse Event Assessments ............................................................................................. 61 
9.2 
Schedule of Visits ........................................................................................................... 62 
9.2.1 
Screening Visit .................................................................................................................. 62 
9.2.2 
Cycle 1, Day 1 .................................................................................................................. 62 
9.2.3 
Cycle 1, Day 7 .................................................................................................................. 63 
9.2.4 
Cycle 1, Day 14 ................................................................................................................ 63 
9.2.5 
Cycle 2, Day 1 .................................................................................................................. 64 
9.2.6 
Cycle 3, Day 1 .................................................................................................................. 64 
9.2.7 
Cycle 4, Day 1 .................................................................................................................. 65 
9.2.8 
Cycles 5+, Day 1 ............................................................................................................... 66 
9.2.9 
Day 15 on Cycle 2 through Cycle 6 .................................................................................. 66 
9.2.10 
End-of-Study Drug Treatment Visit ................................................................................. 66 
9.2.11 
30-Day Follow-Up ............................................................................................................ 67 
9.2.12 
Follow-Up Phone Contact ................................................................................................ 67 
9.2.13 
Unscheduled/AE Resolution Visits: To Occur as Needed ................................................ 67 
10 
REMOVING SUBJECTS FROM STUDY ....................................................... 69 
10.1 Subject Withdrawal ....................................................................................................... 69 
10.1.1 
Subject Treatment Discontinuation ................................................................................... 69 
10.1.2 
Subject Study Termination ............................................................................................... 69 
10.2 Study Discontinuation ................................................................................................... 70 
10.3 Replacements .................................................................................................................. 70 
11 
STUDY DRUG .................................................................................................... 71 
11.1 Tesevatinib (KD019) ...................................................................................................... 71 
11.1.1 
Tesevatinib Administration ............................................................................................... 71 
11.1.2 
Dose Modifications and Delays for Toxicity Related to Study Drug ............................... 72 
11.1.3 
Tesevatinib:  Warnings, Precautions, and Management ................................................... 72 
11.2 Study Drug Accountability and Subject Treatment Compliance ............................. 77 
12 
CONCOMITANT MEDICATION AND TREATMENT ............................... 79 
12.1 Additional Therapy ....................................................................................................... 80 
12.2 Additional Anti-Cancer Treatment and Radiotherapy.............................................. 80 
12.3 Interaction of Tesevatinib with Other Medications ................................................... 80 
12.3.1 
Management of Subjects Requiring Concomitant Medications Associated with QT 
Interval Prolongation .......................................................................................................................... 81 
13 
PHARMACOKINETICS AND PHARMACODYNAMICS .......................... 83 
13.1 Plasma and CSF Pharmacokinetics ............................................................................. 83 
13.2 CSF Pharmacodynamics ............................................................................................... 83 
14 
EFFICACY .......................................................................................................... 84 
14.1 Cohort A and Cohort C– Brain Metastases ................................................................ 86 
14.2 Cohort B – Leptomeningeal Metastases ...................................................................... 86 
15 
SAFETY ............................................................................................................... 87 
15.1 Safety Parameters .......................................................................................................... 87 
15.2 Adverse Event Definition .............................................................................................. 87 
15.3 Evaluating Adverse Events ........................................................................................... 88 
 
 
 
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Page 28 of 129 
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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
15.3.1 
Serious Adverse Events .................................................................................................... 88 
15.3.2 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ........................................... 89 
15.3.3 
Unexpected Adverse Events ............................................................................................. 89 
15.3.4 
Non-Serious Adverse Events ............................................................................................ 90 
15.3.5 
Protocol-Related Adverse Events ..................................................................................... 90 
15.3.6 
Relationship/Causality to Study Drug .............................................................................. 90 
15.3.7 
Recording Adverse Events ................................................................................................ 90 
15.3.8 
Adverse Event Monitoring and Follow-Up ...................................................................... 90 
15.3.9 
Laboratory and ECG Abnormalities ................................................................................. 90 
15.3.10 
Pregnancy.......................................................................................................................... 91 
15.3.11 
Serious Adverse Event Reporting ..................................................................................... 92 
15.3.12 
Regulatory Reporting ........................................................................................................ 94 
15.3.13 
Follow-up Information on a Serious Adverse Event ........................................................ 94 
15.4 Other Safety Considerations ......................................................................................... 95 
15.4.1 
Medication Errors ............................................................................................................. 95 
15.4.2 
Follow-Up of Serious Adverse Events ............................................................................. 95 
16 
STATISTICAL CONSIDERATIONS .............................................................. 96 
16.1 General Design ............................................................................................................... 96 
16.2 Sample Size Justification ............................................................................................... 96 
16.3 Statistical Considerations .............................................................................................. 97 
16.3.1 
Study Populations ............................................................................................................. 97 
16.3.2 
Subject Accountability, Demographics, and Cycle 1 Day 1 Characteristics .................... 97 
16.3.3 
Tesevatinib Exposure ........................................................................................................ 97 
16.3.4 
Concomitant Medications ................................................................................................. 97 
16.3.5 
Pharmacokinetics .............................................................................................................. 97 
16.3.6 
Efficacy/Activity ............................................................................................................... 98 
16.3.7 
Safety Data ........................................................................................................................ 98 
17 
DATA QUALITY ASSURANCE .................................................................... 100 
18 
ETHICAL ASPECTS ....................................................................................... 101 
18.1 Local Regulations......................................................................................................... 101 
18.2 Informed Consent ........................................................................................................ 101 
18.3 Institutional Review Board ......................................................................................... 102 
18.4 Future Use of Subject Samples ................................................................................... 102 
19 
CONDITIONS FOR MODIFYING THE PROTOCOL ............................... 103 
20 
CONDITIONS FOR TERMINATING THE STUDY ................................... 104 
21 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING ............ 105 
21.1 Investigator’s Files and Retention of Documents ..................................................... 105 
21.2 Source Documents and Background Data ................................................................. 106 
21.3 Audits and Inspections ................................................................................................ 106 
21.4 Electronic Case Report Forms ................................................................................... 107 
22 
MONITORING THE STUDY ......................................................................... 108 
23 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS ......................................................................................................... 109 
24 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 110 
 
 
 
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Page 29 of 129 
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Final 03October 2017 
 
 


Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
25 
REFERENCES .................................................................................................. 111 
Appendix A: Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 ...... 113 
Appendix B: ECOG Performance Status Criteria ............................................................... 119 
Appendix C: QTc(F) Calculation ........................................................................................... 120 
Appendix D: Concomitant Drugs That Should Be Used with Caution* ............................ 121 
Appendix E: Concomitant Medications Associated With a Risk of QTc(F) Interval 
Prolongation and/or Torsades de Pointes ....................................................... 124 
Appendix F: Topical Steroid Potency Chart ........................................................................ 125 
Appendix G: EORTC QLQ-C30 Questionnaire ................................................................... 127 
Appendix H: EORTC QLQ-BN20 Questionnaire (one page) .............................................. 129 
 
LIST OF TABLES 
Table 4-1: Study Assessments for Cohort A – Brain Metastases and Cohort C - Brain Metastases 
at Initial Presentation .................................................................................................. 23 
Table 4-2: Study Assessments for Cohort B – Leptomeningeal Metastases ................................ 25 
Table 9-1: Clinical Laboratory Panels .......................................................................................... 58 
Table 14-1: Summary Response Examples .................................................................................. 85 
 
 
 
 
 
 
Kadmon Corporation 
Page 30 of 129 
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Final 03October 2017 
 
 


Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
LIST OF ABBREVIATIONS 
ADPKD 
autosomal dominant polycystic kidney disease 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CSF 
cerebrospinal fluid 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity  
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
HER2 
human epidermal growth factor receptor 2 
ICH 
International Conference on Harmonization 
ICF 
informed consent form 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
LLN 
lower limit of normal 
LM 
leptomeningeal metastases 
LP 
lumbar puncture 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NSCLC 
non-small cell lung cancer 
OS 
overall survival 
PD 
progressive disease 
 
 
 
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PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PT 
prothrombin time 
QD 
once daily 
QOL 
quality of life 
QTc(F) 
QT interval, corrected 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RTK 
receptor tyrosine kinases  
SADR 
suspected adverse drug reactions; also referred to as SAR 
SAE 
serious adverse event 
SAR 
suspected adverse reactions; also referred to as SADR 
SOC 
system organ class  
Src 
sarcoma 
SSRI 
selective serotonin reuptake inhibitor 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse event 
TKI 
tyrosine kinase inhibitor  
TTP 
time to progression 
ULN 
upper limit of normal 
VEGFR2 
vascular endothelial growth factor receptor 2 
 
 
 
