Conditions: Glioblastoma Recurrent Glioblastoma Brain Tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
This is a multicenter, Phase 2 study to assess the activity of tesevatinib in patients with recurrent glioblastoma.

Detailed description:
This is a multicenter, Phase 2 study to assess the activity of tesevatinib in subjects (n = 40) with recurrent glioblastoma. This study will be conducted at up to 10 sites in the United States.

The availability of paraffin-embedded tumor sample diagnostic of glioblastoma is mandatory for entry into the study. Tumor samples will be evaluated for the EGFRvIII mutation and for EGFR gene amplification. Tissue from recurrent surgery is preferred, but tissue from initial surgery is sufficient for study entry. Baseline MRI is mandatory.

After completion of the screening assessments and confirmation of study eligibility by the Medical Monitor upon review of an inclusion package, tesevatinib will be orally administered to all patients at a dose of 300 mg once daily. A cycle will be considered as 28 days. Patients will be evaluated for efficacy according to the Response Assessment in Neuro-Oncology (RANO) criteria.

Patients who develop ≥ Grade 3 adverse event(s) considered by the investigator to be related to study drug will have study treatment interrupted until the drug-related toxicities have resolved to ≤ Grade 1. Once toxicities have resolved to ≤ Grade 1, the patient may resume study treatment at a reduced dose of 250 mg/day. No more than 1 dose reduction is permitted. Patients who require more than one dose reduction will have study drug discontinued and enter the Follow-up Period.

Patients for whom toxicity persists beyond 21 days despite dose interruption may resume study treatment only with permission from the responsible Medical Monitor.

If study treatment is withheld, the patient should be instructed not to make up the withheld doses.

Study treatment will continue until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. Assessments for disease response will occur at Week 4 and Week 8 and then every 8 weeks thereafter using the RANO criteria.

Upon treatment discontinuation, patients will be followed every 8 weeks for survival.

Tumor samples will be used for exploratory biomarker research including, but not limited to, evaluation of EGFRvIII expression by immunohistochemistry or real-time Polymerase Chain Reaction. An appropriate definition and cutoff for EGFRvIII\^pos tumors will be established, and outcome in this subpopulation will be evaluated in addition to the overall study population.

To characterize the safety and tolerability profile of tesevatinib, patients will be monitored throughout the study for adverse events (all grades), serious adverse events, and any adverse events requiring drug interruption or discontinuation. Patients will undergo safety evaluations, including physical examinations, Karnofsky Performance Status (KPS), vital sign measurements, hematology, serum chemistry, urinalysis and electrocardiogram.

Magnetic resonance imaging (MRI) will be used to evaluate the tumor at baseline. All MRIs taken on study patients will be submitted to the sponsor for possible retrospective analysis.

Arms:
arm 1: The single arm design assessing progression-free survival at 6 months (PFS-6) in the overall population with the ability to detect a rate of 25% is appropriate as a preliminary test of activity in patients with glioblastoma. The sample size of this study is also designed to permit the comparison of results with EGFR amplified and non-amplified tumors, as well as EGFRvIII mutated versus wild-type. The sample size is adequate to characterize the safety profile in patients with glioblastoma.

Interventions: intervention 1: Tesevatinib
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
 
 
 
CLINICAL STUDY PROTOCOL COVER LETTER 
 
A Phase 2, Multicenter Study of Tesevatinib Monotherapy in 
Patients with Recurrent Glioblastoma 
 
 
Protocol Number: 
KD019-208 
IND Number: 
129323 
NCT Number: 
NCT02844439 
Document Date:  
Version 4.0 03 April 2019 
 


Tesevatinib 
Protocol Number KD019-208 
 
 
 
  
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Page 1 of 113 
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CLINICAL STUDY PROTOCOL 
 
A Phase 2, Multicenter Study of Tesevatinib Monotherapy in Patients 
with Recurrent Glioblastoma  
 
 
Protocol Number: 
KD019-208 
IND Number: 
129323 
 
Study Drug: 
Tesevatinib  
 
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: 5 February 2016 
Version: 
2.0 25 March 2016 
 
3.0 3 October 2017 
 
4.0 03 April 2019                                                                                  
 
 
 
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. 


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1. 
PROCEDURES IN CASE OF EMERGENCY 
Serious Adverse Events  
All serious adverse events (SAEs)* occurring in patients while on-study or within 30 days of 
receiving the last dose of 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 11.3 Serious Adverse Events for additional information): 
 
Death 
 
Life-threatening adverse drug event 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant disability / incapacity 
 
A congenital anomaly/birth defect 
 
An important medical event that may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed above. 
Some serious events will not be reported as SAEs, including: 
 
Disease progression 
 
Death due to disease progression occurring more than 30 days after the last dose of study drugs 
 
Medical or surgical procedures when the condition that leads to the procedure is an adverse event 
 
Pre-existing diseases, or conditions or laboratory abnormalities present or detected prior to the screening visit, that do not worsen 
 
Situations for which an untoward medical occurrence has not occurred (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 
Section 11.3.2 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 patients with a signed and dated copy of their informed 
consent document, as required by FDA and ICH regulations.  I further agree to report to Kadmon 
any adverse events in accordance with the terms of this protocol and FDA regulation 21 CFR 
312.64.   
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations.  
 
 
 
Investigator Signature 
 
 Date of Signature 
(DD MM YYYY) 
Name of Investigator (please print) 
 
 


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4. 
SYNOPSIS 
Study title 
A Phase 2, Multicenter Study of Tesevatinib Monotherapy in Patients with Recurrent 
Glioblastoma 
Clinical phase 
Phase 2 
Number of study 
centers 
Up to 10 US centers 
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), Src, and vascular endothelial growth factor receptor 2 (VEGFR2). 
Tesevatinib has been evaluated in 6 clinical studies in various solid tumors in more than 
275 patients, of whom at least 50 received the recommended dose of 300 mg daily. The 
safety profile is similar to that of other agents in the class, with predominantly 
gastrointestinal (GI) and skin adverse events (AEs). QTc prolongation has also been 
observed, which appears to be dose related. Efficacy has been observed in non-small cell 
lung cancer (NSCLC) with activating EGFR mutations. For further information see the 
Investigator Brochure (Version 7.0 dated 23 July 2015). 
Study rationale 
Gliomas account for 80% of primary malignancies of the central nervous system (CNS). 
Glioblastomas (World Health Organization (WHO) Grade IV astrocytic tumors) account 
for 60–70% of gliomas and remain the most aggressive subtype. Glioblastoma occurs 
mostly in adults (median age of 64 years at diagnosis) with an estimated incidence of 2–3 
cases per 100,000 people in Europe and North America. With 1- and 5-year overall 
survival (OS) rates of 29% and 3%, respectively, the prognosis of glioblastoma remains 
poor [Central Brain Tumor Registry of the United States 2011] and there is a need to 
develop more effective therapeutic approaches. 
Standard treatment for newly diagnosed glioblastoma is surgical debulking followed by 
radiotherapy and temozolomide (TMZ) with additional maintenance TMZ [Stupp 2005]. 
Despite the survival benefit associated with such treatment, almost all patients relapse 
following initial therapy.  
Patients with recurrent glioblastoma have a median progression-free survival (PFS) of 
about 4 months and OS of less than 10 months. The optimal management for patients 
with recurrent glioblastoma remains unclear, as there have been no randomized trials 
directly comparing active intervention with supportive care. The most important 
prognostic factors for benefit from re-intervention are pre-treatment performance status 
and patient age [Kappelle 2001].  
Active interventions include repeated surgery, re-irradiation, or systemic therapy in order 
to improve or preserve neurological function and prolong PFS and OS. Chemotherapy 
with TMZ demonstrated an increase in survival as second-line therapy in initial trials. 
However, TMZ is now generally used as a component of first-line treatment and hence 
there is no established chemotherapy regimen available for recurrent glioblastoma [Stupp 
2009; Stupp 2010]. Nitrosourea-based chemotherapy, either as single agents or in 
combination regimens such as procarbazine, lomustine, and vincristine (PCV), have 


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shown some activity in Phase 2 studies of patients who progressed after prior 
chemotherapy [Schmidt 2006; Fabrini 2009]. Systemic treatment with the anti-VEGF 
monoclonal antibody bevacizumab has also shown some activity in recurrent 
glioblastoma [Friedman 2009]. Bevacizumab is currently approved for use in patients with 
progressive disease following prior therapy in the United States but not in the European 
Union [Avastin® USPI 2015]. The label specifically mentions that there are no data 
demonstrating an improvement in disease-related symptoms or increased survival. 
EGFR gene abnormalities occur commonly in glioblastomas, suggesting that EGFR 
inhibition could be a useful clinical strategy. Studies indicate that EGFR gene 
amplification and /or mutation are present in approximately 57% of glioblastomas 
[Brennan 2013]. EGFR variant III (EGFRvIII), which leads to constitutive EGFR 
signaling, is seen in approximately 25% of glioblastomas [van den Bent 2009]. Clinical 
trials of EGFR inhibitors in patients with glioblastomas have produced disappointing 
results, perhaps because the available agents have poor blood-brain barrier (BBB) 
penetration. A Phase 2 trial of erlotinib, for instance, led to a 6-month PFS rate of 11% 
with erlotinib, compared to 24% with physician’s choice of temozolomide or carmustine 
[van den Bent 2009]. In vitro data suggest that some EGFR abnormalities will correlate 
with clinical sensitivity to erlotinib [Sarkaria 2007]. In addition to targeting EGFR, 
tesevatinib also has VEGFR2 inhibitory activity, and there may be advantages to the 
simultaneous inhibition of EGFR and VEGFR2 in glioblastomas. Thus, although the 
determinants of glioblastoma responsiveness to EGFR inhibitors remain poorly defined, 
further research on the role of tesevatinib in glioma could be a productive approach to 
improving glioma treatment.   
Unlike other agents in its class, tesevatinib effectively penetrates into the brain, with 
levels in mice and rats with intact BBBs the same or higher than plasma levels [Tonra 
2015].  Tesevatinib has levels in the choroid plexus and meninges that are 10 times the 
plasma levels, suggesting that tesevatinib may penetrate well into cerebrospinal fluid 
(CSF). There is preliminary evidence of clinical benefit in patients with leptomeningeal 
metastases in NSCLC [Kadmon data on file]. Thus, there is a good biologic rationale to 
evaluate tesevatinib in patients with recurrent glioblastoma which has progressed on or 
after prior therapy. Its role in tumors with and without the EGFR activating mutations, 
EGFR protein overexpression and gene amplification also needs to be explored. 
Study objectives 
Primary efficacy objectives 
 
To evaluate the efficacy of tesevatinib as measured by investigator-assessed 
progression-free survival at 6-months (PFS-6) 
Secondary efficacy objectives 
 
To evaluate the efficacy of tesevatinib as measured by investigator-assessed 
PFS-6 in the subgroup of patients with EGFRvIIIpos glioblastoma  
 
To evaluate the efficacy of tesevatinib as measured by investigator-assessed 
PFS-6 in the subgroup of patients with EGFR gene amplified glioblastoma 
 
To evaluate the efficacy of tesevatinib as measured by the overall survival  
rate at 9 months (OS-9) and OS overall, in all patients and in those with 


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EGFRvIIIpos and EGFR gene amplified glioblastoma 
 
To evaluate the efficacy of tesevatinib as measured by PFS, objective 
response rate (ORR) per Response Assessment in Neuro-Oncology 
(RANO) criteria, and duration of response (DOR) in all patients and in 
those with EGFRvIIIpos and EGFR gene amplified tumors 
 
To evaluate the efficacy of tesevatinib as measured by PFS-6, OS-9, RANO 
OOR and DOR in: 
o 
EGFRvIIIpos vs EGFRvIIIneg 
o 
EGFR amplificationpos vs EGFR amplificationneg 
Safety objectives 
 
To evaluate the safety and tolerability of tesevatinib in all patients and in the 
subgroup of patients with EGFRvIIIpos and the subgroup of patients with 
EGFR amplificationpos tumors 
Exploratory objectives 
 
To evaluate the plasma concentration of tesevatinib in patients with and 
without systemic steroid treatment 
 
To evaluate the potential association of exploratory tissue and blood 
biomarkers with response to tesevatinib and with adverse events. These 
include EGFRvIII mutation and gene amplification and may include 
circulating tumor DNA  
 
To evaluate the correlation between patients with EGFRvIIIpos tumor and 
those patients with EGFR gene amplification 
 
To evaluate and compare EGFRvIIIpos expression and/or other tissue 
biomarkers potentially associated with response with tesevatinib, in paired 
primary and recurrent glioblastoma specimens from the same patient, when 
these are available 
 
To evaluate patient-reported outcomes of disease and treatment-related 
symptom severity and interference as measured by the M.D. Anderson 
Symptom Inventory – Brain Tumor questionnaire (MDASI-BT) 
 
To evaluate patient-reported outcomes of disease and treatment-related 
symptom severity and interference as measured by the M.D. Anderson 
Symptom Inventory – Brain Tumor questionnaire (MDASI-BT) in the 
subgroup of patients with EGFRvIIIneg  and EGFR gene amplificationneg 
tumors as compared to those in patients with EGFRvIIIpos and EGFR gene 
amplificationpos tumors 
 