 
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5 
BACKGROUND AND RATIONALE 
5.1 
Tesevatinib  
Tesevatinib (formerly known as KD019) is an orally administered tyrosine kinase inhibitor, 
which has been documented to inhibit multiple molecular drivers of tumor growth, including 
epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2(HER2), 
Src, and VEGFR2. 
Tesevatinib is a highly potent inhibitor of the EGFR activating mutations that, when present, 
drive the growth of non-small cell lung cancers (NSCLCs). When measured in HCC827 cells, 
which are human lung cancer cells with an EGFR exon 19 deletion, the IC50 for inhibition of 
EGFR phosphorylation for tesevatinib (0.6 nM) was very similar to that for erlotinib (0.8 nM). 
The IC50 for inhibition of proliferation in the same cell line was 3.5 nM for tesevatinib and 
4.6 nM for erlotinib. Thus tesevatinib and erlotinib have similar potency in vitro against a cell 
line with an activating EGFR mutation. 
5.1.1 
Tesevatinib Nonclinical Toxicology  
Tesevatinib nonclinical toxicology has been characterized in multiple species using a variety of 
dosing regimens. Details are provided in the Investigator’s Brochure. 
5.1.2 
Clinical Experience with Tesevatinib 
Tesevatinib has been evaluated in two single-agent Phase 1 studies in subjects with advanced 
solid tumors (Studies XL647-001 and XL647-002), in two single-agent Phase 2 studies in 
subjects with NSCLC (Studies XL647-201 and XL647-203), and in a Phase 3 study (Study 
KD019-301) in NSCLC that only enrolled 8 patients. Tesevatinib is also being evaluated in a 
Phase 1/2 study in subjects with HER2+ metastatic breast cancer, and in a Phase 1/2 study in 
subjects with autosomal dominant polycystic kidney disease (ADPKD). 
5.1.2.1 Phase 1 
The single-agent tesevatinib Phase 1 study (XL647-002) concluded that the maximum tolerated 
dose (MTD) for daily dosing of tesevatinib was 300 mg daily because two subjects who received 
350 mg daily had Grade 3 QTc prolongation (>500 ms).  However, when these were later 
reviewed by a central cardiology review, they were both downgraded to Grade 2. In one case, the 
site QTc reading was confounded by a new right bundle branch block and, in the other case, by 
bradycardia. Thus, due to these complicating issues, the MTD for daily administration of 
tesevatinib was evaluated further in combination with trastuzumab in the ongoing study in 
patients with HER2+ breast cancer.  The MTD of 300 mg daily was recently confirmed in the 
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breast cancer study.  This study and others have also determined that tesevatinib has a prolonged 
half-life of approximately 60 hours. 
The other single-agent tesevatinib Phase 1 study (XL647-001) evaluated a schedule of 5 days of 
tesevatinib administered every 2 weeks. This study initially used a powder-in-capsule 
preparation of tesevatinib. At 7 mg/kg, the only two subjects treated both had Grade 3 diarrhea. 
In one subject (11032), the Grade 3 diarrhea occurred on Day 4 of the study and diarrhea 
resolved on Day 8.  In the other subject (11034), the Grade 3 diarrhea occurred on Day 7 and 
diarrhea resolved on Day 25. The next lowest dose, 4.68 mg/kg, was determined to provide 
similar exposure to 350 mg given as formulated tablets, which was called the MTD for this 
schedule.  However, this study was performed from 2004-2007 when aggressively treating 
diarrhea due to EGFR inhibitors was not necessarily routine.  It is unknown whether 350 mg 
administered for 5 days every 2 weeks would be considered to be the MTD if subjects had 
aggressive diarrhea management. 
5.1.2.2 Phase 2 
The first of the two single-agent Phase 2 studies in NSCLC (Study XL647-201) enrolled 
treatment naïve patients with advanced stage NSCLC who were Asian, female, or with minimal 
or no smoking history.17 There were 41 subjects enrolled in an intermittent dosing schedule and 
14 enrolled in a daily dosing schedule.  Subjects in the intermittent cohort received tesevatinib at 
a dose of 350 mg for 5 days every 2 weeks. Subjects in the daily dosing cohort received 
tesevatinib administered at a dose of 300 mg daily. Retrospective sequencing of tumor samples 
identified 14/41 subjects with EGFR mutations. The confirmed partial response (PR) rate in 
subjects with EGFR mutations was 57% (8/14), and an additional 3 subjects with EGFR 
mutations had unconfirmed PRs. Response rates were similar in the daily and intermittent 
tesevatinib schedules. Patients with PRs were those whose tumors had Exon 19 deletions as well 
as those with the L858R mutation.  One subject in this study who is on the intermittent schedule 
has had a long-term response lasting nearly five years and is still receiving tesevatinib therapy. 
In the second single-agent tesevatinib study in NSCLC (Study XL647-203), tesevatinib was 
administered daily at a dose of 300 mg/day to 41 subjects with NSCLC who had disease 
progression after treatment with other EGFR inhibitors (erlotinib or gefitinib).18 The most 
frequently reported adverse events (AEs) were diarrhea, nausea, cough, dry skin, and 
electrocardiogram (ECG) QTc prolongation. Two (2) of the 41 subjects experienced QTc(F) 
> 500 msec confirmed by a central cardiology review. (All subjects in all tesevatinib studies with 
QTc prolongation have been asymptomatic.) Eleven subjects (11; 28%) required a dose 
reduction for toxicity, most commonly for diarrhea (27%) and rash (18%). Whether EGFR-
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related diarrhea or rash were treated aggressively is not clear. There were 12 subjects with 
documented T790M EGFR mutations, none of whom had a response to tesevatinib treatment. 
5.1.2.3 Phase 3 
The Phase 3 study (KD019-301) was a double-blind, randomized, and controlled trial of KD019 
vs erlotinib in subjects with Stage IIIB/IV non-small cell lung cancer who had progressed after 
first- or second-line chemotherapy. The study was closed early due to slow enrollment after 8 
subjects were entered. One subject who carried an EGFR activating mutation had a partial 
response to tesevatinib for eight cycles before progressing. 
5.1.2.4 Ongoing Studies in Other Indications 
A Phase 1b/2a study (KD019-204) of the combination of trastuzumab and tesevatinib is ongoing 
in subjects with HER2+ metastatic breast cancer (study KD019-204).  The Phase 1 portion of the 
study used a 3+3 design that is commonly used in oncology studies. The Phase 1 portion of the 
study has determined that 300 mg daily of tesevatinib in combination with trastuzumab is the 
MTD dose, as the two subjects treated with 350 mg daily had Grade 3 events considered to be at 
least possibly related to tesevatinib (one had Grade 3 diarrhea not recovering to Grade 1 by seven 
days, and the other had Grade 3 QTc prolongation confirmed by central reading). 
A Phase 1b/2a study (KD019-101) of tesevatinib in patients with ADPKD is ongoing. Subjects 
with ADPKD, in whom the drug will be administered chronically for years, did not tolerate the 
Grade 2 acneiform skin rash, which occurred in 2/5 patients at 150 mg daily. In addition, there 
were 2/8 patients receiving tesevatinib at a dose of 100 mg daily who had asymptomatic 
prolongation of the QTc duration (one Grade 3 and one Grade 2). Daily doses below 50 mg are 
being evaluated further. 
5.2 
Safety Profile of Tesevatinib 
5.2.1 
Tesevatinib 
AEs that have been associated with tesevatinib include the following: diarrhea, skin rash, QTc(F) 
prolongation, elevated serum creatinine, elevated serum amylase, and interstitial lung disease 
(see Warnings, Precautions, and Management in Section 11.1.3). 
Diarrhea: Diarrhea is an expected AE for agents like tesevatinib that have significant EGFR 
inhibitor activity. Grade 3 diarrhea was the dose-limiting toxicity (DLT) for both the 5 days out 
of 14 days schedule of tesevatinib in study XL647-001 as well as for the daily dosing of 
tesevatinib in the KD019-204 study of tesevatinib in patients with metastatic breast cancer.  At 
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doses below those that cause DLT, diarrhea has generally been manageable with anti-diarrheal 
medications such as loperamide. 
Skin Rash: Acneiform skin rash is an expected AE for agents like tesevatinib that have 
significant EGFR inhibitor activity.  The rash characteristically involves the chest and face.  
Paronychial involvement, although characteristic of EGFR inhibitors, has not been seen in 
tesevatinib studies.   
QTc(F) Prolongation: In clinical trials of tesevatinib, cases of QTc(F) prolongation have been 
observed. 
Common Terminology Criteria for Adverse Events (CTCAE v4.03) 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 
ProlongedQTc(F) 
interval 
 > 450–470 msec > 470–500 msec or 
≥ 60 msec above 
Cycle 1 Day 1 
> 500 msec 
> 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 
v4.03 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 tesevatinib. 
Clinical trial 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). ECGs for a total of 178 of these 
subjects have been reviewed by the central ECG laboratory. 
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. 
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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. 
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. 
A preliminary analysis of delta QTc(F) (change from Cycle 1 Day 1 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 three models (i.e., ~ 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 (i.e., 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. 
In study KD019-101, subjects treated with doses of tesevatinib as low as 100 mg daily have had 
prolongation of QTc(F) of > 60 ms over Cycle 1 Day 1 levels.  In study KD019-204, one of two 
subjects receiving tesevatinib at 350 mg daily in combination with trastuzumab had QTc(F) 
prolongation to > 500 ms, which was a DLT event for that study.  Subjects in this study will be 
monitored carefully for QTc prolongation, and a central laboratory will review all ECGs in this 
study. 
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Elevations of Serum Creatinine:  Data from study KD019-101 indicate that subjects with 
ADPKD receiving tesevatinib have experienced elevations of creatinine without elevations in 
cystatin C.  For instance, 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 two 
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, indicating 
that the increases in serum creatinine may not be reflective of changes in kidney function. Data 
from the subjects other doses of tesevatinib exhibited a similar pattern.  This increase in 
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 trials 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.  The 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.  Increases in 
creatinine appear to be reversible.  Both serum creatinine and cystatin C will be evaluated in this 
study in order to provide more information about any changes in creatinine that occur. 
Elevations of Serum Amylase: There have been occasional cases of asymptomatic elevation of 
serum amylase in subjects treated with tesevatinib. In KD019-101, a study treating subjects with 
polycystic kidney disease at doses up to 150 mg/day, 5 subjects had amylase levels above the 
normal limit, 2 of which had elevated levels at screening.  None had symptoms of clinical 
pancreatitis. 
Previous oncology 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 treatment-emergent adverse event (TEAE) of an increased amylase level or of possible 
pancreatitis.  This was an elevation of amylase to 922 U/L without clinical pancreatitis in a 
subject with Stage IV non-small cell lung cancer who received tesevatinib at a dose of 300 
mg/day.  On serum amylase isoenzyme analysis, the subject had an elevation in salivary 
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amylase.  The investigator’s conclusion was that the subject appeared to have an increase in 
amylase due to salivary amylase secretion by the tumor.  To date, no subjects receiving 
tesevatinib have had symptoms compatible with clinical pancreatitis. 
Interstitial Lung Disease: Non-fatal interstitial lung disease (ILD) has been reported in 
association with the use of tesevatinib in one subject with NSCLC out of >250 subjects exposed 
to tesevatinib. 
5.3 
Rationale 
5.3.1 
Study Rationale  
Subjects with NSCLC with activating EGFR mutations (exon 19 deletions and the L858R point 
mutation) have a high response rate to tyrosine kinase inhibitors (TKIs) such as gefitinib, 
erlotinib or afatinib. However, these are not curative therapies and tumors inevitably develop 
resistance.1,2  The central nervous system (CNS) is a sanctuary site, as gefitinib, erlotinib and 
afatinib penetrate poorly into the brain.  These drugs penetrate even more poorly into the 
cerebrospinal fluid (CSF), with CSF levels documented to be approximately 1% of plasma levels 
for gefitinib and afatinib and 2.5%–13% for erlotinib.3,4,5 Disease progression after initial 
gefitinib or erlotinib treatment involves the CNS in approximately 28% of patients, and includes 
leptomeningeal metastases (LM) in 8%6.  Progression with LM occurs more commonly in 
patients with previous brain metastases than in patients without previous brain metastases.6 
Patients with brain metastases (BMs) generally present with neurologic symptoms, which can 
include headache, confusion, and seizures. Patients with LM also present with neurologic 
symptoms, which often include headaches or cranial neuropathies or pain, but can be highly 
varied. 
Despite the frequency of progression in the CNS, there are no approved drug treatments 
specifically for the treatment of BM or of LM in patients with NSCLC and activating EGFR 
mutations. Radiation therapy, either Whole Brain Radiotherapy (WBRT) or stereotactic 
radiosurgery (SRS) is often used to control symptoms of BMs. However, these treatments are 
rarely curative, and are not without side effects.  WBRT is associated with early occurring 
fatigue and all too often with neurocognitive decline.  In patients who received WBRT after SRS 
there is a significant decline of learning and memory function at 4 months compared to patients 
receiving only SRS.7  SRS is associated with fewer side effects when used alone, but a higher 
recurrence rate as the entire brain is not irradiated. There are few effective therapies to control 
LM. Intrathecal methotrexate is sometimes used, although response rates are low and time to 
disease progression is short. In patients with NSCLC with activating EGFR mutations, 
intermittent high doses of gefitinib or erlotinib have been used to treat patients with BM and LM 
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with some degree of effectiveness.2,8,9 However, response rates are low and the time to disease 
progression is generally short with this treatment as well. 
Diagnosis of BM is generally obtained by magnetic resonance imaging (MRI) of the brain. The 
diagnosis of LM is more complex. Diagnosis of LM is most definitive when cytologic evaluation 
of CSF specimens detects malignant cells.  However, single CSF analysis has a false negative 
rate of approximately 50%, and thus cytologic diagnosis of LM often requires several separate 
CSF samples.10 MRI findings (such as subarachnoid nodules, enhancement in basal cisterns, and 
enhancement/clumping of nerve roots) are diagnostic, but normal CNS imaging does not exclude 
a diagnosis of LM. Antibodies to EpCam, an epithelial cell adhesion molecule, have been 
utilized to identify rare tumor cells such as circulating tumor cells in the blood. The same 
approach to rare cell capture has been utilized in the analysis of tumor cells in CSF.  In one study 
of patients with LM, cytology had a sensitivity of 67%, MRI had a sensitivity of 73%, and 
EpCam based identification of CSF tumor cells had a sensitivity of 100%.11 Cell-free DNA is 
present in patients with activating EGFR mutations and BM, and can be utilized to evaluate the 
EGFR mutations that are present.12 Evaluation of cell-free DNA in the CSF may provide a 
method independent of cytological analysis for evaluation of the course of patients with LM. 
Approximately 50% of erlotinib-resistant, EGFR-mutant patients harbor a T790M EGFR 
mutation, which gefitinib, erlotinib, and afatinib do not inhibit.1,2  IC50s for one cell line with the 
T790M EGFR mutation were 10.4 µM for gefitinib, 16.1 µM for erlotinib, and 0.9 µM for 
tesevatinib.13 Despite having an IC50 against cells with the T790M EGFR mutation that is much 
lower than that for gefitinib or erlotinib, tesevatinib was not effective in treating NSCLC patients 
with the T790M EGFR mutation in the XL647-203 study.14 However, patients with BM and LM 
occurring while receiving erlotinib therapy have been documented to have a much lower 
frequency (10%) of T790M mutation in the CNS than is the case for patients with progression in 
non-CNS locations (38%).15 This presumably occurs because erlotinib and afatinib and gefitinib 
penetrate poorly into the CNS, and thus tumor cells in the CNS can grow in the presence of the 
low levels of TKI that are present. 
Tesevatinib effectively penetrates into the brain, with levels in mice and rats with intact blood-
brain barriers (BBB) the same or higher than plasma levels. Tesevatinib has levels in the choroid 
plexus and meninges in rats that are 10 times the plasma levels, suggesting that tesevatinib may 
penetrate well into CSF and may be an effective treatment for leptomeningeal metastases 
adhering to the inner surface of meninges.  
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Preliminary data from the initial patients enrolled in this study demonstrate that tesevatinib can 
achieve brain and leptomeningeal exposures with clinically significant effects.  Radiological data 
are available from one of the 6 initial patients enrolled in the study.  A 36 year old female patient 
was enrolled with symptoms of Grade 1 headache, anal numbness, and intermittent left leg 
weakness.  She had a right parietal brain metastasis and leptomeningeal metastases diagnosed 
both by CSF cytology and by MRI.  By study day 14 the headache, anal numbness, and 
intermittent left leg weakness were no longer present.  On MRI at study day 41 there was a 57% 
decrease in size of the right parietal brain metastasis and no evidence of leptomeningeal 
metastases. 
Thus, there is good biologic rational to evaluate tesevatinib in subjects with NSCLC and EGFR 
activating mutations who have disease progression with BM or LM, or have BM or LM at initial 
presentation. This study will enroll subjects with BM or LM occurring while being treated with 
erlotinib or afatinib or gefitinib, or with BM or LM at initial presentation. 
5.3.2 
Rationale for Dosage Selection  
Tesevatinib administered as a single-agent at a dose of 300 mg daily has shown clinically 
significant activity in lung cancer studies.  In study XL647-201, the confirmed partial response 
(PR) rate in subjects with EGFR mutations was 57% (8/14), and an additional 3 subjects with 
EGFR mutations had unconfirmed PRs (Section 5.1.2.2). 
5.4 
Compliance Statement 
This study will be conducted in compliance with Good Clinical Practice (GCP), including 
International Conference on Harmonization (ICH) Guidelines, and in general, consistent with the 
most recent version of the Declaration of Helsinki. In 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 
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personnel where sanctions have been invoked based upon scientific misconduct or fraud (e.g. 
loss of medical licensure, debarment). 
5.4.1 
Good Clinical Practice 
The principal investigator will ensure that the basic principles of Good Clinical Practice, as 
outlined in 21 Code of Federal Regulations (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 trial, the principal investigator is adhered to 21 CFR, part 54, 
(1998). A covered clinical trial 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 Food 
and Drug Administration (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 one 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 
Cohort A 
Primary objective 
• To evaluate the clinical activity of tesevatinib in subjects with non-small cell lung cancer 
(NSCLC), activating EGFR mutations, and brain metastases (BM) as measured by 
Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 evaluated changes in 
BM size. 
Secondary objectives 
• To evaluate changes in Quality of Life (QOL) in subjects receiving tesevatinib for BM. 
• To determine the median progression-free survival (PFS), rate of CNS non-progression at 3 
and 6 months, non-CNS time to progression (TTP), and CNS TTP. 
• To determine the median overall survival (OS). 
Exploratory objective 
• To evaluate the correlation between EGFR DNA mutations seen in plasma cell free DNA 
at screening with response. 
Cohort B  
Primary objective  
• To evaluate the clinical activity of tesevatinib in subjects with NSCLC, activating EGFR 
mutations, and leptomeningeal metastases (LM) as measured by improvement in Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 symptoms and signs. 
Secondary objectives 
• To evaluate the activity of tesevatinib in subjects with NSCLC, EGFR activating mutations 
and LM as measured by decreases in NSCLC cells in the CSF using standard cytology. 
• To evaluate the activity of tesevatinib in subjects with NSCLC, EGFR activating mutations 
and LM as measured by improvement in CNS MRI findings . 
• To evaluate the pharmacokinetics (PK) of tesevatinib in CSF versus plasma 
• To evaluate changes in QOL in subjects receiving tesevatinib for LM. 
• To determine the median PFS, rate of CNS non-progression at 3 and 6 months, non-CNS 
TTP, and CNS TTP.  
• To determine the median OS. 
Exploratory objectives 
• To evaluate the correlation between EGFR DNA mutations seen in plasma cell free DNA 
at screening with response. 
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• To evaluate the activity of tesevatinib in subjects with NSCLC, EGFR activating mutations 
and LM as measured by decreases in NSCLC cells in the CSF using rare cell capture 
techniques. 
• To evaluate the activity of tesevatinib in subjects with NSCLC, EGFR activating mutations 
and LM measured by decreases in CSF cell-free DNA. 
To utilize CSF cell-free DNA to detect activating EGFR mutations in patients receiving 
tesevatinib for LM. 
Cohort C 
Primary objective 
• To evaluate the clinical activity of tesevatinib in subjects with NSCLC, activating EGFR 
mutations, and BM at initial presentation as measured by RECIST 1.1 evaluated changes in 
BM size. 
Secondary objectives 
• To evaluate changes in QOL in subjects receiving tesevatinib for BM. 
• To determine the median PFS, rate of CNS non-progression at 3 and 6 months, non-CNS 