Study design 
This is a multicenter, Phase 2 study to assess the activity of tesevatinib in patients with 
recurrent glioblastoma. 
Screening and Study Treatment 
The availability of paraffin-embedded tumor sample diagnostic of glioblastoma is 
mandatory for entry into the study and should be provided with a copy of the original 
pathology report for central review. Tumor samples will be evaluated for the EGFRvIII 
mutation and for EGFR gene amplification. Tissue from recurrent surgery is preferred, but 
tissue from initial surgery is sufficient for study entry. Baseline magnetic resonance 


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imaging (MRI) is mandatory within 7 days of study drug administration. After completion 
of the screening assessments and confirmation of study eligibility, tesevatinib will be orally 
administered to all patients at a dose of 300 mg once daily.  
Patients who develop ≥ Grade 3 adverse event 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 glucose in a patient 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 patient with diarrhea) will have study treatment 
interrupted until the ≥ Grade 3 drug-related toxicities have resolved to ≤ Grade 1 (refer to 
Section 9.1.3).  
Once toxicities have resolved to ≤ Grade 1, the patient may resume study treatment at a 
reduced dose of 250 mg/day. No more than one dose reduction is permitted. Patients who 
require more than one dose reduction will have study drug discontinued and enter the 
Follow-up Period. 
Patients for whom toxicity persists beyond 21 days despite dose interruption may resume 
study treatment only with permission from the responsible Medical Monitor.   
If study treatment is withheld, the patient should be instructed not to make up the withheld 
doses. 
Study treatment will continue until disease progression, unacceptable toxicity, patient or 
physician decision to discontinue, or death.  Assessments for disease response will occur at 
week 4 and 8 and then every 8 weeks using the RANO criteria (see Appendix 2).  
Upon treatment discontinuation, patients will be followed every 8 weeks for survival. 
Tumor samples will be used for exploratory biomarker research including, but not limited 
to, evaluation of EGFRvIII expression by immunohistochemistry (IHC) or real-time 
Polymerase Chain Reaction (PCR).  An appropriate histopathological definition and cutoff 
for EGFRvIIIpos tumors will be established, and outcome in this subpopulation will be 
evaluated in addition to the overall study population. 
To characterize the safety and tolerability profile of tesevatinib, patients will be monitored 
throughout the study for adverse events (all grades), serious adverse events, and any 
adverse events requiring drug interruption or discontinuation.  Patients will undergo safety 
evaluations, including physical examination (PE), vital sign measurements, hematology, 
serum chemistry, urinalysis and electrocardiogram (ECG).   
MRI will be used to evaluate the tumor at baseline (within 7 days of study drug 
administration). All MRIs taken on study patients will be submitted to the sponsor for 
possible retrospective analysis (refer to Section 10.1).  
Subjects who have completed 24 cycles of treatment and who continue to tolerate treatment 
with KD019 may continue on study with bimonthly visits to clinic for drug dispensing, 
safety and efficacy assessment. 


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End of Treatment Visit 
An End-of-Treatment visit is to be performed as soon as possible after the patient’s last 
dose of study drug.  This may occur at the visit at which disease progression is diagnosed.  
The patient 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. Patients will 
undergo PEs; vital sign measurements; hematology, serum chemistry, urinalysis and ECG, 
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.  If progressive disease 
has not occurred at the end of the follow-up period MRIs should be repeated every 8 weeks 
until disease progression per RANO criteria. 
Long-Term Follow-Up 
Patients are to be contacted by telephone every 8 weeks to assess progression status if 
not PD when study drug stopped, survival status and any subsequent anti-cancer 
treatment. If PD was not observed before the 30-day follow-up period, patients will 
return for follow-up MRI until PD is demonstrated or they start a new anti-cancer 
treatment.  
As of Amendment 4, long-term follow-up will no longer be required. 
Study 
population/Number 
of patients 
A total of approximately 40 patients with recurrent glioblastoma will be enrolled at up to 10 
US centers. 
Diagnosis and main 
criteria for inclusion 
Inclusion criteria:  
Patients will be included if they meet the following criteria: 
1) Willingness and ability to provide written informed consent and to comply with the 
study protocol as judged by the investigator 
2) Age ≥ 18 years old  
3) Karnofsky performance status (KPS) ≥70% (see Appendix 1).  
4) Stable or decreasing dose of corticosteroids within 5 days prior to study enrollment. 
5) Female subjects of childbearing potential have a negative pregnancy test at 
screening. Females of childbearing potential are defined as sexually mature women 
without prior hysterectomy or who have had any evidence of menses in the past 12 
months. However, women who have been amenorrheic for 12 or more months are 
still considered to be of childbearing potential if the amenorrhea is possibly due to 
prior chemotherapy, anti-estrogens, or ovarian suppression. 
 
Women of childbearing potential (i.e., menstruating women) must have a 
negative urine pregnancy test (positive urine tests are to be confirmed by 
serum test) documented within the 24-hour period prior to the first dose of 
study drug.  
 
Sexually active women of childbearing potential enrolled in the study must 
agree to use two forms of accepted methods of contraception during the 
course of the study and for 6 months after their last dose of study drug.  
Effective birth control includes (a) IUD plus one barrier method; (b) on 


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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. 
6) For male patients who are sexually active and who are partners of premenopausal 
women: agreement to use two forms of contraception as in criterion 5 above during 
the treatment period and for at least 6 months after the last dose of study drug. 
7) Histologically confirmed glioblastoma. A local pathology report constitutes adequate 
documentation of histology for study inclusion.  Patients with an initial diagnosis of 
a lower-grade glioma are eligible if a subsequent biopsy was determined to be 
glioblastoma. 
8) First recurrence after concurrent or adjuvant chemoradiotherapy. Imaging 
confirmation of first tumor progression or regrowth as defined by the RANO criteria 
(see Appendix 2).  A minimum of 12 weeks must have elapsed from the completion 
of radiotherapy to study entry to minimize the potential for MRI changes related to 
radiation necrosis that might be misdiagnosed as progression of disease, unless there 
is a new lesion outside the radiation field or unequivocal evidence of viable tumor on 
histopathological sampling. 
9) Prior treatment with TMZ for low grade glioma or glioblastoma. 
10) No more than one prior line of systemic treatment for glioblastoma.  Concurrent and 
adjuvant TMZ-based chemotherapy, including the combination of TMZ with an 
investigational agent, is considered one line of therapy. 
11) Prior therapy with gamma knife or other focal high-dose radiotherapy is allowed, but 
the patient must have subsequent histologic documentation of recurrence, unless the 
recurrence is a new lesion outside the irradiated field. 
12) Recovery from the toxic effects of prior therapy, with a minimum time of: 
a) ≥ 28 days elapsed from the administration of any investigational agent 
b) ≥ 28 days elapsed from the administration of any prior cytotoxic agents, except 
≥ 14 days from vincristine, ≥ 21 days from procarbazine, and ≥ 42 days from 
nitrosureas 
c) ≥ 14 days elapsed from administration of any non-cytotoxic agent (e.g., 
interferon, tamoxifen, thalidomide, cis-retinoic acid) 
13) Patients who have undergone recent surgery for recurrent or progressive tumor are 
eligible provided that: 
a) Surgery must have confirmed the recurrence 
b) There must be residual disease measurable per RANO criteria e.g. 1 cm x 1cm 
c) A minimum of 28 days must have elapsed from the day of surgery to first dose 
of the study drug. For core or needle biopsy, a minimum of 7 days must have 
elapsed prior to study entry 
14) Availability of formalin-fixed paraffin-embedded tumor tissue diagnostic of 
glioblastoma.  
 
Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from study entry: 
1) Concurrent therapeutic intervention (including radiation therapy and NovoTTF). 
2) Prior exposure to EGFR inhibitors. 


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3) Prior exposure to bevacizumab or other VEGF- or VEGF-receptor-targeted agent 
within 8 weeks of study start. 
4) Prior treatment with prolifeprospan 20 with carmustine wafer. 
5) Prior intracerebral agent. 
6) Evidence of recent hemorrhage on baseline MRI of the brain.  However, patients 
with clinically asymptomatic presence of hemosiderin, resolving hemorrhagic 
changes related to surgery, or presence of punctuate hemorrhage in the tumor are 
eligible. 
7) Need for urgent palliative intervention for primary disease (e.g., rapidly increasing 
intracranial pressure, impending herniation, uncontrolled seizures). 
8) Absolute neutrophil count (ANC) < 1.5 x109/L; platelet count < 100 x109/L; or 
hemoglobin (Hb) < 9.0 g/dL within 7 days prior to enrollment.  Note: The use of 
transfusion or other intervention to achieve Hb ≥ 9 g/dL is acceptable. 
9) Total bilirubin ≥ 1.5 x ULN (except in patients diagnosed with Gilbert’s disease). 
10) Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) 
(SGPT), or alkaline phosphatase (ALP) ≥ 2.5 x ULN. 
11) Serum creatinine > 1.5 x ULN. 
12) Serum potassium or magnesium below the lower limit of 
normal. 
13) International normalized ratio (INR), prothrombin time (PT), or  activated partial 
thromboplastin time (APTT) as follows unless on anticoagulation that is expected 
to alter coagulation test results: 
-  INR > 1.5 or PT > 1.5 xULN or aPTT > 1.5 xULN 
14) Known contraindication to MRI, such as cardiac pacemaker, shrapnel or ocular 
foreign body. 
15) Used any prescription medication during the prior 2 weeks that the investigator 
judges is likely to interfere with the study or to pose an additional risk to the 
patient in participating, specifically inhibitors or inducers of cytochrome P450 
(CYP)3A4 (refer to Appendix 4).  A stable regimen (≥ 4 weeks) of antidepressants 
of the selective serotonin re-uptake inhibitor (SSRI) class is allowed (common 
SSRIs include escitalopram oxalate, citalopram, fluvoxamine, paroxetine, 
sertraline, and fluoxetine). 
16) Taking any drugs associated with torsades de pointes or known to moderately or 
severely prolong the QTc(F) interval (see Appendix 4). 
17) 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.  Patients with a history of atrial 
arrhythmias should be discussed with the Medical Monitor. 
18) Uncontrolled diabetes, as evidenced by fasting serum glucose level >200 mg/dL 
19) New York Heart Association (NYHA) Grade II or greater congestive cardiac 
failure. 
20) Has marked prolongation of QTc(F) interval at screening or baseline (QTc[F] 
interval > 470 msec) using the Fridericia method of correction for heart rate. 
21) History of myocardial infarction (within 12 months) or unstable angina 
(within 6 months) prior to study enrolment. 
22) History of stroke or transient ischemic attacks within 6 months prior to study 
enrolment. 
23) Significant vascular disease (e.g., aortic aneurysm requiring surgical 


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repair or recent peripheral arterial thrombosis) within 6 months prior 
to study enrolment. 
24) Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation). 
25) History of intracranial abscess within 6 months prior to study enrolment. 
26) History of another malignancy in the previous 3 years, with a disease-free interval 
of < 3 years. Patients with prior history of in situ cancer or basal or squamous cell 
skin cancer are eligible. 
27) Evidence of any active infection requiring hospitalization or IV antibiotics 
within 2 weeks prior to study enrolment. 
28) Known hypersensitivity to any excipients of tesevatinib. 
29) Inability to swallow or absorb orally-administered medication. 
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 patient-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:  Patients will be treated with study drug until disease progression or 
unacceptable toxicity occurs. 
Discontinuation:  Patients who discontinue tesevatinib treatment will be followed for 
disease progression (if applicable) and survival.   
Concomitant 
medications 
Concomitant treatment and medication information will be collected from the time the 
patient signs the informed consent form until 30 days after the last dose of study drug or 
until the patient starts a new treatment, and is to be reported on the appropriate case 
report form (CRF). 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 CRF including the date, indication, description of the 
procedure(s), and any clinical finding. Any medication that is considered necessary for 
the patient’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 CRF. Any changes in documented, permitted concomitant treatment 
already being taken at the beginning of the clinical study must be recorded in the CRF, 
noting the type of medication, the duration, and indication. 
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, 


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cimetidine, dofetilide, fexofenadine, metformin, procainamide, and pyrimethamine 
should be monitored carefully. 
Prohibited 
treatments 
 
Other investigational drugs 
 
Concurrent anti-tumor therapies such as chemotherapy, gene therapy, 
biologics, tyrosine kinases inhibitors, radiation therapy, or 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 strongly inhibit the CYP3A4 isozyme or any drugs that 
are strong 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). See Appendix 4.    
 