TTP, and CNS TTP in subjects with NSCLC, activating EGFR mutations, and BM at initial 
presentation. 
• To determine the median OS. 
Exploratory objective 
• To evaluate the correlation between EGFR DNA mutations seen in plasma cell free DNA 
at screening with response. 
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7 
STUDY DESIGN 
7.1 
Study Sites 
This study will be conducted at approximately 10 sites in the United States, and at up to 6 sites in 
South Korea and Taiwan. 
7.2 
Overview of Study Design 
This is a multicenter, Phase 2 study to assess the activity of tesevatinib in subjects with NSCLC 
and activating EGFR mutations and BM or LM. Up to 20 subjects with NSCLC who have 
progressed with BM will be enrolled in Cohort A, up to 20 subjects who have LM will be 
enrolled in Cohort B, and up to 20 subjects who have BM at initial presentation will be enrolled 
in Cohort C.  All three cohorts will be open for enrollment simultaneously; when one cohort has 
completed enrollment the other cohorts will remain open for enrollment until enrollment in all 
cohorts is complete. 
After completion of the screening assessments and confirmation of study eligibility, tesevatinib 
will be orally administered to all subjects at a dose of 300 mg once daily. 
Tumor response, both in the CNS and outside the CNS, will be assessed after the second cycle of 
treatment and then at the end of every two cycles of treatment thereafter.  Subjects will usually 
receive treatment with tesevatinib only until disease progression occurs, however treatment 
beyond progression is permissible in certain circumstances (See Section 11.1.1). Measuring 
response in LM is complex and there are no validated methods to do so.10 
Subjects with LM entering the study will be required to have MRI evidence of LM or cytological 
evidence of LM or both.  Thus in subjects with LM, response will be measured by improvement 
in symptoms and signs attributed to leptomeningeal metastases, disappearance of signs of LM on 
MRI and/or by improvement in cytological results. 
Subjects will undergo safety evaluations, including physical examination, vital sign 
measurements, hematology, serum chemistry, and urinalysis, and ECG. MRI/computed 
tomography (CT) will be performed to evaluate peripheral tumor lesions. MRI will be performed 
to evaluate both BM and LM tumor involvement. For subjects with LM in Cohort B, lumbar 
puncture (LP) will be performed to evaluate CSF levels of tesevatinib, CSF malignant cell 
numbers by standard cytology and by rare cell capture techniques, CSF cell-free DNA, and 
detection of activating EGFR mutations in CSF cell-free DNA. 
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 up to 60 subjects with NSCLC and activating EGFR mutations  
with BM at progression (n=20), LM at initial presentation or progression (n=20), or BM at initial 
presentation (n=20). 
8.2 
Inclusion Criteria – Cohort A 
A subject must meet the following criteria to be eligible for entry into the study: 
1) Age ≥ 18 years old.  
2) History of NSCLC with EGFR mutation (either exon 19 deletion or L858R mutation or an 
EGFR mutation that has had a clinical response to erlotinib, afatinib, or gefitinib in the 
patient being enrolled). 
3)  Occurrence or progression of BM while receiving first line therapy (either erlotinib or 
afatinib or gefitinib) for at least 14 days. Patients may have received osimertinib (or other 
agents inhibiting the T790M EGFR mutation) as second line therapy. If BM progression 
occurs after osimertinib, patient will be eligible.  
4) At least 1 measurable BM by RECIST 1.1 criteria (≥ 10mm in longest diameter). Target 
lesions must not have received stereotactic radiotherapy (SRS). If subject had prior whole 
brain radiotherapy (WBRT), progression in any measurable BM lesion must have occurred at 
least 3 months after the end of WBRT. Subjects with asymptomatic brain metastases may be 
enrolled without prior radiation therapy to the brain. Subjects with minimally symptomatic 
brain metastases may be enrolled without prior radiation therapy to the brain if they do not 
require immediate surgical or radiation therapy in the opinion of the treating investigator and 
in the opinion of a radiation therapy or neurosurgical consultant. 
5) Subjects in Cohort A may have asymptomatic LM detected by MRI. (Subjects with 
symptoms or signs attributed to LM will be enrolled in Cohort B whether or not they have 
brain metastases.) 
6) No clinically significant progression outside of the CNS on most recent EGFR inhibitor 
therapy. 
7) Eastern Cooperative Oncology Group (ECOG) Score ≤2. 
8) 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. 
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9) Adequate organ and bone marrow functions as follows: 
a) Serum creatinine ≤ 1.5 mg/dL 
b) Total bilirubin ≤ 1.5 × the upper limit of normal (ULN; except in patients diagnosed with 
Gilbert’s disease where bilirubin must be ≤ 3 × ULN). 
c) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3× ULN 
d) WBC > 3000/mm3 
e) Absolute neutrophil count ≥ 1500/mm3 
f) Platelet count > 100,000/mm3 
g) Hemoglobin > 8 g/dL  
10) Serum potassium and magnesium levels above LLN. 
11) No coexisting medical problems of sufficient severity to limit compliance with the study. 
12) Willing and able to sign written informed consent and be able to comply with the study 
protocol for the duration of the study.  
13) 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. 
a) 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.  
b) 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 3 
months after their last dose of study drug.  Effective birth control includes (a) intrauterine 
device (IUD) plus one barrier method; (b) on stable doses of hormonal contraception for 
at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; (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 
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c) For male patients who are sexually active and who are partners of premenopausal 
women: agreement to use two forms of contraception as in criterion 13 above during the 
treatment period and for at least 3 months after the last dose of study drug 
8.3 
Exclusion Criteria – Cohort A 
A subject who meets any of the following criteria is ineligible for entry into the study: 
1. First day of dosing with tesevatinib is less than 2 weeks from the last treatment of cytotoxic 
chemotherapy, biological therapy, or immunotherapy, and less than 6 weeks for nitrosoureas 
and mitomycin C. Surgical procedures must have been performed at least 2 weeks prior to 
the start of study treatment.  Subjects must have recovered from the reversible effects of prior 
lung cancer treatments, including surgery and radiation therapy (excluding alopecia). 
2. First day of dosing with tesevatinib is less than 4 weeks from the last radiotherapy of the 
brain or spinal cord/cauda equina. 
3. First day of dosing with tesevatinib is less than 2 weeks from treatment with another 
investigational agent. 
4. Treatment with erlotinib must be discontinued at least 3 days prior to first dose of tesevatinib 
and treatment with afatinib or other tyrosine kinase inhibitor must be discontinued at least 
3 days prior to first dose of tesevatinib. 
5. Any concurrent therapy for BM other than the specified treatment in this study.  
6. Taking any medication known to moderately or severely inhibit the CYP3A4 isozyme or any 
drugs that are CYP3A4 inducers (including anti-epileptic agents such as phenytoin). A stable 
regimen (≥ 4 weeks) of antidepressants of the selective serotonin reuptake inhibitor (SSRI) 
class is allowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine, 
paroxetine, sertraline, and fluoxetine). 
7. Taking any drugs associated with torsades de pointes or known to moderately or severely 
prolong the QTc(F) interval. 
8. Has evidence of active heart disease such as myocardial infarction within the 3 months prior 
to study entry; symptomatic coronary insufficiency congestive heart failure; moderate or 
severe pulmonary dysfunction. 
9. History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus 
bradycardia (< 50 bpm), heart block (excluding first degree block, being PR interval only), or 
congenital long QT syndrome. Subjects with a history of atrial arrhythmias should be 
discussed with the medical monitor. 
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10. Has an active infectious process. 
11. Female subject who is pregnant or lactating. 
12. Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign 
body. 
13. Has marked prolongation of QTc(F) interval at screening or Cycle 1 Day 1 (QTc[F] interval 
> 470 msec) using the Fridericia method of correction for heart rate. 
14. Gastrointestinal (GI) condition that interferes with drug absorption. 
15. Non-malignant neurological disease that would interfere with evaluation of symptoms or 
signs attributed to brain metastases. 
8.4 
Inclusion Criteria – Cohort B 
A subject must meet the following criteria to be eligible for entry into the study: 
1. Age ≥ 18 years old.  
2. History of NSCLC with EGFR mutation (either exon 19 deletion or L858R mutation or of an 
EGFR mutation that has had a clinical response to erlotinib, afatinib, or gefitinib in the 
patient being enrolled). 
3. Presentation with LM at initial presentation with no prior systemic treatment, or occurrence 
or progression of LM while receiving first line therapy (either erlotinib or afatinib or 
gefitinib) for at least 14 days. Patients may have received osimertinib (or other agents 
inhibiting the T790M EGFR mutation) as second line therapy. If LM progression occurs after 
osimertinib, patient will be eligible. 
4. Presence of at least one CTCAE 4.03 symptom or sign of at least Grade 1 attributed to 
leptomeningeal metastases. 
5. Diagnosis of LM by: 
a) Cytological evidence in CSF sample of LM due to NSCLC, and/or 
b) Findings on gadolinium-enhanced MRI  
6. No clinically significant progression outside of the CNS on most recent EGFR inhibitor 
therapy. 
7. Concomitant brain metastases and brain metastases previously treated with radiation therapy 
are allowed.  (Subjects with symptoms or signs attributed to LM will be enrolled in Cohort B 
whether or not they have brain metastases.) 
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8. ECOG Score ≤2. 
9. 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. 
10. Adequate organ and bone marrow functions as follows: 
a) Serum creatinine ≤ 1.5 mg/dL 
b) Total bilirubin ≤ 1.5 × ULN (except in patients diagnosed with Gilbert’s disease where 
bilirubin must be ≤ 3 × ULN). 
c) ALT and AST ≤ 3× ULN 
d) WBC > 3000/mm3 
e) Absolute neutrophil count ≥ 1500/mm3 
f) Platelet count > 100,000/mm3 
g) Hemoglobin > 8 g/dL  
11. Serum potassium and magnesium levels above the LLN. 
12. No coexisting medical problems of sufficient severity to limit compliance with the study. 
13. Willing and able to sign written informed consent and be able to comply with the study 
protocol for the duration of the study.  
14. 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. 
a) 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.  
b) 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 3 
months after their last dose of study drug.  Effective birth control includes (a) intrauterine 
device (IUD) plus one barrier method; (b) on stable doses of hormonal contraception for 
at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; (c) 
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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 
c) For male patients who are sexually active and who are partners of premenopausal 
women: agreement to use two forms of contraception as in criterion 14 above during the 
treatment period and for at least 3 months after the last dose of study drug 
8.5 
Exclusion Criteria – Cohort B 
A subject who meets any of the following criteria is ineligible for entry into the study: 
1. First day of dosing with tesevatinib is less than 2 weeks from the last treatment of cytotoxic 
chemotherapy, biological therapy, or immunotherapy, and less than 6 weeks for nitrosoureas 
and mitomycin C. Surgical procedures must have been performed at least 2 weeks prior to 
the start of study treatment. Subjects must have recovered from the reversible effects of prior 
lung cancer treatments, including surgery and radiation therapy (excluding alopecia). 
2. First day of dosing with tesevatinib is less than 4 weeks from the last radiotherapy of the 
brain or spinal cord/cauda equina. 
3. First day of dosing with tesevatinib is less than 2 weeks from treatment with another 
investigational agent. 
4. Treatment with erlotinib must be discontinued at least 3 days prior to first dose of tesevatinib 
and treatment with afatinib or other tyrosine kinase inhibitor must be discontinued at least 3 
days prior to first dose of tesevatinib. 
5. Any concurrent therapy for LM other than the specified treatment in this study.  
6. Taking any medication known to moderately or severely inhibit the CYP3A4 isozyme or any 
drugs that are CYP3A4 inducers (including anti-epileptic agents such as phenytoin).  A stable 
regimen (≥ 4 weeks) of antidepressants of the SSRI class is allowed (common SSRIs include 
escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and fluoxetine). 
7. Taking any drugs associated with torsades de pointes or known to moderately or severely 
prolong the QTc(F) interval. 
8. Has evidence of active heart disease such as myocardial infarction within the 3 months prior 
to study entry; symptomatic coronary insufficiency congestive heart failure; moderate or 
severe pulmonary dysfunction. 
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9. History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus 
bradycardia (< 50 bpm), heart block (excluding first degree block, being PR interval only), or 
congenital long QT syndrome. Subjects with a history of atrial arrhythmias should be 
discussed with the medical monitor. 
10. Has an active infectious process. 
11. Female subject who is pregnant or lactating. 
12. Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign 
body. 
13. Has marked prolongation of QTc(F) interval at screening or Cycle 1 Day 1 (QTc[F] interval 
> 470 msec) using the Fridericia method of correction for heart rate. 
14. GI condition that interferes with drug absorption. 
15. Non-malignant neurological disease that would interfere with evaluation of symptoms or 
signs attributed to leptomeningeal disease. 
16. Contraindications to lumbar puncture: 
a) International normalized ratio (INR) > 1.5 
b) Platelets < 50 × 109/L (Note that platelets are required to be ≥100× 109/L at screening) 
c) Therapeutic anticoagulant treatment that can’t be held for 24 hours.  Low dose low 
molecular weight heparin given for deep vein thrombosis (DVT) prophylaxis is allowed. 
d) CNS lesions considered to be at risk for cerebral herniation, myelocompression, or 
conus/cauda compression 
8.6 
Inclusion Criteria – Cohort C 
Subjects will be included if they meet the following criteria: 
1. Age ≥ 18 years old. 
2. NSCLC with EGFR mutation (either exon 19 deletion or L858R mutation or an EGFR 
mutation). 
3. No prior systemic treatment for NSCLC.  Treatment with systemic steroids is not considered 
systemic treatment for NSCLC.   
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4. No prior radiation therapy to the CNS (brain or spinal cord) 
5. At least one measurable BM by RECIST 1.1 criteria (≥ 10mm in longest diameter) in  a 
subject with asymptomatic or minimally symptomatic brain metastases who does not require 
immediate surgical or radiation therapy in the opinion of the treating investigator and in the 
opinion of a radiation therapy or neurosurgical consultant.  
6. Subjects in Cohort C may have asymptomatic LM detected by MRI. 
7. ECOG Score ≤2. 
8. 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 surgically treated and have not recurred.   
9. Adequate organ and bone marrow functions as follows: 
a. Serum creatinine ≤ 1.5 mg/dL 
b. Total bilirubin ≤ 1.5 × ULN (except in patients diagnosed with Gilbert’s disease 
where bilirubin must be ≤ 3 × ULN). 
c. ALT and AST ≤ 3× ULN 
d. WBC > 3000/mm3 
e. Absolute neutrophil count ≥ 1500/mm3 
f. Platelet count > 100,000/mm3 
g. Hemoglobin > 8 g/dL  
10. Serum potassium and magnesium levels above the LLN. 
11. No coexisting medical problems of sufficient severity to limit compliance with the study. 
12. Willing and able to sign written informed consent and be able to comply with the study 
protocol for the duration of the study. 
13. 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. 
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a. 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.  
b. 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 3 months after their last dose of study drug.  Effective birth control 
includes (a) intrauterine device (IUD) plus one barrier method; (b) on stable doses 
of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, 
transdermal) plus one barrier method; (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 
c. For male patients who are sexually active and who are partners of premenopausal 
women: agreement to use two forms of contraception as in criterion 13 above 
during the treatment period and for at least 3 months after the last dose of study 
drug 
8.7 
Exclusion Criteria – Cohort C 
Subjects will be excluded if they meet any of the following criteria: 
1. Surgical procedures that were performed less than 2 weeks prior to the start of study 
treatment.   
2. Any concurrent therapy for BM other than the specified treatment in this study.  
3. Taking any medication known to moderately or severely inhibit the CYP3A4 isozyme or any 
drugs that are CYP3A4 inducers (including anti-epileptic agents such as phenytoin).  A stable 
regimen (≥ 4 weeks) of antidepressants of the SSRI class is allowed (common SSRIs include 
escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and fluoxetine). 
4. Taking any drugs associated with torsades de pointes or known to moderately or severely 
prolong the QTc(F) interval. 
5. Has evidence of active heart disease such as myocardial infarction within the 3 months prior 
to study entry; symptomatic coronary insufficiency congestive heart failure; moderate or 
severe pulmonary dysfunction. 
6. History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus 
bradycardia (< 50 bpm), heart block (excluding first degree block, being PR interval only), or 
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congenital long QT syndrome. Subjects with a history of atrial arrhythmias should be 
discussed with the medical monitor. 
7. Has an active infectious process. 
8. Female subject who is pregnant or lactating. 
9. Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign 
body. 
10. Has marked prolongation of QTc(F) interval at screening or Cycle 1 Day 1 (QTc[F] interval 
> 470 msec) using the Fridericia method of correction for heart rate. 
11. GI condition that interferes with drug absorption. 
12. Non-malignant neurological disease that would interfere with evaluation of symptoms or 
signs of brain metastases. 
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9 
STUDY ASSESSMENTS AND PROCEDURES  
Informed consent must be obtained before any study-specific samples are taken or study-specific 
tests or evaluations are conducted. 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 for each cohort. 
Study Day 1 is defined as the date the subject takes the first dose of study drug, with subsequent 
study days numbered sequentially thereafter. 
If significant changes from Cycle 1 Day 1 are noted during the course of the study, additional 
unscheduled clinic visits may be undertaken by the investigator, or requested by the sponsor, in 
order to determine both the relevance of the finding(s) and the duration of the event(s). 
9.1 
Procedures to be Performed 
9.1.1 
Informed Consent 
All subjects must take part in the informed consent process. Adequate time must be allowed for 
the subject to ask questions and make a voluntary decision. No protocol-specific procedures, 
including screening procedures that are not standard of care procedures, are to be performed until 
the subject has signed and dated an IRB/IEC-approved ICF. 
9.1.2 
Demographics and Medical History 
A complete medical history will be taken.  Information to be documented includes demographic 
information, prior and ongoing medical illnesses and conditions, and surgical procedures (not 
related to the primary diagnosis). 
9.1.3 
Complete and Symptom-Directed Physical Examinations 
On days 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). On days in which a limited physical examination is required, the investigator 
should inquire about signs/symptoms, general appearance, eyes, heart and pulses, lungs, 
abdomen (liver/spleen), kidneys, and neurological (symptom directed). Interval history should be 
recorded at all study visits. 
9.1.4 
Vital Sign Measurements 
Vital sign measurements will be collected after the subject has been sitting for 5 minutes. Vital 
sign assessments will include measurements of sitting blood pressure (mm Hg), heart rate (beats 
per minute), respiration rate (breaths per minute), and temperature (Celsius/Fahrenheit). 
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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. Record cuff size, arm used, and subject’s position (if not seated). 
9.1.5 
ECOG Performance Status 
Subject’s performance status will be assessed using the ECOG performance status tool (see 
Appendix B). 
9.1.6 
Hematology, Serum Chemistries, and Urinalysis 
Samples for laboratory assessments (hematology, serum chemistries, and urinalysis) are to be 
collected.  A central laboratory will perform hematology, serum chemistry, and urinalysis tests 
and results will be provided to the investigator.  Blood and urine samples for hematology, serum 
chemistry, and urinalysis will be prepared using standard procedures. Laboratory panels are 
defined as listed in Table 9-1.  In addition to central laboratory testing, a local laboratory will 
perform serum chemistry tests on Day 15 of each cycle from Cycle 2 through Cycle 6 for 
additional safety data.  The local laboratory will perform all the serum chemistry tests included 
in Table 9-1 with the exception of Cystatin C.    
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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) 
• 
albumin 
• 
amylase 
• 
alkaline phosphatase 
• 
ALT 
• 
AST 
• 
bicarbonate 
• 
BUN 
• 
calcium 
• 
chloride 
• 
creatinine 
• 
creatine phosphokinase 
• 
phosphorous 
• 
potassium 
• 
random glucose 
• 
sodium 
• 
total & direct bilirubin 
• 
total protein 
• 
magnesium 
• 
cystatin C 
• 
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) 
Other 
 