Steroid medications are allowed 
 
Radiation therapy: need for radiation will be considered to be progressive 
disease 
Safety assessments 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE; Version 4.03) will be used for grading toxicities. Safety assessments will 
include AEs, serious adverse events (SAEs), PEs including full neurologic exam, vital 
sign measurements, clinical safety laboratory evaluations (hematology, serum 
chemistry, and urinalysis), KPS, and ECGs.   
The AE reporting period for a patient enrolled in the study begins when the patient 
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 patients 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 at least 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. 
Plasma 
Concentration 
Evaluation of 
Tesevatinib 
Plasma samples for tesevatinib concentration analysis will be drawn predose of 
tesevatinib on Days 15 of Cycle 1; and predose of tesevatinib on Day 1 of every 
subsequent cycle (up to cycle 6). Data from these samples will contribute to a 
population PK analysis, and will be used to explore exposure-response relationships. 
Pharmacodynamic 
Evaluation 
Samples will be evaluated for the EGFRvIII mutation and for EGFR gene amplification.   
Efficacy 
Disease assessments will be based on the RANO criteria [Wen 2010] and will comprise 
radiological assessments, clinical assessments, and corticosteroid use 
(see Appendix 2). Per the study’s schedule of assessments, full disease assessments 


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should be performed at week 4 and 8 after the date of first study drug administration and 
then every 8 weeks. Disease assessments as initially planned according to the schedule 
of assessments should be maintained regardless of treatment delays. Unscheduled 
disease assessments may be performed at the discretion of the investigator to allow a 
decision on further study treatment administration for individual patients. For patients 
who discontinue treatment for reasons other than progressive disease, disease 
assessment in the follow-up period should continue every 8 weeks until disease 
progression. 
Radiological Assessment 
Radiological assessments will be performed using MRI scans. The acquisition protocol 
for MRI (provided as a separate document) will provide further details for scan 
standardization. All efforts should be made to perform MRI scans according to the 
corresponding specification in order to ensure that quality of MRI will be standardized 
among all sites. Consistency of subsequent MRIs should be ensured during all 
assessments for each patient, with the same technique being used for evaluating lesions. 
Patients should be imaged on the same MRI scanner for the duration of the study. A 
1.5T or 3T scanner must be used for this study. The use of IV contrast should, as long as 
clinically possible, be kept consistent. The following sequences of the entire brain must 
be acquired: 
 
T1 pre-gadolinium 
 
T2/FLAIR 
 
T1 post-gadolinium 
Target Lesions: Lesions should be measured on the greatest size (bi-dimensional 
measurement of the longest cross-sectional diameters) observed either on axial, coronal, 
or sagittal slices, and the most representative observed chosen to be followed for 
response evaluation (i.e., once selected at baseline, the plane should be maintained 
across the study, to allow comparison). If there are multiple contrast- enhancing lesions, 
a minimum of two of the largest lesions, and a maximum of five lesions, should be 
measured, and the sum of the products of the perpendicular diameters of these lesions 
should be determined. Occasionally, the largest lesions may not lend themselves to 
reproducible measurements, and the next largest lesions that can be measured 
reproducibly should be selected. For patients with recurrent disease who have multiple 
lesions of which only one or two are increasing in size, the enlarging lesions should be 
considered the target lesions for evaluation of response. 
Nontarget Lesions: All other lesions will be considered nontarget lesions and should 
also be recorded. Rarely, unequivocal progression of a nontarget lesion requiring 
discontinuation of therapy or development of a new contrast-enhancing lesion may 
occur, even in the setting of stable disease or partial response in the target lesions. These 
changes would qualify as progression. 
Tumor measurements should be made by the same investigator/radiologist for each 
patient during the study to the extent that this is feasible. 
A radiological assessment of complete response (CR) or partial response (PR) requires 
confirmatory imaging at least 4 weeks after the initial assessment of response was 
observed. In the event that the radiographic changes are equivocal and it is unclear 


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whether the patient has stable or progressive disease, treatment should be 
continued and the patient should be closely observed. If subsequent imaging studies 
demonstrate that progression has occurred, the date of progression should be the date of 
the scan at which disease progression was first suspected. 
Clinical Status 
Clinical deterioration is defined as a decline in the Karnofsky performance status from 
100% or 90% to ≤ 70%; a decline of ≥ 20% from 80% or less; or a decline from any 
baseline value to 50% or less, for at least 7 days, unless attributable to comorbid events 
(e.g., seizures, medication adverse effects, complications of therapy, cerebrovascular 
events, infection, etc.). Clinical status must be recorded as Improved, Stable, or 
Worsened. 
Corticosteroid Dose 
At the time of each disease assessment, the corticosteroid intake will be compared with 
corticosteroid intake at the time of the last disease assessment. The changes will be 
recorded as Increased, Unchanged, or Decreased. Increases or decreases in 
corticosteroid dose should be clinically justified. 
Note: Increases in corticosteroid dose for reasons other than disease control do not need 
to be taken into consideration when making this comparison. 
Overall Disease Assessment 
Based on radiological assessments, clinical status, and corticosteroid use, an overall 
evaluation of CR, PR, stable disease (SD), or progressive disease (PD) should be made 
at each disease assessment after baseline according to the RANO criteria (Appendix 2). 
Progressive disease is defined as any of the following: 
 
≥ 25% increase in sum of the products of perpendicular diameters of 
enhancing lesions (compared with baseline if no decrease or otherwise 
compared with the smallest recorded sum [nadir] during the study) on stable 
or increasing doses of corticosteroids 
 
Significant increase in T2/FLAIR non-enhancing lesions on stable or 
increasing doses or corticosteroids (compared with baseline or best response 
after initiation of therapy) 
 
Appearance of any new lesions 
 
Clear progression of nonmeasurable lesions 
 
Definite clinical deterioration not attributable to other causes apart from the 
tumor, or to decrease in corticosteroid dose 
 
Failure to return for evaluation as a result of death or deteriorating condition 
Note: Increase in corticosteroid dose alone, in the absence of persistent clinical 
deterioration related to tumor, will not be used as a determinant of progression. Patients 
whose corticosteroid dose was increased for new symptoms and signs without 
confirmation of disease progression on neuroimaging do not qualify for disease 
progression and should continue study treatment. If subsequent follow-up imaging 
shows that this increase in corticosteroids was required because of disease progression, 
the date of progression should be the first timepoint at which the increase in 


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corticosteroids was necessary. 
Patient Reported 
Outcomes and Mini-
Mental State 
Examination 
Patient reported outcomes (PROs) of disease- and treatment-related symptom severity 
and symptom interference will be assessed using the MDASI-BT questionnaire. 
The MDASI is a validated and reliable self-report measure that was developed to assess 
symptom severity and interference [Cleeland 2000; Armstrong 2006]. 
Thirteen items ask patients to rate how severe the symptoms were when “at their worst” 
in the last 24 hours with regard to pain, fatigue, nausea, disturbed sleep, distress, 
shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sad, 
vomiting, and numbness or tingling. An additional six items ask patients to rate how 
much the symptoms have interfered with six areas of function (general activity, 
walking, work, mood, relations with other people, and enjoyment of life) in the last 24 
hours. The MDASI-BT (see Appendix 3) contains an additional nine items that assess 
symptoms and concerns specific to primary brain tumor patients (difficulty 
understanding, difficulty speaking, difficulty concentrating, seizures, weakness, change 
in appearance, change in vision, change in bowel patterns, irritability), for a total of 28 
items. 
Subjects completing 24 cycles of tesevatinib will no longer be required to complete 
patient reported outcomes and mini-mental state examinations. 
Statistical methods 
Analysis populations 
Adult patients with recurrent glioblastoma, meeting all inclusion criteria and no 
exclusion criteria, with availability of paraffin-embedded tumor samples diagnostic of 
glioblastoma will be enrolled. 
Two subgroups of patients are defined as having: EGFRvIIIpos and EGFR 
amplificationpos tumors. 
Primary and secondary efficacy analyses will include all patients who were included in 
the study. The same analysis methods for the primary and secondary analyses will be 
applied to both the ITT population and the EGFRvIIIpos and EGFR gene amplificationpos 
population. 
Safety analyses will include all patients who enrolled and received at least one dose of 
study treatment (the safety population). 
All patients who take at least one dose of tesevatinib will be evaluable for safety and 
efficacy assessments. 
Patients 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.   
For statistical purposes, completion of the study will be defined as six months after the 
last patient starts study treatment.  
The plasma concentration analysis population will consist of all patients who receive at 
least one dose of tesevatinib, and who have at least one sample analyzed for plasma 
concentrations. 


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Sample Size Justification and power calculations: 
The power calculation is based on simulations in the Weibull distribution to describe the 
progression and survival times. The estimation of PFS-6 is done using the Cox model. 
Based on a one-stage design, with a sample size of 40 patients in the overall population, 
a PFS-6 of 25% and median PFS of 4.5 months, the trial has 95% power to demonstrate 
an estimated PFS-6 >15%. Based on a one-sided test on a 5% significance level, the trial 
has 95% power to show a significant difference above the null hypothesis of 7% and 
80% power to show a significant difference above 10%. The study is not powered to 
detect differences in the secondary endpoints. 
 Interim Analysis 
An interim analysis is included with the possibility to stop for futility. The stopping rule 
is based on an unacceptable PFS-6 rate of 5% and a desirable PFS-6 rate of 20% or 
more. The trial will continue after the interim analysis if more than 1 responders are 
seen in 21 patients giving a 72% probability of stopping if the PFS-6 rate is ≤5%.   
Primary efficacy endpoint: PFS-6  
PFS is defined as the time between date of first dose and the date of first documented 
disease progression or death, whichever occurs first. The PFS-6 is defined as a patient 
being alive and progression free at 6 months (24 weeks). Disease progression will be 
determined based on investigator assessment with use of radiological assessments, 
clinical status, and corticosteroid use. Patients without a date of disease progression or 
death will be analyzed as censored observations on the date of the last disease 
assessment; if no post-baseline disease assessment is available, PFS will be censored at 
the date of 1st dose. 
The analysis of the primary endpoint and the estimation of PFS-6 is performed with a 
Cox model. Karnofsky performance status is included as a covariate. Study center is 
included as a random effect assumed to follow a gamma distribution. Thus, this is a 
shared Cox gamma frailty model. The model is used to estimate PFS-6 with 2-sided 
95% and 90% confidence intervals. 
Furthermore, Kaplan-Meier methodology will be used to estimate median PFS with 
95% CI and the Kaplan-Meier curve will be constructed to provide a visual description 
of the PFS over time.  
Descriptive statistics overall and for each parameter (radiological assessment, clinical 
status and corticosteroid dose) in the disease progression assessment are presented for 
the entire assessment period as well as for 3-, 6-, and 9- month time points. 
The analysis of secondary and exploratory endpoints is described in Section 13.4.6 and 
will be further outlined in the SAP. 
Safety and PK: 


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AEs/SAEs will be graded using Common Terminology Criteria for Adverse Events 
Common Terminology Criteria for Adverse Events (CTCAE) V4.03, coded and 
tabulated using MedDRA (version 18.1 or greater). 
Laboratory results, ECGs, KPS, PK and vital signs will be tabulated and presented in 
listings. 
Concomitant medications will be coded using WHO Drug and tabulated. 
Expectedness of the AEs will be assessed against the current tesevatinib IB. 
A statistical analysis plan (SAP) will be written to describe thoroughly the planned 
analyses. 
 


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Table 1: 
Schedule of Study Assessments  
Timepoint  
(Study Day) 
Screen 
Cycle 1 
Cycle 2 
Cycle 3
Cycle 4 
Cycle 5 
Cycle 6
Cycle 7+
EOS Tx o
30-Day 
FU p 
(± 5d) 
LTFU UNS q 
-22 to -1 
Day 1 
Day 15 
(± 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 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor sample(s) a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Neurological Examination c 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Vital Signs d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety Labs e, f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy Test g 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-Lead ECG h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Disease Assessment j 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
 
X 
 Karnofsky performance 
status 
X 
 
 
X 
X 
 
X 
 
X 
X
 
 
X 
 Corticosteroid use 
X 
X
X
X 
X
X
X 
 MRI tumor assessment 
X 
 
 
X 
X 
 
X 
 
X 
X
 
X r 
X 
Pt. Reported Outcomes 
(MDASI-BT) k 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
Plasma concentration l 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Tesevatinib Dosing m 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Collect/Issue Diary 
 
X 
 
X 
X 
X 
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 Monitoring n 
To be collected from the time of informed consent through 30 days after last dose of study drug. 
Follow-Up Phone Contact 
 
 
 
 
 
 
 
 
 
 
 
X r 
 
d = day; ECG = electrocardiogram; EOS = end of study; FU = follow-up; KPS = Karnofsky Performance Status; LTFU = long-term follow-up; MRI = magnetic resonance 
imaging; PK = pharmacokinetic; UNS = unscheduled; Tx = treatment 
a: 
Tumor tissue samples (20 slides cut as recently as possible and sections containing adequate tumor) must be available and ready to be sent to the central laboratory or the 
Sponsor. Samples from the original tumor and any subsequent biopsies will be required. An optional biopsy should be considered. For core or needle biopsy, a minimum of 7 
days must have elapsed prior to study entry. See lab manual for definition of adequate tumor sample.     