 
• 
Fasting triglyceridesa 
 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; MCH = mean corpuscular 
hemoglobin; MCHC = mean cell hemoglobin concentration; MCV = mean cell volume 
a 
To be drawn in the event that amylase increases to > 1.5 × ULN. 
Abnormalities in clinical laboratory tests that lead to a change in subject management (e.g. dose 
delay, requirement for additional medication or monitoring) are considered clinically significant 
for the purposes of this study, and will be recorded on the AE 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 15.3.11). 
9.1.7 
Pregnancy Test 
Urine pregnancy tests are to be performed for females of childbearing potential.  Positive urine 
tests are to be confirmed with serum pregnancy testing.   
9.1.8 
12-Lead Electrocardiogram (ECG)   
Supine 12-Lead ECGs will be performed at screening; Days 1, 7 and 14 of Cycle 1; on Day 1 of 
Cycles 2 and Day 1 of each Cycle including at End of Study Drug Treatment visit. Assessment to 
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be performed at predose, and once within 4 – 8 hours postdose for Days 1, 7 and 14 of Cycle 1 
ECGs are to be performed before any blood sample collection when possible. 
ECGs are to be repeated three times consecutively within 30 minutes (must have an interval of at 
least 1–2 minutes between ECGs). 
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: 
𝑄𝑄𝑄𝑄𝐹𝐹=
𝑄𝑄𝑄𝑄
𝑅𝑅𝑅𝑅1/3 
Refer to Appendix C for sample calculation. 
Prior to enrollment, all subjects must demonstrate an average screening QTc(F) value of 
≤ 470 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 Cycle 1 
Day 1 or to the level of ≥ 500 msec requires further monitoring.  After collection of a PK blood 
sample and discussion with the medical monitor (if ≥ 500 msec) on appropriate management, the 
subject may be removed from the trial (see guidelines in Section 11.1.3.3). 
Abnormalities in the ECG that lead to a change in subject management (e.g. 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
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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abnormalities meet criteria defining them as serious, they must be reported as SAE (see 
Section 15.3.11). 
9.1.9 
Bone Imaging 
Bone scans are to be performed at Screening. Additional scans are to be performed as clinically 
indicated. 
9.1.10 
Lumbar Puncture (LP) – Cohort B Only 
For subjects with LM, CSF will be collected via LP for PK analysis on Cycle 1 Day 14 and on 
Cycle 3 Day 1 at approximately 4–8 hours after administration of the tesevatinib dose that day. 
NSCLC cells in the CSF will be evaluated by both standard cytology and by a central rare cell 
detection methodology at screening, on Day 14 of Cycle 1 and on Day 1 of Cycle 3. Samples 
will be evaluated for EGFR mutations (both the EGFR mutation or mutations known to be 
present in the tumor of a particular subject by prior investigation as well as for the T790M 
mutation and other EGFR mutations) as well as by immunochemistry for EGFR expression and 
phosphorylation. 
9.1.11 
Pharmacokinetics – Cohort B Only 
For subjects with LM (Cohort B), PK samples will be drawn to evaluate tesevatinib 
pharmacokinetics. Plasma samples for tesevatinib PK analysis will be drawn predose of 
tesevatinib on Day 14 of Cycle 1; and predose of tesevatinib on Day 1 of Cycle 3. Plasma 
samples also will be drawn on Cycle 1 Day 14 and on Cycle 3 Day 1 at 4–8 hours after 
administration of the tesevatinib dose that day (at as close to the same time as the CSF PK 
sample is obtained as possible). 
For all cohorts, additional samples for the preparation of plasma will be collected for tesevatinib 
analyses if the QTc(F) interval increases to the level of ≥ 500 msec (sample to be drawn as soon 
as possible after ECG performed). 
9.1.12 
Tesevatinib Administration 
Tesevatinib will be administered at the dose of 300 mg once daily. Tesevatinib will be used in 
dosage strength of 100-mg, and 150-mg tablets.  Patient diaries will be utilized to evaluate 
compliance. One cycle will be defined as 28 days of treatment. 
Tesevatinib should be taken in the morning (unless there is a subject-specific rationale to take it 
regularly at a different time of day) and can be administered without regard to food intake. 
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9.1.13 
Tumor Assessments 
In addition to bone scan at screening, CT scans of the thorax and abdomen will be performed at 
screening, after Cycle 2, and then every two cycles thereafter until disease progression. 
Radiological disease assessments by brain MRI will be performed at screening, at Cycle 2 Day 1, 
at Cycle 3 Day 1, and after every two cycles until disease progression. Response for peripheral 
disease and for BM will be evaluated according to RECIST, Version 1.1. Response will be 
recorded separately for non-CNS disease, for BM, and for LM.  All CT and MRI scans will be 
collected for central review. All clinical decisions during the study will be based on local site 
radiology assessments, which will also be used for the primary efficacy analysis. 
For subjects in cohort B, symptoms or signs attributed to leptomeningeal metastases will be 
followed.  Symptoms attributed to leptomeningeal metastases will be evaluated at screening, at 
Cycle 1 Day 1; at Cycle 1, Day 14; at Cycle 2 Day 1, at Cycle 3 Day 1, and then every 2 cycles 
(approximately 8 weeks) thereafter until disease progression, as well as at the End of Drug 
Treatment visit. 
9.1.14 
Quality of Life Questionnaires 
QOL will be evaluated using the European Organization for Research and Treatment of Cancer 
(EORTC) EORTC QLQ-C30 and EORTC QLQ-BN20 questionnaires administered at screening, 
on Day 1 of Cycle 3, on Day 1 of odd-numbered cycles thereafter, and at the EOS visit. Samples 
of the questionnaires are located in Appendix G and Appendix H. 
9.1.15 
Study Diary 
Subjects will be required to keep a study drug diary in which they will record the date and time 
that each dose of tesevatinib is taken as well as any missed doses. Diaries will be reviewed at 
each visit during the treatment periods. 
9.1.16 
Prior and Concomitant Medications 
All concomitant medications will be recorded from the time the subject signs the informed 
consent form through 30 days after the last dose of study drug. 
9.1.17 
Adverse Event Assessments 
Information regarding the occurrence of AEs will be collected from the time the subject signs the 
informed consent form throughout their participation in the study, including a period of 30 days 
after the subject’s last dose of study drug, unless a new treatment has been started. Any known 
untoward event that occurs beyond the AE reporting period that the investigator assesses as 
possibly related to tesevatinib also should be reported to Kadmon. 
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Note:   AEs resulting in a subject’s permanent discontinuation from the study, regardless 
of seriousness or relationship to study drug, MUST be promptly reported to the sponsor. 
9.2 
Schedule of Visits 
9.2.1 
Screening Visit 
At the screening visit, information will be collected and subjects will have clinical evaluations as 
follows: 
• Informed consent 
• Medical history including demographics 
• Complete physical examination, including height and weight 
• Vital sign measurements (sitting blood pressure, pulse, respiratory rate, temperature) 
• ECOG Performance status 
• Hematology, serum chemistry and urinalysis 
• Urine pregnancy test, if applicable (positive results to be confirmed by serum pregnancy 
testing) 
• Supine 12-Lead ECG (repeat three 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 when possible) 
• Tumor assessment (brain MRI, thoracic and abdominal CT/MRI) 
• Bone scan (additional scans to be performed as clinically indicated) 
• Plasma cell free DNA  
• Leptomeningeal metastasis symptom assessment – (Cohort B only) 
• CSF collection for Rare Cell Capture and Cell-Free DNA (Cohort B) 
• QOL Questionnaires 
• AE assessment 
• Baseline concomitant medications 
9.2.2 
Cycle 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: 
• Complete physical examination, including weight   
• Vital sign measurements (predose and 1 and 4 hours postdose) (sitting blood pressure, 
pulse, respiratory rate, temperature) 
• ECOG Performance status 
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• Leptomeningeal metastasis symptom assessment –(Cohort B only) 
• Clinical laboratory tests (hematology and serum chemistry panel) (Need not be repeated 
if screening visit occurred within 4 days prior to Day 1 visit.) 
• Urinalysis (need not be repeated if screening visit occurred within 4 days prior to Day 1 
visit) 
• Urine pregnancy test, if applicable (positive results to be confirmed by serum pregnancy 
testing) 
• Supine 12-Lead ECG (to be performed predose, and 4 - 8 hours post dose prior to any 
blood sample collection) (repeat three times consecutively within 30 minutes [must have 
an interval of at least 1-2 minutes between ECGs]) 
• Tesevatinib administration  
• Concomitant medications 
• AE assessment 
• Dispense study drug diary 
• Dispense study drug 
9.2.3 
Cycle 1, Day 7  
At the Day 7 visit (± 3 days), the following evaluations will be performed: 
• Limited physical examination 
• Vital sign measurements (sitting blood pressure, pulse, respiratory rate, temperature) 
• Hematology, serum chemistry and urinalysis 
• Supine 12-Lead ECG (to be performed predose and 4-8 hours postdose); perform ECG 
before any blood sample collection) (repeat three times consecutively within 30 minutes 
[must have an interval of at least 1-2 minutes between ECGs]) 
• Tesevatinib administration 
• Concomitant medications 
• AE assessment 
9.2.4 
Cycle 1, Day 14 
At the Day 14 visit (± 3 days), the following evaluations will be performed: 
• Limited physical examination 
• Vital sign measurements (predose and at 1 and 4 hours postdose) (sitting blood pressure, 
pulse, respiratory rate, temperature) 
• ECOG Performance status; 
• Leptomeningeal metastasis symptom assessment – Cohort B only 
• Hematology, serum chemistry and urinalysis 
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• Supine 12-Lead ECG (to be performed predose and 4-8 hours postdose); perform ECG 
before any blood sample collection) (repeat three times consecutively within 30 minutes 
[must have an interval of at least 1-2 minutes between ECGs]) 
• Plasma PK samples predose and 4-8 hours postdose (at approximately the same time the 
CSK PK sample is drawn) – Cohort B Only 
• Tesevatinib administration 
• CSF Sampling for PK and CSF Cytology and cell-free DNA at 4-8 hours postdose – 
Cohort B Only 
• Concomitant medications 
• AE assessment 
9.2.5 
Cycle 2, Day 1 
At the Cycle 2, Day 1 visit (± 3 days), the following procedures and evaluations will be 
performed: 
• Physical examination, including weight   
• Vital sign measurements (sitting blood pressure, pulse, respiratory rate, temperature) 
• ECOG Performance status 
• Leptomeningeal metastasis symptom assessment – Cohort B only 
• Hematology, serum chemistry and urinalysis 
• Urine pregnancy test, if applicable (positive results to be confirmed by serum pregnancy 
testing) 
• Supine 12-Lead ECG (to be performed predose prior to any blood sample collection) 
(repeat three times consecutively within 30 minutes [must have an interval of at least 1-
2 minutes between ECGs]) 
• Tumor assessment - brain MRI only 
• Tesevatinib administration 
• Concomitant medications 
• AE assessment 
• Perform drug accountability, review subject diary, and collect old and dispense new study 
drug  
9.2.6 
Cycle 3, Day 1 
At the Day 1 visit of Cycle 3 (± 3 days), the following procedures and evaluations will be 
performed: 
• Physical examination, including weight 
• Vital sign measurements (sitting blood pressure, pulse, respiratory rate, temperature) 
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• ECOG Performance status 
• Leptomeningeal metastasis symptom assessment – Cohort B only 
• Hematology, serum chemistry and urinalysis 
• Urine pregnancy test, if applicable (positive results to be confirmed by serum pregnancy 
testing) 
• Supine 12-Lead ECG (to be performed predose) (repeat three times consecutively within 
30 minutes [must have an interval of at least 1-2 minutes between ECGs]) 
• Tumor assessment (brain MRI, thoracic and abdominal CT/MRI) to be obtained after 
every 2 cycles beginning on Day 1 of Cycle 3 (± 7 days) and odd numbered cycles 
thereafter 
• Plasma PK samples predose and 4-8 hours postdose (at approximately the same time the 
CSK PK sample is drawn) – Cohort B Only 
• Tesevatinib administration 
• CSF Sampling for PK and CSF Cytology and cell-free DNA at 4-8 hours postdose – 
Cohort B Only 
• QOL Questionnaires (to be obtained after every 2 cycles [beginning on Day 1 of Cycle 
3]) 
• Concomitant medications 
• AE assessment 
• Perform drug accountability, review subject diary, and collect old and dispense new study 
drug  
9.2.7 
Cycle 4, Day 1 
At the Day 1 visit of Cycle 4 (± 3 days), the following procedures and evaluations will be 
performed: 
• Physical examination, including weight   
• Vital sign measurements (sitting blood pressure, pulse, respiratory rate, temperature) 
• ECOG Performance status 
• Hematology, serum chemistry and urinalysis 
• Urine pregnancy test, if applicable (positive results to be confirmed by serum pregnancy 
testing) 
• Supine 12-Lead ECG (to be performed predose) (repeat three times consecutively within 
30 minutes [must have an interval of at least 1-2 minutes between ECGs]) 
• Tesevatinib administration 
• Concomitant medications 
• AE assessment 
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• Perform drug accountability, review subject diary, and collect old and dispense new study 
drug  
9.2.8 
Cycles 5+, Day 1 
Subjects will return to the clinic on Day 1 of each subsequent cycle (every 28 ± 3 days) and the 
following procedures will be performed: 
• Physical examination, including weight   
• Vital sign measurements (sitting blood pressure, pulse, respiratory rate, temperature) 
• ECOG Performance status 
• Leptomeningeal metastasis symptom assessment – Cohort B only.  (to be obtained every 
2 cycles [beginning on Day 1 of Cycle 3]) 
• Hematology, serum chemistry, and urinalysis 
• Urine pregnancy test, if applicable (positive results to be confirmed by serum pregnancy 
testing) 
• Supine 12-Lead ECG (to be performed predose) (repeat three times consecutively within 
30 minutes [must have an interval of at least 1-2 minutes between ECGs]) 
• Tumor assessment (brain MRI, thoracic and abdominal CT/MRI); (to be obtained every 
2 cycles [beginning on Day 1 of Cycle 3]) 
• Tesevatinib administration 
• QOL Questionnaires (to be obtained every 2 cycles [beginning on Day 1 of Cycle 3]) 
• Concomitant medications 
• AE assessment 
• Perform drug accountability, review subject diary, and collect old and dispense new study 
drug  
9.2.9 
Day 15 on Cycle 2 through Cycle 6 
At the Day 15 visit of Cycles 2, 3, 4, 5, and 6 (± 3 days), the following procedure and evaluation 
will be performed: 
• Serum chemistry (Cystatin C does not need to be tested) 
9.2.10 
End-of-Study Drug Treatment Visit  
Subjects are to return to the study site within 3 days after the subject’s last dose of study drug to 
complete all end-of-study drug treatment assessments as described below. This may occur at the 
visit at which disease progression is diagnosed.  
• Complete physical examination, including weight  
• Vital sign measurements (sitting blood pressure, pulse, respiratory rate, temperature) 
• ECOG Performance status 
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• Leptomeningeal metastasis symptom assessment – Cohort B only. 
• Hematology, serum chemistry, and urinalysis 
• Urine pregnancy test, if applicable (positive results to be confirmed by serum pregnancy 
testing) 
• Supine 12-Lead ECG (repeat three times consecutively within 30 minutes [must have an 
interval of at least 1-2 minutes between ECGs]) 
• Tumor assessment (brain MRI, thoracic and abdominal CT/MRI) (only required if one 
hasn’t been performed in the previous 8 weeks) 
• Quality of Life Questionnaire 
• Concomitant medications 
• AE assessment 
• Final return and accounting of study drug 
9.2.11 
30-Day Follow-Up 
The 30-Day Follow-Up should occur 30 days (± 5 days) after the subjects’ last dose of 
tesevatinib, but prior to starting new therapy.  This may occur prior to 30 days if new therapy is 
started within 30 days of last dose of study drug.  
• Complete physical examination, including weight  
• Vital sign measurements (sitting blood pressure, pulse, respiratory rate, temperature) 
• ECOG Performance status 
• Hematology, serum chemistry, and urinalysis 
• Urine pregnancy test, if applicable (positive results to be confirmed by serum pregnancy 
testing) 
• Concomitant medications 
• AE assessment 
9.2.12 
Follow-Up Phone Contact 
Beginning 8 weeks after the 30-Day Follow-Up Visit, subjects are to be contacted by telephone 
every 8 weeks to assess survival status and any subsequent anti-cancer treatment. 
9.2.13 
Unscheduled/AE Resolution Visits: To Occur as Needed 
If additional visits are needed (e.g. for resolution of an AE), the following procedures and 
evaluations may be performed as needed: 
• Complete physical examination, including weight; 
• Vital sign measurements (sitting blood pressure, pulse, respiratory rate, temperature); 
• ECOG Performance status 
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• Hematology, serum chemistry and urinalysis; 
• Urine pregnancy test, if applicable (positive results to be confirmed by serum pregnancy 
testing); 
• Supine 12-Lead ECG (repeat three times consecutively within 30 minutes [must have an 
interval of at least 1-2 minutes between ECGs]; 
• Tesevatinib administration (if appropriate) 
• AE assessment; 
• Concomitant medications; 
• Perform drug accountability, review subject diary, and collect old and dispense new study 
drug (if appropriate). 
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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 (e.g. laboratory tests, physical examination including an evaluation 
of toxicity/AEs). Refer to Table 4-1 and Table 4-2. 
A termination eCRF must be completed for all enrolled subjects. 
10.1 Subject Withdrawal  
A subject’s participation in the study may be prematurely discontinued for any of the following 
reasons:  
10.1.1 
Subject Treatment Discontinuation  
• Progression of disease 
• An AE requires permanent discontinuation of study drug 
• Voluntary withdrawal by subject 
• Noncompliance to protocol 
• Subject lost to follow-up 
• Termination of the study by sponsor 
• Subject death 
• Other 
10.1.2 
 Subject Study Termination  
• Voluntary withdrawal by subject 
• Subject lost to follow-up 
• Termination of the study by sponsor 
• Subject death 
• Other 
In the event of premature discontinuation, every effort should be made to perform the end-of-
study follow-up procedures. Refer to Table 4-1 and Table 4-2. If a subject dies, Kadmon will 
actively seek to know the date of death.  
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Subjects who are withdrawn from the study due to toxicity are to be followed until there is 
either: 
• Resolution or stabilization to Cycle 1 Day 1 or Grade 1 
• The subject is lost to follow-up 
• The event is otherwise explained 
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 three (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-Study (Final) visit (see Section 9.2.9). 
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 (e.g. violation of eligibility criteria, dosing errors, missing 
data for study endpoint analysis). 
10.3 Replacements 
Subjects discontinued from the trial will not be replaced. 
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11 STUDY DRUG 
11.1 Tesevatinib (KD019) 
Tesevatinib will be provided in 100-, and 150-mg tablets. Kadmon will provide each investigator 
with adequate supplies of tesevatinib. Study drug must be stored at controlled room temperature 
and inventoried according to applicable regulations. 
Subjects will be provided with either a weekly or monthly supply of study drug and instructions 
for taking the study drug at home. After the initial 28-day cycle, study drug will be supplied on 
Day 1 of each subsequent cycle to those continuing on study. 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 API in a lactose-based 
immediate release (IR) formulation. Tesevatinib tablets are packaged in high-density 
polyethylene (HDPE) bottles capped with childproof caps. The following information will be 
printed on the label for clinical lots of tesevatinib: 
 