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b: 
At screening, PE to include height and weight. Complete PE including weight is required at all visits except for Day 15 of Cycle 1, when an abbreviated PE is acceptable (to 
be completed in a targeted manner covering related body systems). 
c: 
Neurological exam should include full cranial nerve central and peripheral, motor and sensory assessments. 
d: 
Vital sign measurements (blood pressure, heart rate, respiratory rate, and temperature) to be obtained with patient in sitting position.  On Cycle 1, Day 1, and Cycle 1, Day 15 
vital signs are to be measured predose and 1 and 4 hours postdose. 
e: 
Safety labs = hematology, coagulation, cystatin-C, clinical chemistry and urinalysis.  See Table 2.  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. 
f: 
Coagulation function to be tested at baseline only. INR, PT, APTT. 
g: 
Urine test in women of childbearing potential within 24-hours prior to first dose of study drug. Positive urine results are to be confirmed by serum pregnancy test. 
h: 
Supine 12-Lead ECGs will be performed at screening; predose, and once within the 4 – 8 hours postdose on Days 1 and 15 of Cycle 1; pre-dose on Day 1 of Cycles 2 and 
beyond; and at End of Study Drug Treatment visit.  At each timepoint, repeat ECG three times consecutively within 30 minutes (must have an interval of at least 1–2 minutes 
between ECGs).  ECGs will be read by a central laboratory. Following dose reduction and resumption of study drug treatment, ECGs must be repeated weekly for 2 weeks, 
then on Day 1 of each cycle following restart of study drug.  
i: 
The assessment is intended to be done prior to starting cycle 2, 3, 5, 7+ but should be performed every 8 weeks. Radiological assessment must be performed with a brain MRI 
scan. The method of radiological assessment should be consistent throughout all visits.  Disease assessment during the screening period is to be performed within 7 days 
before study drug administration and must be used as the baseline radiological assessment. The corticosteroid dose should be kept stable for 5 days prior to the MRI scan. 
During the study, disease assessments should be performed at week 4 and 8 after the date of first study treatment and then every 8 weeks (at Week 16, 24, etc.), regardless of 
treatment delays. For patients who discontinue treatment for other reasons than PD, disease assessment in the follow-up period should continue every 8 weeks (according to 
the original schedule) until disease progression. For patients with PD, disease assessment at the EOS is only required if not performed within the previous 8 weeks. 
j: 
Patients will complete the questionnaire pre-dose on Day 1 of Cycles 1 and 2; every 8 weeks after study drug administration (i.e., coinciding with the schedule of disease 
assessments); and at the EOS. Patients who discontinue study treatment for reasons other than disease progression will also complete the questionnaire every 8 weeks during 
follow-up until the time of documented disease progression. Patients must complete the questionnaire prior to any other tests or assessments and prior to any discussion of the 
patient’s progress with their physician or any other healthcare personnel at the site. 
k: 
Blood samples for tesevatinib plasma concentrations should be drawn prior to study drug administration. 
l: 
Tesevatinib will be administered at the dose of 300 mg once daily. Study drug should be dispensed and accounted for from previous visit. 
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 as soon as possible after the patient’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 patients’ 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.  Assessments for the 30-day follow up may be done by telephone. 
p: 
For unscheduled visits, study assessments are at the investigator’s discretion. 
q: 
Patients are to be contacted by telephone every 8 weeks to assess progression status if not PD when study drug stopped, survival status and any subsequent anti-cancer 
treatment. If PD was not observed before the 30-day follow-up period patients will return for follow-up MRI until PD is demonstrated or they start a new anti-cancer 
treatment. In the case of a patient receiving a new anti-cancer treatment in the absence of PD, the date of the most recent MRI will be used as the date of PD. 
 
 


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Table 2b: 
Schedule of Study Assessments for Subjects Completing 24 Cycles of Tesevatinib Treatment 
Timepoint  
(Study Day) 
Cycle 26
Cycle 28
Cycle 30
Cycle 32
Cycle 34  Cycle 36+
EOS Tx i
30-Day 
FU j 
(± 5d) 
UNS k
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1 (± 
3d) 
Day 1 
(± 3d) 
Physical Examination a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological Examination b 
X 
X 
X 
X 
X 
X 
 
 
X 
Vital Signs c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Labs d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG e 
X 
X 
X 
X 
X 
X 
X 
 
X 
Disease Assessment f 
X 
X 
X 
X 
X 
X 
X 
 
X 
Karnofsky performance 
status 
X 
X 
X 
X 
X 
X 
X 
 
X 
Corticosteroid use 
X 
X 
X 
X 
X 
X 
X 
 
X 
MRI tumor assessment 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tesevatinib Dispensing g 
X 
X 
X 
X 
X 
X 
 
 
X 
AE Monitoringh 
X 
X 
X 
X 
X 
X 
X 
X 
d = day; ECG = electrocardiogram; EOS = end of study; FU = follow-up; KPS = Karnofsky Performance Status; LTFU = long-term follow-up; MRI = magnetic resonance 
imaging; PK = pharmacokinetic; UNS = unscheduled; Tx = treatment 
a: 
Abbreviated PE is acceptable (to be completed in a targeted manner covering related body systems). 
b: 
Neurological exam should include full cranial nerve central and peripheral, motor and sensory assessments. 
c: 
Vital sign measurements (blood pressure, heart rate, respiratory rate, and temperature) to be obtained with patient in sitting position. 
d: 
To be drawn and analyzed locally.  Safety labs = hematology and clinical chemistry.  See Table 2b.   
e: 
Supine 12-Lead ECGs will be performed at each visit.   
f: 
The assessment should be performed every 8 weeks. Radiological assessment must be performed with a brain MRI scan and should be consistent throughout all visits.   
g: 
Study drug should be dispensed and accounted for from previous visit. 
h: 
AEs are to be collected from the time of informed consent through 30 days after last dose of study drug.   
i: 
The End-of-Study Drug Treatment visit is to occur as soon as possible after the patient’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.   
j: 
The 30-Day Follow-Up visit should occur 30 days (±5 days) after the patients’ 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.  Assessments for the 30-day follow up may be done by telephone. 
k: 
For unscheduled visits, study assessments are at the investigator’s discretion. 
 
 


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Table 3: 
Clinical Laboratory Panels 
Hematology 
Serum Chemistry 
Urinalysis (dipstick) 
 
WBC with differential (including neutrophils, 
basophils, eosinophils, lymphocytes, monocytes) 
 
hemoglobin 
 
hematocrit 
 
platelet count 
 
mean corpuscular volume (MCV) 
 
 
cystatin-c 
 
albumin 
 
amylase (trigger fasting 
triglycerides if amylase is 1.5 x 
normal) 
 
alkaline phosphatase 
 
ALT 
 
AST 
 
bicarbonate 
 
BUN 
 
calcium 
 
chloride 
 
creatinine 
 
creatine phosphokinase 
 
phosphorous 
 
potassium 
 
glucose (non-fasting) 
 
sodium 
 
total bilirubin 
 
total protein 
 
magnesium 
 
appearance 
 
color 
 
pH 
 
specific gravity 
 
ketones 
 
leukocytes 
 
protein 
 
glucose 
 
bilirubin 
 
urobilinogen 
 
occult blood (microscopic examination of 
sediment will be performed only if the results of 
the urinalysis dipstick evaluation are positive) 
Coagulation* 
 
INR 
 
PT 
 
aPTT 
ALT = alanine aminotransferase; APTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; INR = International normalized 
ratio; MCV = mean cell volume; PT = prothrombin time  
*Coagulation function only to be tested at baseline visit. 
 