Tesevatinib Tablets 100-mg – 32 count 
Lot Number:  XXXXX.XXX   Bottle #: XXXX  
Store at 20°C - 25°C (68°F - 77°F).  Brief excursions permitted to 15°C to 30°C (59°F 
and 86°F) 
Caution:  New Drug--Limited by Federal (or United States) Law to Investigational Use 
 
Tesevatinib Tablets 150-mg – 32 count 
Lot Number:  XXXXX.XXX Bottle #: XXXX  
Store at 20°C - 25°C (68°F - 77°F).  Brief excursions permitted to 15°C to 30°C (59°F 
and 86°F) 
Caution: New Drug--Limited by Federal (or United States) Law to Investigational Use 
11.1.1 
Tesevatinib Administration 
Tesevatinib will be administered at the dose of 300 mg once daily. One cycle will be defined as 
28 days of treatment. 
Study drug may be taken with or without food at approximately the same time every morning 
(unless there is a patient-specific rationale to take it regularly at a different time of day). Subjects 
should drink a full glass of water (approximately 8 ounces [240 mL]) immediately after study 
drug administration. Grapefruit and similar (pomelo fruit, Seville oranges, etc.) products should 
be avoided for the duration of study treatment. 
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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 be treated with study drug until disease progression or unacceptable toxicity occurs. 
However, subjects with limited peripheral disease progression (oligoprogressive disease) may 
receive local ablative (radiation therapy or surgery) and then be continued on tesevatinib. 
Subjects who discontinue tesevatinib treatment will be followed for survival.  (Both CNS and 
non-CNS disease progression are defined in Appendices A and B.) 
All subjects also will be followed for a period of 30 days following their last dose of tesevatinib.  
Additionally, subjects will be contacted every 8 weeks to collect information on survival and 
other therapies. 
11.1.2 
Dose Modifications and Delays for Toxicity Related to Study Drug 
Subjects who develop ≥ Grade 3 AE considered by the investigator to be related to study drug 
(with the exception of asymptomatic Grade 3 elevations of amylase or lipase, Grade 3 elevation 
of alkaline phosphatase in a subject known to have bone metastases, Grade 3 elevation of 
glucose in a subject receiving systemic corticosteroids, Grade 3 creatine phosphokinase [CPK] 
elevation in the absence of muscle symptoms, or Grade 3 sodium values ≥126 mmol/L in a 
subject with diarrhea) will have study treatment interrupted until all drug-related toxicities have 
resolved to ≤ Grade 1. 
Tesevatinib will be withheld for any Grade 3 rash or diarrhea related toxicities. Once toxicities 
have resolved to ≤ Grade 1, the subject may resume study treatment at a reduced dose of 
250 mg/day if the dose was 300 mg/day, or at a reduced dose of 200 mg/day if the dose was 
250 mg/day. No more than two dose reductions are permitted. Subjects who require more than 
two dose reductions will have study drug discontinued and enter the Follow-up Period. 
Subjects for whom toxicity persists beyond 28 days despite dose interruption may resume study 
treatment only with permission from the responsible medical monitor.   
If study treatment is withheld, the subject should be instructed not to make up the withheld 
doses. 
11.1.3 
Tesevatinib:  Warnings, Precautions, and Management 
AEs that have been associated with tesevatinib include the following: diarrhea, skin rash, QTc(F) 
prolongation, elevated serum creatinine, elevated serum amylase and interstitial lung disease. 
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Unless otherwise specified, study drug may be withheld for up to 28 days at the discretion of the 
investigator. 
11.1.3.1 Diarrhea 
Diarrhea should be managed according to accepted practice (e.g. with loperamide).  Subjects 
with severe diarrhea who are unresponsive to loperamide or other antidiarrheals or who become 
dehydrated may require interruption of study drug until resolution to ≤ Grade 1 in severity. If 
Grade 3 diarrhea occurs, the medical monitor should be consulted about study drug decreases or 
discontinuation.  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 fluid administration. In 
addition, renal function and serum electrolytes, including potassium and magnesium, should be 
monitored in subjects at risk of dehydration. 
11.1.3.2 Skin Rash  
Skin rash should be managed according to locally accepted clinical recommendations. Study 
drug may be withheld up to 28 days for Grade 3 rash. 
Suggestions for Rash Management  (Lacouture 2011, Kiyohara 2013, 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 Week 4–6 
• Then will decrease in severity at Week 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) 
• Hypoallergenic makeup when possible 
Suggestions for treatment once a rash appears (see Appendix F for steroid potency 
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chart): 
• Ongoing use of treatments from ‘preventative treatments’ above 
• Grade 1 (<10 % BSA involved, without pruritus or tenderness) 
 Topical steroids (refer to Appendix F 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 
• Grade 2 (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) 
• Grade 3 (> 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 once daily (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 100mg 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. 
11.1.3.3 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 Grade 3 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 (i.e., 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 range16 and may require additional monitoring or adjustment if subjects develop 
diarrhea. 
11.1.3.4 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. 
If the QTc(F) interval increases to an absolute value of  ≥ 60 msec above Cycle 1 Day 1 (predose 
on Day 1) but < 500 msec and the subject is asymptomatic (does not have palpitations, dizziness, 
syncope, orthostatic hypotension, or a significant ventricular arrhythmia on ECG), the following 
actions should be taken: 
• Re-check and confirm concomitant medications for any medications that may be 
contributing to QTc(F) prolongation.  Consult medical monitor for discontinuation of any 
medication found; 
• Check electrolytes, especially magnesium and potassium; correct abnormalities as 
clinically indicated; 
• Obtain blood sample (plasma) for PK analysis. 
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If the QTc(F) interval increases to an absolute value of ≥ 500 msec at any evaluation and if the 
subject is asymptomatic (does not have palpitations, dizziness, syncope, orthostatic hypotension, 
or a significant ventricular arrhythmia on ECG), then the following actions should be taken: 
• Consult with medical monitor; 
• Hold study drug; 
• Re-check and confirm concomitant medications for any medications that may be 
contributing to QTc(F) prolongation.  Consult medical monitor for discontinuation of any 
medication found; 
• Check electrolytes, especially magnesium and potassium; correct abnormalities as 
clinically indicated; 
• Obtain blood sample (plasma) for PK analysis; 
• Contact medical monitor to discuss appropriate management; 
• QTc(F):  When QTc(F) is within 30 msec of Cycle 1 Day 1 or ≤ 470 msec (whichever is 
lower), then study drug may be restarted with one dose level reduction; 
• Following dose reduction and resumption of study drug treatment, ECGs must be 
repeated weekly for 2 weeks, then on Day 1 of each cycle per protocol following restart 
of study drug; 
• Study drug may be restarted at the pre-event dose level if QTc(F) values of ≥ 500 msec 
are not confirmed by the central lab and if there is no evidence of drug-related abnormal 
ECG findings. This may be done as soon as the data are confirmed. 
If the QTc(F) interval increases to an absolute value of ≥ 500 msec at any evaluation, and if the 
subject is or has recently been symptomatic (has palpitations, dizziness, syncope, orthostatic 
hypotension, a significant ventricular arrhythmia on ECG), then the following actions should be 
taken: 
• Consult with medical monitor; 
• The subject should be hospitalized and undergo a thorough cardiology evaluation; 
• Do not dose with study drug again;   
• Obtain blood (plasma) for PK sample; 
• Check electrolytes especially magnesium and potassium; correct abnormalities as 
clinically indicated; 
• ECGs should be monitored until the QTc(F) returns to within 30 msec above the average 
Cycle 1 Day 1 value or ≤ 470 msec. 
Study drug should be permanently discontinued if the cardiac/electrophysiology evaluation 
confirms that symptoms are the consequence of a drug-induced QTc(F) interval prolongation.  
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However, if the subject has objective tumor response, consideration will be given to continuing 
treatment with tesevatinib at a reduced dose after discussion with the medical monitor. 
11.1.3.5 Elevated Serum Creatinine 
Subjects with increases in serum creatinine to > 2 × ULN should be evaluated for non-renal 
causes of renal dysfunction, such as dehydration due to diarrhea. Cystatin C values should also 
be utilized to evaluate renal function. Management of subjects without clinically likely non-renal 
causes of renal dysfunction should be discussed with the medical monitor. 
11.1.3.6 Elevated Serum Amylase 
In the event of asymptomatic increase of serum amylase to > 1.5 × ULN, lipase, fasting 
triglycerides, and amylase isoenzymes should be drawn. Further management should be 
discussed with the medical monitor. 
11.1.3.7 Interstitial Lung Disease 
Dyspnea in subjects in the study should be evaluated with chest X-ray or CT of the chest to 
determine whether interstitial lung disease is present. Tesevatinib should be discontinued if 
interstitial lung disease is suspected, and further management discussed with the medical 
monitor. 
11.2 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) (e.g. 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. 
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.  
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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 orange fruits (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 moderately or severely inhibit 
(e.g. ketoconazole, itraconazole, erythromycin, clarithromycin) or induce (e.g. phenytoin, 
carbamazepine, rifampicin, or phenobarbital) the CYP3A4 isozyme.  Steroid medications are 
allowed. 
Administration of acid-reducing medications should be avoided during the study as these agents 
may decrease exposure to tesevatinib. If acid-reducing agents are needed, H-2 antagonists or 
antacids will be recommended rather than proton pump inhibitors.  Administration of acid-
reducing agents such as H-2 antagonists or antacids, if required, should take place no less than 2 
hours before or after dosing with tesevatinib.   
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. 
Other prohibited treatments include the following: 
• Other investigational drugs; 
• Concurrent anti-tumor therapies such as chemotherapy, gene therapy, biologics, radiation 
therapy, or other immunotherapy; 
• Medications known to moderately or severely inhibit the CYP3A4 isozyme or any drugs 
that are moderate or severe CYP3A4 inducers.  A stable regimen (≥ 4 weeks) of 
antidepressants of the SSRI class is allowed (common SSRIs include escitalopram 
oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and fluoxetine) ; 
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• Drugs associated with torsades de pointes or known to prolong the QTc interval, 
including anti-arrhythmic medications within 2 weeks prior to Day 1 of treatment on 
study. 
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. 
12.1 Additional Therapy  
A subject should not receive additional therapeutics treatment during the study period without 
the approval of the sponsor’s medical monitor. 
12.2 Additional Anti-Cancer Treatment and Radiotherapy 
Subjects should not receive additional therapeutic anti-cancer treatment until after progressive 
disease (PD) has been documented on study and End of Treatment study assessments have been 
completed.  If a subject requires additional anti-cancer treatment, study treatment will be 
discontinued and the subject will enter the Post-Treatment Period and followed every 8 weeks by 
phone call.  However, subjects with limited peripheral disease progression (oligoprogressive 
disease) may receive local ablative treatment (radiation therapy or surgery) and then be 
continued on tesevatinib. Any such patients will be considered to have disease progression at the 
time of detection of oligoprogressive disease. 
12.3 Interaction of Tesevatinib with Other Medications 
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 CYP3A4-
mediated metabolic pathways. 
In vitro studies have indicated that tesevatinib has a moderate potential to inhibit the CYP2C8 
family of liver enzymes. This inhibition, should it occur clinically, could increase exposure to 
other drugs that are substrates for this pathway. However, the inhibition of CYP2C8, CYP2C9 
and CYP2C9*2 in enzyme assays required tesevatinib levels of 7–9 µM.  These levels are well 
above plasma concentrations achievable in vivo at the doses proposed in this study. 
Although not expected to be an issue, inhibitors, inducers, and substrates of CYP2C8, CYP2D6, 
and CYP1A2 should be avoided in all subjects while receiving study drug. These medications 
should be used with caution and discussed with the medical monitor prior to use. In addition, 
subjects must be closely monitored for the desired drug effect and potential AE. 
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See Appendix D for a list of drugs that are substrates, inhibitors, and inducers of CYP3A4, 
CYP2C8, CYP2D6, and CYP1A2.  
12.3.1 
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 
(e.g. quinidine, procainamide); Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide); 
phenothiazine anti-psychotics: (e.g. chlorpromazine, mesoridazine, pimozide, thioridazine); 
quinolone antibiotics: (e.g. gatifloxacin, moxifloxacin, sparfloxacin); macrolide antibiotics 
(e.g. erythromycin, clarithromycin, and troleandomycin) and other drugs that have a 
contraindication or boxed warning regarding QT prolongation in the prescribing information. 
Appendix E, 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 unless deemed clinically necessary. 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 long-term follow-up, subjects who require short-term (2 to 3 weeks, not to exceed 
21 days) treatment with a concomitant medication associated with QT interval prolongation 
while receiving study drug should have the study drug withheld until the concomitant treatment 
course is complete. The decision about whether the subject can continue on trial following this 
interruption will be determined by the medical monitor. 
During long-term follow-up, subjects who require chronic treatment with a concomitant 
medication associated with QT interval prolongation while receiving study drug should be 
monitored as follows: 
• Three ECGs should be obtained prior to start of the concomitant medication. These ECGs 
should be obtained within a total span of 30 minutes with an interval of approximately 1–
2 minutes between recordings; 
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• If the average QTc(F) interval from these 3 ECGs is > 60 msec above the average Cycle 
1 Day 1 (Day 1 predose) value or is ≥ 500 msec, study drug may be discontinued or dose 
reduced after discussion with the medical monitor; 
• If both of the above criteria are not met (i.e., the average QTc[F] interval is no more than 
60 msec above Cycle 1 Day 1 and is < 500 msec), ECGs should be obtained daily for the 
first 3 days of treatment with the concomitant medication; 
• Additionally, an ECG should be obtained weekly for 2 weeks, then every 2 weeks for 
1 month and monthly thereafter until the concomitant medication is no longer required or 
study drug is discontinued. 
QTc(F) interval prolongation should be managed as noted in Section 11.1.3.3. 
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13 PHARMACOKINETICS AND PHARMACODYNAMICS 
13.1 Plasma and CSF Pharmacokinetics 
For subjects with LM (Cohort B), PK samples will be drawn to evaluate tesevatinib 
pharmacokinetics. A plasma sample for tesevatinib PK analysis will be obtained at predose of 
tesevatinib on Cycle 1 Day 14 and at predose of tesevatinib on Cycle 3 Day 1. A plasma sample 
also will be obtained on Cycle 1 Day 14 and on Cycle 3 Day 1, within 4–8 hours after tesevatinib 
administration of the tesevatinib dose that day (i.e., at approximately the same time as the CSF 
PK sample is obtained). 
For subjects with LM (Cohort B), CSF PK samples will be obtained on Cycle 1 Day 14 and on 
Cycle 3 Day 1, within approximately 4–8 hours after tesevatinib administration of the tesevatinib 
dose that day. 
For all cohorts, additional samples for the preparation of plasma will be collected for tesevatinib 
analyses if the QTc(F) interval increases to the level of ≥ 500 msec (sample to be drawn as soon 
as possible after ECG performed). 
13.2 CSF Pharmacodynamics 
For subjects with LM (Cohort B), NSCLC cells in the CSF will be evaluated by both standard 
cytology and by a central rare cell detection methodology at Screening, on Day 14 of Cycle 1, 
and on Day 1 of Cycle 3. Samples will be evaluated for EGFR mutations (both the EGFR 
mutation or mutations known to be present in the tumor of a particular subject by prior 
investigation as well as for the T790M mutation and other EGFR mutations) and for EGFR copy 
number. 
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14 EFFICACY 
In addition to bone scan at screening, CT scans of the thorax and abdomen will be performed at 
screening, after Cycle 2, and then every two cycles thereafter until disease progression. 
Radiological disease assessments by brain MRI will be performed at screening, at C2D1, at 
C3D1, and then every two cycles until disease progression. Response for peripheral disease and 
for BM will be evaluated according to RECIST, Version 1.1. Response will be recorded separately 
for non-CNS disease, for BM, and for LM.  All CT and MRI scans will be collected for central 
review.  All clinical decisions during the study will be based on local site radiology assessments, 
which will also be used for the primary efficacy analysis. 
For subjects with BM (Cohort A and Cohort C) efficacy will be evaluated by RECIST 1.1 
criteria separately for non-CNS tumor lesions and for BMs at Screening, at Cycle 2 Day 1 (for 
BM), at Cycle 3, and then every 2 cycles (approximately 8 weeks) thereafter until disease 
progression. 
For subjects with LM (Cohort B), symptoms attributed to leptomeningeal disease will be 
evaluated at screening, Cycle 1 Day 1, at Cycle 1 Day 14, at Cycle 2 Day 1, at Cycle 3, and then 
every 2 cycles (approximately 8 weeks) thereafter until disease progression.   
The response efficacy endpoints will be evaluated separately for peripheral disease, for BM, and 
for LM, and a summary response will also be derived (See Table 14-1). For LM, if positive CSF 
cytology and MRI diagnostic findings were both present at screening, complete response (CR) 
requires the absence of LM by both modalities. For LM, CR also requires the complete 
resolution of symptoms and signs attributed to LM. Best overall response, duration of response, 
and duration of stable disease will be reported, based on the examples in Table 14-1. The median 
PFS, rate of CNS non-progression at 3 and 6 months, non-CNS time to progression, CNS TTP, 
and median OS also will be assessed. 
Subjects with limited CNS or extra-CNS disease progression (oligoprogressive disease) may 
receive local ablative therapy (radiation therapy or surgery) and then be continued on tesevatinib. 
This practice is consistent with data indicating that some patients with NSCLC on TKI therapy 
who have oligoprogressive disease appear to have significant periods of additional disease 
control with this approach.19 Any such patients will be considered to have disease progression 
for analyses of PFS and for analyses of progression in the relevant (CNS or extra-CNS) 
compartment at the time of detection of oligoprogressive disease. 
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Subjects with scans that are on the “borderline” of disease progression (e.g. 21% increase in sum 
of target lesion diameters or equivocal findings on CSF cytology or MRI) but for whom the 
investigator determines a clinical benefit may occur in the study. These subjects will be allowed 
to continue in the study after discussion with the medical monitor. If improvement is 
documented at the next subsequent staging time point (e.g. 17% increase in sum of target lesion 
diameters or stable CNS symptoms), the subject will continue on study. If worsening is 
documented (e.g. 30% increase in sum of target lesion diameters or worsening of CNS 
symptoms), the subject should be discontinued from the study, and the progression date should 
be the original date on which “borderline” disease progression was first documented.  If stable, 
then they will be followed until improvement or worsening occurs. 
Table 14-1: 
Summary Response Examples 
Peripheral Tumor1 
Brain Metastases1 
Leptomeningeal 
Metastases 
Summary 
Response3 
Measurable 
Non-
measurable 
Measurable 
Non-
Measurable 
CR 
CR 
CR2 
CR2 
CR2 
CR, peripheral, 
BM and LM 
Non-CR, 
non-PD 
Non-CR, 
non-PD 
PR2 
None 
Non-CR, non-PD 
PR, BM only 
Non-CR, 
non-PD 
Non-CR, 
non-PD 
CR2 
CR2 
Non-CR, non-PD 
CR, BM only 
Non-CR, 
non-PD 
Non-CR, 
non-PD 
Non-CR, 
non-PD 
Non-CR, 
non-PD 
CR2 
CR, LM only  
Non-CR, 
non-PD 
Non-CR, 
non-PD 
Non-CR, 
non-PD 
Non-CR, 
non-PD 
None 
CR, LM only  
Non-CR, 
non-PD 
Non-CR, 
non-PD 
CR2 
None 
CR2 
CR, BM and 
LM only 
Non-CR, 
non-PD 
Non-CR, 
non-PD 
Non-CR, 
non-PD 
Non-CR, 
non-PD 
Non-CR, non-PD 
SD 
BM = bone metastases; CR = complete response; LM = leptomeningeal metastases; PD = progressive disease; PR = progressive 
response; SD = stable disease 
1 
Using RECIST 1.1 criteria 
2 
Diagnosis of BM CR or PR, or LM CR, requires that steroids be at or lower than dose of steroids at Cycle 1 Day 1 (if 
subject is receiving steroids) 
3 
All summary response examples assume that no new lesions are present.  A new peripheral tumor or brain metastasis, or 
symptom progression of LM will lead to a summary response of PD in that category.  
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14.1 Cohort A and Cohort C– Brain Metastases 
For subjects with BM (Cohorts A and C) efficacy will be evaluated by RECIST 1.1 criteria 
separately for non-CNS tumor lesions and for BMs at screening, Cycle 2 Day 1, Cycle 3 Day 1, 
and then every 2 cycles (approximately 8 weeks) thereafter until disease progression. 
14.2 Cohort B – Leptomeningeal Metastases 
For subjects with LM, symptoms attributed to leptomeningeal metastases will be evaluated at 
screening, Cycle 1 Day 1, Cycle 1 Day 14, Cycle 2 Day 1, Cycle 3 Day 1, and then every 
2 cycles (approximately 8 weeks) thereafter until disease progression, as well as at the End of 
Drug Treatment visit.  CTCAE v4.03 
(www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf) will be utilized 
for the evaluation of symptoms and signs attributed to leptomeningeal metastases. Symptom 
improvement is defined as a decrease in 1 grade in at least one CTCAE v4.03 symptom or sign 
attributed to leptomeningeal metastases without worsening of other neurologic symptoms or 
signs attributed to leptomeningeal metastases. Symptom progression is defined as an increase of 
1 grade in at least one CTCAE v4.03 symptom attributed to leptomeningeal metastases or the 
appearance of new symptoms or signs of LM. Symptoms or signs attributed to leptomeningeal 
metastases will be followed as one component of the efficacy evaluation for Cohort B. 
For subjects with LM, NSCLC cells in the CSF will be evaluated during the study (screening, 
Day 14 of Cycle 1, and on Day 1 of Cycle 3) for malignant cells both by standard cytological 
analysis and by a rare cell detection methodology. CSF obtained at the same time points will be 
evaluated for protein and glucose levels. Response will be based on standard cytological analysis 
if cytology was positive at screening. Response categories will be CR (no malignant cells, which 
must be present on 2 consecutive CSF evaluations to support response of CR), and non-PR, non-
PD (continued presence of malignant cells).  PD will not be defined by CSF cytology. 
For subjects with LM (Cohort B), CSF for isolation of cell-free DNA will be collected at 
screening, Day 14 of Cycle 1, and Day 1 of Cycle 3. Evaluation for EGFR mutations will be 
performed.  Quantitation of EGFR mutations in cell-free DNA will be utilized for an exploratory 
efficacy analysis. 
LM will also be evaluated by serial MRI of the brain. For patients with positive findings of LM 
on MRI at screening, response categories will be CR (no evidence of LM on MRI), or non-PR, 
non-PD (continued presence of evidence of LM on MRI). PD for LM will not be defined by 
MRI. 
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15 SAFETY 
15.1 Safety Parameters 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE; 
Version 4.03 - www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf) 
will be used for grading toxicities unless otherwise specified.  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 vital sign measurements, physical 
examinations, concomitant medications, hematology, serum chemistries, urinalysis, pregnancy 
testing, ECGs, and ECOG performance status. 
15.2 Adverse Event Definition 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  AEs include: 
• Suspected adverse drug reactions (abbreviated as either SADR or SAR). This may be 
serious or not serious; 
• 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; 
• Other medical events, regardless of their relationship to the study drug, such as injury, 
surgery, accidents, extensions of symptoms, or apparently unrelated illnesses. 
Findings existing prior to signing informed consent will be recorded as medical history. For the 
purpose of data collection, all untoward events that occur after informed consent through 30 days 
after last dose of study treatment are to be recorded on eCRFs by the investigational site. This 
requirement includes AEs from unscheduled as well as scheduled visits. 
An AE does not include:  
• Medical or surgical procedures (e.g. surgery, endoscopy, tooth extraction, transfusion); 
when the condition that leads to the procedure is an AE; 
• 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 (e.g. hospitalization 
for elective surgery, social, and/or convenience admissions); 
• Overdose of either tesevatinib or a concomitant medication without any signs or 
symptoms, unless the subject is hospitalized for observation. 
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15.3 Evaluating Adverse Events 
The investigator will determine the seriousness, intensity, and causality of an AE associated with 
the use of the study drug (i.e., events where there is a reasonable possibility that the event may 
have been caused by the study drug) based on the definitions that follow. 
15.3.1 
Serious Adverse Events 
(Notify sponsor or designee within 24 hours of first awareness) 
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, with Title 21 Part CFR 312.32, and the Guidance for Industry and Investigators 
Safety Reporting Requirements for INDs and BA/BE Studies. 
SAE:  An AE is considered "serious" if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: 
• Death:  This includes any death that occurs while the subject is “on study” as well as any 
death that occurs within 30 days after last dose of study drug administration.  
Note: Death is an outcome of an AE, and not an AE in itself.  The event(s) that 
caused death (e.g. illness, accident) is the SAE.  Death due to any other 
cause(s) must also be reported as an outcome of the reportable SAE. 
• Life-threatening adverse event:  An AE or suspected adverse reaction is considered 
“life-threatening” if, in the view of either the investigator or sponsor, its occurrence 
places the patient or subject at immediate risk of death. It does not include an AE or 
suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death). 
• Inpatient hospitalization or prolongation of existing hospitalization: 
In the absence of an AE, the investigator should not report hospitalization or prolongation of 
hospitalization. This is the case in the following situations: 
• Hospitalization or prolongation of hospitalization is needed for a procedure 
required by the protocol; 
• Hospitalization or prolongation of hospitalization is part of routine procedure 
followed by study center; 
• Hospitalization for survey visits or annual physicals. 
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In addition, a hospitalization planned before the start of the study for a pre-existing condition 
which has not worsened does not count as an SAE. 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions;  
• Congenital anomaly/birth defect; 
• Important medical event: An event that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, it may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
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 
AE; 
• 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 
(e.g. hospitalization for elective surgery, social and/or convenience admissions). 
15.3.2 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
(Notify sponsor or designee within 24 hours of first awareness) 
A suspected unexpected serious adverse reaction is any adverse drug event, the specificity or 
severity of which is not consistent with those noted in the current protocol and/or Investigator’s 
Brochure (IB).  This refers to any AE that has not been previously observed (e.g. included in the 
IB), rather than from the perspective of such an event not being anticipated from the 
pharmacological properties of the product.  
15.3.3 
Unexpected Adverse Events  
An AE is considered “unexpected” if it is not listed in the Investigator Brochure (IB) or is not 
listed at the specificity or severity that has been observed; or, if an IB is not required or available, 
is not consistent with the risk information described in the General Investigational Plan or 
elsewhere in the current application. Also refers to AEs that are mentioned in the IB as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, but are 
not specifically mentioned as occurring with the particular drug under investigation. 
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15.3.4 
Non-Serious Adverse Events  
All other AEs, not fulfilling the previous definitions, are classified as non-serious. 
15.3.5 
Protocol-Related Adverse Events 
AEs that are not test drug related may nevertheless 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. 
15.3.6 
Relationship/Causality to Study Drug 
The investigator will attempt to assess the relationship of the event to study drug using a 5- point 
scale (not related, unlikely-related, possibly related, probably related, or definitely related). 
15.3.7 
Recording Adverse Events 
All AEs (including SAEs) are to be accurately recorded on the Adverse Event page of the 
subject’s eCRF.  The date of onset as well as the duration of the event also should be recorded. 
In addition, the method used to treat the AE and the outcome of the AE also will be noted. The 
investigator will assess the relationship of the event to study drug (not related, unlikely-related, 
possibly related, probably related, or definitely related). 
15.3.8 
Adverse Event Monitoring and Follow-Up 
The investigator will follow all subjects who experience AEs until there is a return to the 
subject’s baseline condition, Grade 1 severity or until a clinically satisfactory resolution has been 
achieved. 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.  
15.3.9 
Laboratory and ECG Abnormalities 
For the purposes of grading creatinine, the ULN – not the subject’s Cycle 1 Day 1 value - will be 
used to determine grade. 
For the purpose of grading sodium, values of 126–130 mmol/L will be considered to be Grade 2 
and values of 120–125 mmol/L will be considered Grade 3. 
For the purposes of this study, ECG abnormalities will be handled in the same manner as 
laboratory abnormalities. 
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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, i.e., 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 AEs. 
Clinically Significant (CS) Laboratory Abnormalities 
Any laboratory abnormality that is considered to be clinically significant by the investigator will 
be recorded on the AE eCRF. A clinically significant 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 
AE eCRF/record and the SAE Form. If a subject experiences a serious toxicity or dies, the FDA 
will be notified within 24 hours, as required. 
15.3.10 
Pregnancy 
If any subject becomes pregnant following the first dose of tesevatinib, the subject will be taken 
off study and 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 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. 
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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. 
15.3.11 
Serious Adverse Event Reporting 
15.3.11.1 
Governing Regulatory Requirements 
Compliance with this request for prompt reporting is essential in that the sponsor is responsible 
for informing the USFDA as well as all other participating investigators of the event.  
Under FDA ruling (US CFR, Title 21 CFR Part 312.32) and the Guidance for Industry and 
Investigators Safety Reporting Requirements for INDs and BA/BE Studies, the sponsor is 
required to submit written documentation, in the form of an IND safety report, detailing: 
Any event associated with the use of the drug, that is both serious and unexpected, or  
Any findings from clinical, epidemiological, or pooled analysis of multiple studies or any 
findings from animal or in vitro testing that suggest a significant risk in humans exposed to the 
drug.  
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.  
Any unexpected fatal or life-threatening suspected adverse reaction must be reported to FDA no 
later than 7 calendar days after the sponsor’s initial receipt of the information. The sponsor shall 
also inform all investigators. 
15.3.11.2 
Time-Frame for Reporting 
Any death, pregnancy, or SAE experienced by a subject 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). Fax: 1-646-430-9549. 
In the event of an issue with the fax line, forward the SAE form via email to 
ClinicalSAEReporting@kadmon.com. 
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The investigator will be able to contact the safety medical monitor at all times: 
Sanjay Aggarwal, MD 
Vice President Clinical Development, Medical Monitor 
Kadmon Corporation 
55 Cambridge Parkway 
Cambridge, MA 02142 
Mobile Phone:   857-253-8642 
 
E-mail:   Sanjay.aggarwal@kadmon.com 
15.3.11.3 
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 (i.e., the seriousness criteria) and the investigator’s assessment of the 
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. There is no requirement that the chosen SAE term be listed 
in the NCI-CTCAE Version 4.03; 
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• Death should not be reported as an SAE, but as an outcome of a specific SAE, unless the 
event preceding the death is unknown.  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, e.g. 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, e.g. 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. 
15.3.12 
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. 
15.3.13 
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 (e.g. 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. 
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15.4 Other Safety Considerations 
15.4.1 
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. 
15.4.2 
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 either resolution of the event or determination by the 
investigator that the event has returned to baseline/resolved, Grade 1 or has become stable. This 
follow-up guidance also applies to SAEs that occur more than 30 days after last dose of study 
treatment.  
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16 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. The summary of time-to-event variables will 
include Kaplan-Meier methods as appropriate. 
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.  
Additional statistical details will be provided in a prospective statistical plan. 
16.1 General Design  
This is a multicenter, open-label Phase 2 study to assess the activity of tesevatinib in subjects 
with NSCLC and activating EGFR mutations and BM or LM. 
16.2 Sample Size Justification  
For Cohort A, assuming that 20% of subjects with BM have RECIST 1.1 response (CR or PR), 
the study has an approximately 80% chance of having at least 3 subjects with RECIST 1.1 
response, and an over 90% chance of at least 2 subjects having a response. All subjects who take 
at least one dose of study drug will be evaluable for safety and efficacy assessments. 
For Cohort B, assuming that 20% of subjects with LM have improvement in at least one 
symptom or sign attributed to leptomeningeal metastases, the study has an approximately 80% 
chance of having at least 3 subjects with improvement in at least one symptom or sign attributed 
to leptomeningeal metastases and an over 90% chance of at least 2 subjects having improvement 
attributed to leptomeningeal metastases.  All subjects who take at least one dose of study drug 
will be evaluable for safety and efficacy assessments. 
For Cohort C, assuming that 20% of subjects with BM have RECIST 1.1 response (CR or PR), 
the study has an approximately 80% chance of having at least 3 subjects with RECIST 1.1 
response, and an over 90% chance of at least 2 subjects having a response.  All subjects who take 
at least one dose of study drug will be evaluable for safety and efficacy assessments. 
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16.3 Statistical Considerations  
16.3.1 
Study Populations  
Adult subjects with NSCLC who have progressed with BM or LM, or who have brain metastases 
at initial presentation, will be enrolled.  
All subjects who take at least one dose of study drug will be evaluable for safety and efficacy 
assessments. 
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 will be defined as completion of the first cycle of study drug 
administration, or discontinuation prior to that time for an AE. 
The PK population will consist of all subjects who receive at least one dose of tesevatinib, and 
who have at least one sample for PK for a dosing interval. 
16.3.2 
Subject Accountability, Demographics, and Cycle 1 Day 1 Characteristics  
Subject disposition, demographic information and Cycle 1 Day 1 characteristics will be tabulated 
by dose cohort and overall for tesevatinib. 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. 
16.3.3 
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.  The distribution of the number of cycles 
achieved per subject will also be summarized. In addition, delays and all other alterations in 
tesevatinib administration will be presented.  
16.3.4 
Concomitant Medications  
Concomitant medications will be coded using WHO Drug Dictionary (WHO-DD March 2014, 
Type B2 or later) and the data will be summarized by dose cohort and presented in tables and 
listings. 
16.3.5 
Pharmacokinetics 
In Cohort B only, plasma samples will be obtained at predose on Day 14 of Cycle 1; and at 
predose on Day 1 of Cycle 3. A plasma sample will also be obtained on Cycle 1 Day 14, and Day 
1 of Cycle 3 within the 4-8 hours after tesevatinib administration. 
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In all cohorts, additional samples for the preparation of plasma will be collected for tesevatinib 
analyses if the QTc(F) interval increases by > 60 msec above average Cycle 1 Day 1 (predose on 
Day 1) or to the level of ≥ 500 msec. 
Plasma concentrations of tesevatinib will be summarized by dose, sample collection day, and 
sample collection time for each drug using descriptive statistics. 
For subjects in Cohort B, CSF PK samples will be obtained on Cycle 1 Day 14 and on Cycle 3 
Day 1, within approximately 4–8 hours after tesevatinib administration of the tesevatinib dose 
that day.  Tesevatinib concentrations in the plasma and CSF will be summarized at each 
scheduled collection time point using descriptive statistics, and displayed graphically.  These 
data alone, or pooled with data from other studies, may be analyzed in a population PK analysis 
using nonlinear mixed effects modeling. 
16.3.6 
Efficacy/Activity 
Descriptive statistics, including 95% confidence intervals for improvement in symptoms 
attributed to leptomeningeal metastases, clearing of NSCLC cells in the CSF, and clearing of 
CNS MRI findings will be presented.  Exploratory evaluation of efficacy results by EGFR 
mutation will be performed. 
Efficacy/Activity analyses will present results by Cohort and, where appropriate, the three 
cohorts combined. 
In addition, identical statistics for the change and percent change from Cycle 1 Day 1 tumor 
measurements will be presented. These analyses will be done after each two cycles of therapy, 
and will include peripheral (non-CNS) tumors as well as brain metastases. Summary statistics 
will be produced for PFS and OS. The percentage of subjects without disease progression after 3 
and 6 months of dosing will also be presented separately by local and central radiograph results.  
16.3.7 
Safety Data  
Safety analyses will be performed on all subjects who received any quantity of study drug.  AEs 
that are not related 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 analyses will present results by Cohort and, where appropriate, the three cohorts 
combined. 
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Safety observations and measurements include AEs, safety laboratory tests, vital sign 
measurements, physical examinations, pregnancy status, ECG assessments, and pharmacokinetic 
data.  
Treatment-emergent AEs will be summarized using the Medical Dictionary for Regulatory 
Activities (MedDRA®) (Version 18.1 or higher) 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 grade using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE; 
Version 4.03). The number of events per preferred term will also be summarized.  Causality 
(relationship to study treatment) will be summarized separately. 
AEs, SAEs, related AEs, related SAEs, ≥ Grade 3 AEs, related ≥ Grade 3 AEs, and AEs leading 
to withdrawal, dose modification, or treatment discontinuation will be summarized by cohort and 
tesevatinib overall according to SOC and preferred terms.  AEs will also be summarized in 
listings. Duration of AEs will be determined and included in listings, along with action taken and 
outcome. 
Laboratory results will be classified according to NCI-CTCAE Version 4.03 and summarized by 
cohort. Laboratory results not corresponding to a coded term will not be graded. 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 ≥ Grade 3 laboratory abnormalities under 
treatment and shifts in toxicity grading from Cycle 1 Day 1 to highest grade post-Cycle 1 Day 1 
will be displayed. Results for variables that are not coded will be presented in the listings as 
below, within, and above the normal limits of the local laboratory. 
Vital sign measurements will be summarized at each scheduled time point using descriptive 
statistics.  ECOG performance status results will be summarized by scheduled time point. 
Additional statistical details will be provided in a prospective statistical plan. 
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 
summarized separately. Covariate analyses will be employed as necessary (e.g. QTc[F] interval 
vs. plasma drug concentration). 
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17 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 (e.g. CRO) to view the eCRFs after completion of the 
individual 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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18 ETHICAL ASPECTS 
18.1 Local Regulations 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
ICH E6 Tripartite Guideline (January 1997), and in general, be conducted 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”. 
18.2 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 trial, 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. 
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 
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the new information, should be given a copy of the revised form, and should give their written 
consent to continue in the study. 
18.3 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. 
18.4 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 trial. 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 oncology 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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19 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 trial (e.g. 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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20 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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21 STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
21.1 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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21.2 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 AEs; 
• 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 trial; 
• 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. 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. 
21.3 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 
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designee), or to health authority inspectors after appropriate notification. The verification of the 
eCRF data must be by direct inspection of source documents. 
21.4 Electronic Case Report Forms 
Clinical trial 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.  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, 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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22 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 trial 
(eCRFs and other pertinent data) provided that subject confidentiality is maintained in 
accordance with local requirements.  The principal investigator and key trial 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 must 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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23 CONFIDENTIALITY OF TRIAL 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 showing codes, names, and 
addresses. The investigator should maintain documents not for submission to Kadmon 
(e.g. 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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24 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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25 REFERENCES 
1) 
Ohashi K, Maruvka YE, Michor F, et al.  Epidermal growth factor receptor tyrosine kinase 
inhibitor-resistant disease.  J Clin Oncol.  2013;31:1070-80. 
2) 
Gainor JF and Shaw AT.  Emerging paradigms in the development of resistance to tyrosine 
kinase inhibitors in lung cancer.  J Clin Oncol. 2013; 31:3987-96. 
3) 
Jackman DM, Cioffredi LA, Jacobs L, et al.  A Phase 1 trial of high dose gefitinib for patients 
with leptomeningeal metastases from non-small cell lung cancer.  Oncotarget. 2015 Feb 
28;6(6):4527-36.. 
4) 
Hoffknecht P, Tufman A, Wehler, et al.  Efficacy of the irreversible ErbB family blocker 
afatinib in EGFR TKI-pretreated non-small-cell lung cancer patients with brain metastases or 
leptomeningeal disease.  J Thorac Oncol. 2015;10:156-163. 
5) 
Togashi Y, Masago K, Masuda S, et al.  Cerebrospinal fluid concentration of gefitinib and 
erlotinib in patients with non-small cell lung cancer.  Cancer Chemother Pharmacol. 2012; 
70:399-405.  
6) 
Heon S, Yeap BY, Britt GJ, et al.  Development of central nervous system metastases in 
patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with 
gefitinib or erlotinib.  Clin Cancer Res. 2010;16:5873-82. 
7) 
Chang EL, Wefel JS, Hess KR, et al.  Neurocognition in patients with brain metastases 
treated with radiosurgery or radiosurgery plus whole-brain irradiation: A randomized 
controlled trial.  Lancet Oncol 2009; 10:1037-1044. 
8) 
Jackman DM, Holmes AJ, Lindeman N, et al.  Response and resistance in a non-small-cell 
lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal 
metastases treated with high-dose gefitinib.  J Clin Oncol. 2006; 24:4517-20. 
9) 
Katayama T, Shimuzu J, Suda K, et al.  Efficacy of erlotinib for brain and leptomeningeal 
metastases in patients with lung adenocarcinoma who showed initial good response to 
gefitinib.  J Thorac Oncol. 2009;4:1415-19. 
10) Chamberlain M, Soffietti R, Raizer J, et al.  Leptomeningeal metastasis: a response 
assessment in neuro-oncology.  Critical review of endpoints and response criteria of published 
randomized clinical trials.  Neuro-Oncology. 2014;16:1176-1185. 
11) Nayak L, Fleisher M, Gonzalez-Espinosa R, et al.  Rare cell capture technology for the 
diagnosis of leptomeningeal metastases in solid tumors.  Neurology. 2013;80:1598-1605. 
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12) Yang H, Cai L, Zhang Y, et al.  Sensitive detection of EGFR mutations in cerebrospinal fluid 
from lung adenocarcinoma patients with brain metastases.  J Molec Diagnostics 2014; 16:558-
563. 
13) Gendreau SB, Ventura R, Keast P, et al.  Inhibition of the T790M gatekeeper mutant of the 
epidermal growth factor receptor by EXEL-647.  Clin Cancer Res. 2007; 13:3713-23. 
14) Pietanza MC, Lynch TJ, Lara PN, et al.  XL-647 – A multitargeted tyrosine kinase inhibitor.  
Results of a Phase II study in subjects with non-small cell lung cancer who have progressed 
after responding to treatment with either gefitinib or erlotinib.  J Thorac Oncol. 2012; 7:219-
26. 
15) Hata A, Katakami N, Yoshioka H, et al.  Rebiopsy of non-small cell lung cancer patients with 
acquired resistance to EGFR-TKI: Comparison between T790M mutation-positive and –
negative populations.  J Clin Oncol. 2012; 30:(suppl; abstr 7528). 
16) Strevel EL, Ing DJ, Siu LL. Molecularly targeted oncology therapeutics and prolongation of 
the QT interval. J Clin Oncol. 2007;25(22): 3362–3371. 
17) Pietanza MC, Gadgeel SM, Dowlati A, et al.  Phase II study of the multitargeted tyrosine 
kinase inhibitor XL647 in patients with non-small cell lung cancer.  J Thorac Oncol. 
2012;7:856-865. 
18) Pietanza MC, Lynch TJ, Lara PN, et al.  XL647 – A multitargeted tyrosine kinase inhibitor: 
Results of a phase II study in subjects with non-small cell lung cancer who have progressed 
after responding to treatment with either gefitinib or erlotinib.  J Thorac Oncol. 2012;7:219-
226. 
19) Weickhardt AJ, Scheler B, Burke JM, et al.  Local ablative therapy of oligoprogressive 
disease prolongs disease control by tyrosine kinase inhibitors in oncogene addicted non-small 
cell lung cancer.  J Thorac Oncol 2012;7:1807-14. 
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APPENDIX A: 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST), VERSION 1.1 
Use for Non-CNS Response 
Quick Reference 
Source: van Persijn van Meerten EL, Gelderblom H, Bloem JL. RECIST revised: Implications for the radiologist. A 
review article on the modified RECIST guideline (Version 1.1).  European Journal of Cancer. 2009; 
45:228-247. Eur Radiol. 2010:20; 1456–1467. 
 
RESPONSE CRITERIA  
 
 
Definitions 
Evaluable for objective response: Only those subjects who have measurable disease present at 
screening, have received at least 2 cycles of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These subjects will have their response classified 
according to the definitions stated below. (Note:  Subjects who exhibit objective disease 
progression prior to the end of Cycle 2 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response: Subjects who have lesions present at screening that 
are evaluable but do not meet the definitions of measurable disease, have received at least 2 
cycles of therapy, and have had their disease re-evaluated will be considered evaluable for non-
target disease. The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions. 
 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least 1 dimension (longest diameter for non-nodal lesions and short axis for nodal lesions to be 
recorded) as ≥ 20 mm by chest X-ray, as ≥ 10 mm with chest, abdominal, or pelvic CT scan or 
with MRI of brain, or ≥ 10 mm with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area may be considered 
measurable if they have increased in size.   
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At Screening and in follow-up, only the short axis 
will be measured and followed. 
 
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Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at Screening. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the Screening sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The Screening sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at Screening. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
Screening evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at Screening and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
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Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g. skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers 
(e.g. skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
 
Chest X-ray:  Lesions on chest X-ray are not acceptable as measurable lesions in this study. 
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI in this study is required for evaluation for brain metastases. 
 
FDG-PET-CT:  Not acceptable for this study. 
 
Ultrasound:  Not acceptable for this study. 
 
Endoscopy, Laparoscopy:  Not acceptable for this study. 
 
FDG-PET: Not acceptable for this study. 
 
Response Criteria 
Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to < 10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the Screening sum diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the Screening sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note:  the 
appearance of 1 or more new lesions is also considered 
progression). 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
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diameters while on study. 
 
Note for subjects with scans that are on the “borderline” of disease progression (e.g. 21% 
increase in sum of target lesion diameters) but for whom the investigator determines a clinical 
benefit:  These subjects will be allowed to continue in the study after discussion with the medical 
monitor. If improvement is documented at the next subsequent staging time point (e.g. 17% 
increase), the subject will continue on study.  If worsening is documented (e.g. 30% increase in 
sum of target lesion diameters), the subject should be discontinued from the study, and the 
progression date should be the original date on which “borderline” disease progression was first 
documented. 
 
Target lesions that become “too small to measure”.   
While on study, all lesions (nodal and non-nodal) recorded at Cycle 1 Day 1 should have their 
actual measurements recorded at each subsequent evaluation, even when very small (e.g. 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at Cycle 1 Day 
1 become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being “too small to measure”. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the 
lesion has likely disappeared, the measurement should be recorded as 0mm. If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5mm 
should be assigned. (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible; 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, 
that should be recorded, even if it is below 5 mm. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological 
in size (< 10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal 
limit, they must normalize for a subject to be considered in 
complete clinical response. 
 
Non-CR/Non-PD:  
Persistence of 1 or more non-target lesion(s) and/or 
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maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): 
Appearance of 1 or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It 
must be representative of overall disease status change, not a 
single lesion increase.     
 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
principal investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The subject's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
For Subjects with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥ 4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
≥ 4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once 
≥ 4 wks. from Screening** 
PD 
Any 
Yes or No 
PD 
 
No prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
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For Subjects with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD 
is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
 
Note for subjects with scans that are on the “borderline” of disease progression (e.g. 21% 
increase in sum of target lesion diameters) but for whom the investigator determines a clinical 
benefit:  These subjects will be allowed to continue in the study after discussion with the medical 
monitor.  If improvement is documented at the next subsequent staging time point (e.g. 17% 
increase), the subject will continue on study.  If worsening is documented (e.g. 30% increase in 
sum of target lesion diameters), the subject should be discontinued from the study, and the 
progression date should be the original date on which “borderline” disease progression was first 
documented. 
 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the Screening measurements.  
 
Progression-Free Survival 
PFS will be calculated as a secondary endpoint for all subjects and will represent the time 
between initiation of therapy to the time of documentation of progression of disease or death. 
 
 
 
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APPENDIX B: 
ECOG PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g. light 
housework, office work). 
2 
In bed < 50 % of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50 % of waking 
hours. 
3 
In bed > 50 % of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100 % bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
 
 
 
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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
APPENDIX C: 
QTC(F) CALCULATION 
 
The formula is:  
 
𝑄𝑄𝑄𝑄𝐹𝐹=
𝑄𝑄𝑄𝑄
𝑅𝑅𝑅𝑅1/3 
 
 
1. Manually and carefully measure the QT msec (use the longest) 
2. The "RR interval in seconds" = dividing 60/heart rate 
3. Power of 1/3 = 0.34 
4. Take the RR and elevate it to the power of 0.34 
5. Divide the QT by that number 
 
Example: 
 
1. For a QT of 400 msec and a heart rate of 80 bpm 
2. RR interval = 60/heart rate = 60/80 = 0.75 
3. 0.750.34 = 0.9 
4. 400/0.9 = QTc(F) = 444 msec 
5. The QTc(F) for a QT of 400 msec and a heart rate of 80 bpm is 444. 
 
 
 
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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
APPENDIX D: 
CONCOMITANT DRUGS THAT SHOULD BE USED WITH 
CAUTION* 
Use of drugs that are substrates of the CYP3A4/5 family should be with caution in subjects who 
are receiving tesevatinib if deemed clinically necessary and the subject can be closely monitored 
for the desired drug effect and potential AEs. The following drugs induce or are a substrate for 
CYP3A4/5. This list is not comprehensive, and all concomitant medications should be 
evaluated for possible interactions with tesevatinib. 
Drug Type 
Drug Names 
Anti-arrhythmics 
quinidine**  
Anti-epileptics 
carbamazepine, phenytoin, phenobarbital 
Antihistamines 
astemizole, chlorpheniramine 
Benzodiazepines 
alprazolam, diazepam, midazolam, triazolam 
Calcium channel blockers 
amlodipine, felodipine, lercanidipine, nifedipine, nisoldipine, 
nitrendipine 
Central nervous system depressants  
barbiturates  
HMG CoA reductase inhibitors 
atorvastatin, cerivastatin, lovastatin, simvastatin 
Immune modulators 
cyclosporine, tacrolimus 
Miscellaneous 
amodiaquine, repaglinide, rifampin, torsemide, St John’s Wort 
Neuro-psychotropics 
buspirone, haloperidol, methadone, pimozide 
Steroids 
estradiol, hydrocortisone, progesterone, testosterone 
Reference: http://medicine.iupui.edu/flockhart/table.htm 
HMG CoA, hydroxyl-methylglutaryl coenzyme A. 
*Should be discussed with medical monitor 
**Drugs that must be avoided per Appendix F, Concomitant Medications Associated With a Risk of QTc Interval Prolongation 
and/or Torsades de Pointes 
 
Use of drugs that are substrates of the CYP2D6 also should be with caution in subjects who are 
receiving tesevatinib if deemed clinically necessary and the subject can be closely monitored for 
the desired drug effect and potential AEs. 
 
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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
Substrates of CYP2D6 
Amitriptyline 
Amoxapine 
Aripiprazole 
Atomoxetine 
Betaxolol 
Captopril 
Carvedilol 
Chloroquine 
Chlorpromazine 
Clomipramine 
Codeine 
Desipramine 
Dextroamphetamine 
Dextromethorphan 
Dihydrocodeine 
Doxepin 
Doxorubicin 
Duloxetine 
Flecainide 
Fluoxetine 
Fluphenazine 
Fluvoxamine 
Haloperidol  
Hydrocodone 
Imipramine 
Labetalol 
Lidocaine 
Lomustine 
Maprotiline 
Methamphetamine 
Methylphenidate 
Metoprolol 
Mexiletine 
Mirtazapine 
Moclobemide 
Nefazodone 
Nortriptyline 
Oxycodone 
Paroxetine 
Perphenazine 
Pindolol 
Pipotiazine 
Procainamide 
Promethazine 
Propafenone 
Propranolol 
Protriptyline 
Risperidone 
Sertraline 
Tamoxifen 
Tamsulosin 
Thioridazine 
Timolol 
Tolterodine 
Tramadol 
Trimipramine 
Venlafaxine 
Zuclopenthixol 
 
In addition, use of drugs that are CYP1A2 inducers and inhibitors should be with caution in 
subjects who are receiving tesevatinib if deemed clinically necessary and the subject can be 
closely monitored for the desired drug effect and potential AEs. 
CYP1A2 Inducers 
CYP1A2 Inhibitors 
Barbiturates 
Carbamazepine (e.g. Tegretol) 
Primidone 
Rifampin (e.g. Rifadin) 
 
Artemisinin 
Atazanavir (Reyataz) 
Cimetidine (Tagamet) 
Ciprofloxacin (Cipro) 
Enoxacin 
Ethinyl Estradiol 
Fluvoxamine 
Mexiletine 
Tacrine (Cognex) 
Thiabendazole 
Zileuton (Zyflo 
 
 
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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
Concomitant Drugs That Should Be Used with Extreme Caution* 
Use of drugs that are inhibitors of the CYP3A4/5 family should be with caution in subjects who 
are receiving tesevatinib if deemed clinically necessary and the subject can be closely monitored 
for the desired drug effect and potential AEs. The following drugs are inhibitors of the 
CYP3A4/5 family. Use of these drugs may alter the pharmacokinetics of the study drug. This list 
is not comprehensive, and all concomitant medications should be evaluated for possible 
interactions with tesevatinib. 
Drug Type 
Drug Names 
Anti-arrhythmics 
amiodarone** 
Antibiotic 
norfloxacin, trimethoprim 
Antidepressant 
fluvoxamine, nefazodone, norfluoxetine 
Antiemetic 
Aprepitant 
Antifungal medications 
fluconazole, itraconazole, ketoconazole 
Calcium channel blockers 
diltiazem, verapamil 
Macrolide antibiotics 
clarithromycin*, erythromycin*, telithromycin 
Miscellaneous 
cimetidine, gemfibrozil, montelukast, quercetin, grapefruit juice 
Oral hypoglycemic agents 
Glitazones 
*Should be discussed with medical monitor first 
**Drugs that must be avoided per Appendix F, Concomitant Medications Associated with a Risk of QTc Interval Prolongation 
and/or Torsades de Pointes 
 
 
 
 
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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
APPENDIX E: 
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 tesevatinib unless deemed 
clinically necessary.  Discuss with medical monitor the appropriate monitoring of subjects while 
receiving any of these drugs in conjunction with tesevatinib. Subjects 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 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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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
APPENDIX F: 
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  
Cordran Ointment, 0.05% 
Flurandrenolide 
Elocon Cream/Lotion, 0.1% 
Mometasone furoate 
Kenalog Cream/Spray, 0.1% 
Triamcinolone acetonide 
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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
Brand Name 
Generic Name 
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). 
 
 
 
 
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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
APPENDIX G: 
EORTC QLQ-C30 QUESTIONNAIRE 
EORTC QLQ-C30 (two pages) 
 
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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
 
 
 
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Tesevatinib  
Protocol Number KD019-206 
Amendment 4 
 
APPENDIX H: 
EORTC QLQ-BN20 QUESTIONNAIRE (ONE PAGE) 
 
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SAP_001.pdf: 
 
Kadmon Corporation 
 
 
KD019-206                                                                                            Statistical Analysis Plan 
 
SAP Version 1.0, 5 October 2018 
 
 
 
 
       Page 1 of 14 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 2, Multicenter Study of Tesevatinib in Subjects with Non-Small 
Cell Lung Cancer, EGFR Activating Mutation, Prior Treatment with a 
Tyrosine Kinase Inhibitor, and Brain Metastases or Leptomeningeal 
Metastases 
 
Protocol Number: KD019-206 
 
 
 
Statistical Analysis Plan Version: 
Date of Statistical Analysis Plan: 
 
 
Version 1 
 
5 October 2018 
 
 
 
 
 
 
 
 




 
Kadmon Corporation 
 
 
KD019-206                                                                                            Statistical Analysis Plan 
 
SAP Version 1.0, 5 October 2018 
 
 
 
 
       Page 3 of 14 
 
DOCUMENT HISTORY 
 
Version 
Author 
Description 
1.0 
Zhongming Yang 
New Document 
 
 


 
Kadmon Corporation 
 
 
KD019-206                                                                                            Statistical Analysis Plan 
 
SAP Version 1.0, 5 October 2018 
 
 
 
 
       Page 4 of 14 
 
Table of Contents 
1 
Study Summary ................................................................................................... 6 
1.1 
Study Objectives .............................................................................................. 6 
1.1.1 
Cohort A.................................................................................................. 6 
1.1.2 
Cohort B .................................................................................................. 6 
1.1.3 
Cohort C .................................................................................................. 7 
1.2 
Study Design .................................................................................................... 7 
1.2.1 
Sample Size Justification ........................................................................ 7 
1.2.2 
Study Population / Number of Subjects .................................................. 8 
1.2.3 
Dosage and Admiration .......................................................................... 8 
1.2.4 
Duration of treatment/ Discontinuation .................................................. 8 
1.2.5 
Analysis Populations ............................................................................... 8 
1.3 
Efficacy Assessments ....................................................................................... 9 
1.3.1 
Efficacy Endpoints .................................................................................. 9 
1.3.2 
Safety Assessments ................................................................................. 9 
1.3.3 
Pharmacokinetic Endpoints .................................................................. 10 
1.3.4 
Pharmacodynamic Endpoints ................................................................ 10 
2 
Statistical Methods ............................................................................................ 10 
 
Table of Tables 
Table 1  Content of efficacy tables ............................................................................... 12 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Full Term 
AE 
Adverse event 
BM 
Brain metastases 
CNS 
Central nervous system 
CR 
Complete response 
CSF 
Cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
HLT 
High level terms 
LM 
Leptomeningeal metastases 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
OS 
Overall survival 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Preferred Term 
QLQ 
Quality of Life Questionnaire 
QOL 
Quality of Life 
QTcF 
QT interval corrected by Fredericia 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TTP 
Time to progression 
VS 
Vital signs 
 


 
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1 Study Summary 
1.1 Study Objectives 
1.1.1 Cohort A 
Primary objectives: 
• To evaluate the clinical activity of tesevatinib in subjects with non-small cell 
lung cancer (NSCLC), activating epidermal growth factor (EGFR) mutations, 
and brain metastases (BM) as measured by Response Evaluation Criteria In 
Solid Tumors (RECIST) version 1.1 evaluated changes in BM size. 
Secondary objectives: 
• To evaluate changes in Quality of Life (QOL) in subjects receiving tesevatinib 
for BM. 
• To determine the median progression-free survival (PFS), rate of central 
nervous system (CNS) non-progression at 3 and 6 months, non-CNS time to 
progression (TTP), and CNS TTP. 
• To determine the median overall survival (OS). 
Exploratory Objective 
• To evaluate the correlation between EGFR deoxyribonucleic acid (DNA) 
mutations seen in plasma cell free DNA at screening with response. 
1.1.2 Cohort B 
Primary objectives: 
• To evaluate the clinical activity of tesevatinib in subjects with NSCLC, 
activating EGFR mutations, and leptomeningeal metastases (LM) as measured 
by improvement in Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03 symptoms and signs. 
Secondary objectives: 
• To evaluate the activity of tesevatinib in subjects with NSCLC, EGFR 
activating mutations and LM as measured by decreases in NSCLC cells in the 
cerebrospinal fluid (CSF) using standard cytology. 
• To evaluate the activity of tesevatinib in subjects with NSCLC, EGFR 
activating mutations and LM as measured by improvement in CNS magnetic 
resonance imaging (MRI) findings. 
• To evaluate the pharmacokinetics (PK) of tesevatinib in CSF versus plasma. 
• To evaluate changes in QOL in subjects receiving tesevatinib for LM. 


 
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• To determine the median PFS, rate of CNS non-progression at 3 and 6 months, 
non-CNS TTP, and CNS TTP. 
• To determine the median OS. 
Exploratory Objective 
• To evaluate the correlation between EGFR DNA mutations seen in plasma cell 
free DNA at screening with response. 
• To evaluate the activity of tesevatinib in subjects with NSCLC, EGFR 
activating mutations and LM as measured by decreases in NSCLC cells in the 
CSF using rare cell capture techniques. 
• To evaluate the activity of tesevatinib in subjects with NSCLC, EGFR 
activating mutations and LM measured by decreases in CSF cell-free DNA. 
• To utilize CSF cell-free DNA to detect activating EGFR mutations in patients 
receiving tesevatinib for LM. 
1.1.3 Cohort C 
Primary objectives: 
• To evaluate the clinical activity of tesevatinib in subjects with NSCLC, 
activating EGFR mutations, and BM at initial presentation as measured by 
RECIST 1.1 evaluated changes in BM size. 
Secondary objectives: 
• To evaluate changes in QOL in subjects receiving tesevatinib for BM. 
• To determine the median PFS, rate of CNS non-progression at 3 and 6 months, 
non-CNS TTP, and CNS TTP in subjects with NSCLC, activating EGFR 
mutations, and BM at initial presentation. 
• To determine the median OS. 
Exploratory Objective 
• To evaluate the correlation between EGFR DNA mutations seen in plasma cell 
free DNA at screening with response. 
1.2 Study Design 
This is a multicenter, open-label Phase 2 study to assess the activity of tesevatinib in 
subjects with NSCLC and activating EGFR mutations and BM or LM. 
1.2.1 Sample Size Justification 
For Cohort A, assuming that 20% of subjects with BM have response (complete 
response [CR] or partial response [PR]), N=20 has an approximately 80% chance of 


 
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       Page 8 of 14 
 
having at least 3 subjects with response, and an over 90% chance of at least 2 subjects 
having a response.  
 
For Cohort B, assuming that 20% of subjects with LM have improvement in at least 
one symptom or sign attributed to LM, N=20 has an approximately 80% chance of 
having at least 3 subjects with improvement in at least one symptom or sign attributed 
to leptomeningeal metastases and an over 90% chance of at least 2 subjects having 
improvement attributed to LM. 
 
For Cohort C, assuming that 20% of subjects with BM have response (CR or PR), 
N=20 has an approximately 80% chance of having at least 3 subjects with response, 
and an over 90% chance of at least 2 subjects having a response.  
1.2.2 Study Population / Number of Subjects 
Up to 20 subjects with NSCLC who have progressed with BM will be enrolled in 
Cohort A. Up to 20 subjects who have initial presentation or progressed with LM will 
be enrolled in Cohort B. Up to 20 subjects with NSCLC and BM and no prior systemic 
therapy will be enrolled in Cohort C. Cohort A, Cohort B, and Cohort C will be open 
for enrollment simultaneously; when one cohort has completed enrollment the other 
cohorts will remain open for enrollment until enrollment in those cohorts are also 
complete. 
1.2.3 Dosage and Admiration 
Tesevatinib will be administered at the dose of 300 mg once daily. Tesevatinib will be 
used in dosage strength of 100-mg, and 150-mg tablets. Patient diaries will be utilized 
to evaluate compliance. One cycle will be defined as 28 days of treatment. 
1.2.4 Duration of treatment/ Discontinuation 
Subjects will be treated with study drug until disease progression or unacceptable 
toxicity occurs. However, subjects with limited peripheral disease progression 
(oligoprogressive disease) may receive local ablative (radiation therapy or surgery) 
while study drug is withheld for up to 28 days, and then be continued on tesevatinib. 
 
Subjects who discontinue tesevatinib treatment will be followed for survival. 
1.2.5 Analysis Populations 
All subjects who take at least one dose of study drug will be included in efficacy and 
safety analysis. Non-evaluable response will be classified as non-responder. 
 


 
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1.3 Efficacy Assessments 
1.3.1 Efficacy Endpoints 
1.3.1.1 Primary endpoints 
Cohorts A and C: efficacy (changes in BM size) will be evaluated by RECIST 1.1 
criteria separately for non-CNS tumor lesions and for BMs at screening, at Cycle 2 
Day 1 (for BM), at Cycle 3 Day 1, and then every 2 cycles (approximately 8 weeks) 
thereafter until disease progression. 
For Cohort B: symptoms and signs attributed to leptomeningeal disease will be 
evaluated at screening, Cycle 1 Day 1, at Cycle 1 Day 14, at Cycle 2 Day 1, at Cycle 
3, and then every 2 cycles (approximately 8 weeks) thereafter until disease progression 
National Cancer Institute CTCAE (NCI CTCAE; Version 5). Symptom improvement 
is defined as a decrease in 1 grade in at least one CTCAE v4.03 symptom or sign 
attributed to LM without worsening of other symptoms or signs that are attributed to 
LM. Symptom progression is defined as an increase of 1 grade in at least one CTCAE 
v4.03 symptom or the appearance of new symptoms or signs of LM.   
1.3.1.2 Secondary endpoints 
• The PFS, the OS, rate of CNS non-progression at 3 and 6 months, non-CNS TTP, 
and CNS TTP 
• QOL will be evaluated via the European Organisation for Research and Treatment 
of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and EORTC 
QLQ-BN20 questionnaires administered at Screening, on Day 1 of Cycle 3, and on 
Day 1 of odd-numbered cycles thereafter. 
• For Cohort B, decreases in NSCLC cells in the CSF using standard cytology 
• For Cohort B, improvement in CNS MRI findings 
1.3.1.3 Exploratory Endpoints 
• For Cohort B, decreases in NSCLC cells in the CSF using rare cell capture 
techniques  
• For Cohort B, decreases in CSF cell-free DNA 
• For Cohort B, To utilize CSF cell-free DNA to detect activating EGFR mutations 
1.3.2 Safety Assessments 
The NCI CTCAE; Version 5 will be used for grading toxicities. Safety assessments 
will include adverse events (AEs), serious adverse events (SAEs), physical 
examinations, vital sign measurements, clinical safety laboratory evaluations 
(hematology, serum chemistry, and urinalysis), Eastern Cooperative Oncology Group 
(ECOG) scores, and electrocardiograms (ECGs). 
The AE reporting period for a subject enrolled in the study begins when the subject 
provides informed consent and is continued through 30 days after the last dose of 


 
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study drug or until start of new treatment. All AEs that occur in enrolled subjects 
during the AE reporting period specified in the protocol must be recorded, regardless 
of the relationship of the AE to study drug. Any known untoward event that occurs 
beyond the AE reporting period that the investigator assesses as possibly related to 
tesevatinib should be included. 
Vital sign measurements, including sitting blood pressure, pulse rate, respiratory rate, 
and temperature will be monitored throughout the study. 
1.3.3 Pharmacokinetic Endpoints 
For subjects in Cohort B 
• Plasma and CSF PK samples will be obtained on Cycle 1 Day 14 and on 
Cycle 3 Day 1, within approximately 4–8 hours after tesevatinib administration 
• Plasma PK sample will be obtained at predose on Day 14 of Cycle 1 and at 
predose on Day 1 of Cycle 3 
Tesevatinib concentrations in the plasma and CSF will be summarized at each 
scheduled collection time point using descriptive statistics, and displayed graphically  
 
1.3.4 Pharmacodynamic Endpoints 
Some pharmacodynamics endpoints have been included as exploratory endpoints.   
 
2 Statistical Methods 
No formal hypothesis testing will be conducted. Descriptive statistics including 95% 
confidence intervals for response rate, time-to-event and continuous measurements 
will be summarized by cohorts.   
Tesevatinib concentrations in the plasma and CSF will be summarized at each 
scheduled collection time point using descriptive statistics, and displayed graphically. 
AEs, SAEs, Grade 3&4 AEs, related AEs, related SAEs, related Grade 3&4 AEs, 
death, and AEs leading to withdrawal, dose modification, or treatment discontinuation 
will be summarized by cohort and overall according to high level terms (HLT) and 
preferred terms (PT). Adverse events will also be summarized in listings. Duration of 
AEs will be determined and included in listings, along with action taken and outcome. 
Vital sign measurements will be summarized at each scheduled time point using 
descriptive statistics. The ECOG performance status results will be summarized by 
scheduled time point. 


 
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Laboratory results will be classified according to NCI-CTCAE Version 4.03 and 
summarized by cohort. The worst on-study grade after the first dose of study drug will 
be summarized. The incidence of ≥ Grade 3 laboratory abnormalities under treatment 
and shifts in toxicity grading from Cycle 1 Day 1 to highest grade post-Cycle 1 Day 1 
will be displayed. Results for variables that are not coded will be presented in the 
listings as below, within, and above the normal limits of the local laboratory. 
The table of list of tables, listings, and figures is displayed in Table 1. 
 
 
 


 
Kadmon Corporation 
 
 
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SAP Version 1.0, 5 October 2018 
 
 
 
 
       Page 12 of 14 
 
Table 1  Content of efficacy tables 
 
T/F/L 
Number 
Title 
Order 
Population 
Summary Statistics 
T 
1.1.1 
Response rate by cohort 
Primary efficacy 
All treated subjects 
ORR, CR, PR, exact CI  
T 
1.1.2 
Response rate by visit and cohort 
Primary efficacy 
All treated subjects 
ORR, CR, PR, exact CI 
L 
1.1.1 
Tumor size / symptoms and signs  by visit and cohort 
Primary efficacy 
All treated subjects 
T 
1.2.1 
Progression-free survival (PFS) by cohort  
Secondary efficacy 
All treated subjects 
descriptive statistics  
T 
1.2.2 
Overall survival (OS) by cohort  
Secondary efficacy 
All treated subjects 
descriptive statistics  
T 
1.2.3 
non-CNS time to progression by cohort  
Secondary efficacy 
All treated subjects 
descriptive statistics  
T 
1.2.4 
CNS time to progression by cohort  
Secondary efficacy 
All treated subjects 
descriptive statistics  
F 
1.2.1 
Progression-free survival (PFS) by cohort  
Secondary efficacy 
All treated subjects 
KM curve 
F 
1.2.2 
Overall survival (OS) by cohort  
Secondary efficacy 
All treated subjects 
KM curve 
F 
1.2.3 
non-CNS time to progression by cohort  
Secondary efficacy 
All treated subjects 
KM curve 
F 
1.2.4 
CNS time to progression by cohort  
Secondary efficacy 
All treated subjects 
KM curve 
T 
1.3.1 
QOL by visit and cohort 
Secondary efficacy 
All treated subjects 
Descriptive Statistics  
L 
1.4.1 
NSCLC cells in the CSF using standard cytology by visits  
Secondary efficacy 
All treated cohort B subjects 
Descriptive Statistics 
T 
1.4.2 
CNS MRI findings by visits and change from baseline  
Secondary efficacy 
All treated cohort B subjects 
Descriptive Statistics 
L 
1.4.2 
CNS MRI findings by visits  
Secondary efficacy 
All treated cohort B subjects 
source date 
L 
1.5.1 
NSCLC cells in the CSF using rare cell capture techniques by visits 
Exploratory Endpoints 
All treated cohort B subjects 
source date 
L 
1.5.2 
CSF cell-free DNA by visits  
Exploratory Endpoints 
All treated cohort B subjects 
source date 
L 
1.5.3 
EGFR mutations by visits  
Exploratory Endpoints 
All treated cohort B subjects 
source date 
T 
1.6.1 
Plasma concentration by visit  
PK 
All treated cohort B subjects 
Descriptive Statistics 
L 
1.6.1 
Plasma concentration by subject and visit   
PK 
All treated cohort B subjects 
source date 
F 
1.6.1 
Plasma concentration by subject and visit   
PK 
All treated cohort B subjects 
source date 
T 
1.6.2 
CSF concentration by visit  
PK 
All treated cohort B subjects 
Descriptive Statistics 
L 
1.6.2 
CSF concentration by subject and visit  
PK 
All treated cohort B subjects 
Descriptive Statistics 


 
Kadmon Corporation 
 
 
KD019-206                                                                                            Statistical Analysis Plan 
 
SAP Version 1.0, 5 October 2018 
 
 
 
 
       Page 13 of 14 
 
F 
1.6.2 
CSF concentration by subject and visit  
PK 
All treated cohort B subjects 
source date 
Table 2 Content of safety tables 
T/F/L 
Part 
Number 
Title 
Population 
T 
Disposition 
1.1.1 
Patient disposition by cohort 
All enrolled patients 
L 
Disposition 
1.1.1 
Patient disposition  
All enrolled patients 
L 
Disposition 
1.2.1 
Protocol deviations 
All enrolled patients 
T 
Demo 
2.1.1 
Demographics and baseline characteristics by cohort 
All treated patients 
L 
Demo 
2.1.1 
Demographics and baseline characteristics  
All treated patients 
L 
Demo 
2.2.1 
Medical history 
All treated patients 
L 
Demo 
2.3.1 
Disease history 
All treated patients 
L 
CM 
3.1.1 
Prior and concomitant medications 
All treated patients 
T 
Exposure 
4.1.1 
Treatment exposure and compliance by cohort 
All treated patients 
L 
Exposure 
4.1.1 
Treatment exposure and compliance 
All treated patients 
L 
Exposure 
4.2.1 
Dose modifications 
All treated patients 
T 
AE 
6.1.1 
Overall summary of TEAEs by cohort 
All treated patients 
T 
AE 
6.1.2 
TEAEs by SOC/PT and cohort 
All treated patients 
T 
AE 
6.1.3 
Treatment related AEs by SOC/PT and cohort 
All treated patients 
T 
AE 
6.1.4 
Serious TEAEs by SOC/ PT and cohort 
All treated patients 
T 
AE 
6.1.5 
Serious Treatment Related AEs by SOC/PT and cohort 
All treated patients 
T 
AE 
6.1.6 
Grade 3 and 4 TEAEs by SOC/PT and cohort 
All treated patients 
T 
AE 
6.1.7 
Treatment Related Grade 3 and 4 AEs by SOC/PT and cohort 
All treated patients 
T 
AE 
6.1.8 
TEAEs by HLT and cohort 
All treated patients 
T 
AE 
6.1.9 
Treatment related AEs by HLT and cohort 
All treated patients 
T 
AE 
6.1.10 
Grade 3 and 4 TEAEs by HLT and cohort 
All treated patients 
T 
AE 
6.1.11 
Treatment Related Grade 3 and 4 AEs by HLT and cohort 
All treated patients 
L 
AE 
6.1.1 
AEs 
All treated patients 


 
Kadmon Corporation 
 
 
KD019-206                                                                                            Statistical Analysis Plan 
 
SAP Version 1.0, 5 October 2018 
 
 
 
 
       Page 14 of 14 
 
L 
AE 
6.1.2 
AE Leading to Treatment Discontinuation 
All treated patients 
L 
AE 
6.1.4 
Death 
All treated patients 
T 
Lab 
7.1.1 
Lab values and their change from baseline by cohort 
All treated patients 
T 
Lab 
7.1.3 
Shifts in toxicity grading from baseline to highest grade post-baseline of 
laboratory abnormalities by cohort 
All treated patients 
L 
Lab 
7.1.1 
Lab values with CTCAE grade >= 3 
All treated patients 
T 
VS 
8.1.1 
Vital signs and their change from baseline by cohort 
All treated patients 
L 
VS 
8.1.1 
Vital signs 
All treated patients 
L 
VS 
8.2.1 
Physical examinations 
All treated patients 
T 
ECG 
9.1.1 
ECG parameters and their change from baseline by cohort 
All treated patients 
T 
ECG 
9.2.1 
QTcF abnormalities by cohort 
All treated patients 
L 
ECG 
9.1.1 
ECG values 
All treated patients 
 
Abbreviations:  AE = adverse event; CNS = central nervous system; CSF = cerebrospinal fluid; CTCAE = Common Terminology Criteria for 
Adverse Events; DNA = deoxyribonucleic acid; ECG = electrocardiogram; EGFR = epidermal growth factor receptor; HLT = high level terms; 
MRI = magnetic resonance imaging; NSCLC = non-small cell lung cancer; OS = overall survival; PFS = progression-free survival; TEAEs = 
treatment-emergent adverse events; VS = vital signs