 


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 Table 4: 
Clinical Laboratory Panels for Subjects Completing 24 Cycles of Tesevatinib Treatment 
Hematology 
Serum Chemistry 
 
 
WBC with differential (including neutrophils, 
basophils, eosinophils, lymphocytes, monocytes) 
 
hemoglobin 
 
hematocrit 
 
platelet count 
 
mean corpuscular volume (MCV) 
 
 
albumin 
 
amylase (trigger fasting 
triglycerides if amylase is 1.5 x 
normal) 
 
alkaline phosphatase 
 
ALT 
 
AST 
 
bicarbonate 
 
BUN 
 
calcium 
 
chloride 
 
creatinine 
 
creatine phosphokinase 
 
phosphorous 
 
potassium 
 
glucose (non-fasting) 
 
sodium 
 
total bilirubin 
 
total protein 
 
magnesium 
 
 
 
ALT = alanine aminotransferase; APTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; INR = International normalized 
ratio; MCV = mean cell volume; PT = prothrombin time  


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TABLE OF CONTENTS 
1. 
PROCEDURES IN CASE OF EMERGENCY ............................................................2 
2. 
SPONSOR SIGNATURE .............................................................................................3 
3. 
INVESTIGATOR SIGNATURE .................................................................................4 
4. 
SYNOPSIS ...................................................................................................................5 
5. 
BACKGROUND AND RATIONALE .......................................................................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 ......................................................................................33 
5.3. 
Rationale .....................................................................................................................35 
5.3.1. 
Study Rationale ...........................................................................................................35 
5.3.2. 
Rationale for Dosage Selection ..................................................................................36 
6. 
STUDY OBJECTIVES ..............................................................................................37 
6.1. 
Primary Objectives .....................................................................................................37 
6.1.1. 
Primary efficacy objective ..........................................................................................37 
6.1.2. 
Primary safety objective .............................................................................................37 
6.2. 
Secondary Objectives .................................................................................................37 
6.3. 
Exploratory objectives ................................................................................................37 
7. 
INVESTIGATIONAL PLAN .....................................................................................39 
7.1. 
Overview of Study Design ..........................................................................................39 
7.2. 
Discussion of Study Design ........................................................................................40 
7.3. 
Conditions for Terminating the Study ........................................................................40 
8. 
STUDY POPULATION .............................................................................................42 
8.1. 
Target Population ........................................................................................................42 
8.2. 
Inclusion Criteria ........................................................................................................42 
8.3. 
Exclusion Criteria .......................................................................................................43 
8.4. 
Removal of Patients from Study .................................................................................45 
8.5. 
Replacement of Patients in Study ...............................................................................47 
9. 
STUDY DRUG ...........................................................................................................48 


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9.1. 
Tesevatinib ..................................................................................................................48 
9.1.1. 
Randomization and Blinding ......................................................................................49 
9.1.2. 
Tesevatinib Administration ........................................................................................49 
9.1.3. 
Dose Modifications and Delays for Toxicity Related to Study Drug .........................49 
9.1.3.1. 
Requirements for Continuation of Treatment Post Cycle 1 ........................................50 
9.1.3.2. 
Study Drug Discontinuation .......................................................................................51 
9.1.4. 
Management of Adverse Events of Special Interest ...................................................51 
9.1.4.1. 
Diarrhea ......................................................................................................................51 
9.1.4.2. 
Skin Rash ....................................................................................................................51 
9.1.4.3. 
QT Interval Prolongation ............................................................................................53 
9.1.4.4. 
Elevated Serum Creatinine .........................................................................................55 
9.1.4.5. 
Elevated Serum Amylase ............................................................................................55 
9.1.4.6. 
Interstitial Lung Disease .............................................................................................55 
9.2. 
Study Drug Accountability and Patient Treatment Compliance ................................55 
9.3. 
Concomitant Medication and Treatment ....................................................................56 
9.3.1. 
Additional Therapy .....................................................................................................57 
9.3.2. 
Additional Anti-Cancer Treatment and Radiotherapy ................................................57 
9.3.3. 
Interaction of Tesevatinib with Other Medications ....................................................57 
9.3.3.1. 
Management of Patients Requiring Concomitant Medications Associated 
with QT Interval Prolongation ....................................................................................57 
10. 
EFFICACY ASSESSMENTS ....................................................................................59 
10.1. 
Radiological Assessment by Brain MRI .....................................................................59 
10.2. 
Clinical Status by Karnofsky Performance .................................................................60 
10.3. 
Corticosteroid Dose ....................................................................................................60 
10.4. 
Overall Disease Assessment .......................................................................................61 
11. 
SAFETY .....................................................................................................................62 
11.1. 
Safety Parameters .......................................................................................................62 
11.2. 
Adverse Event Definition ...........................................................................................62 
11.3. 
Evaluating Adverse Events .........................................................................................63 
11.3.1. 
Serious Adverse Events ..............................................................................................63 
11.3.2. 
Suspected Unexpected Serious Adverse Reactions (SUSAR) ...................................64 


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11.3.3. 
Unexpected Adverse Events .......................................................................................64 
11.3.4. 
Non-Serious Adverse Events ......................................................................................64 
11.3.5. 
Protocol-Related Adverse Events ...............................................................................64 
11.3.6. 
Relationships/Causality to Study Drug .......................................................................65 
11.3.7. 
Recording Adverse Events .........................................................................................65 
11.3.8. 
Adverse Event Monitoring and Follow-up .................................................................65 
11.3.9. 
Laboratory and ECG Abnormalities ...........................................................................65 
11.3.10. 
Pregnancy ...................................................................................................................66 
11.3.11. 
Serious Adverse Event Reporting ...............................................................................66 
11.3.11.1.  Governing Regulatory Requirements .........................................................................66 
11.3.11.2.  Time-Frame for Reporting ..........................................................................................67 
11.3.11.3.  Information to be Provided by the Investigator ..........................................................67 
11.3.12. 
Regulatory Reporting ..................................................................................................68 
11.3.13. 
Follow-up Information on a Serious Adverse Event ..................................................69 
11.4. 
Other Safety Considerations .......................................................................................69 
11.4.1. 
Medication Errors .......................................................................................................69 
11.4.2. 
Follow-Up of Serious Adverse Events .......................................................................69 
11.5. 
Safety Monitoring .......................................................................................................69 
12. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................70 
12.1. 
Procedures to be Performed ........................................................................................70 
12.1.1. 
Informed Consent .......................................................................................................70 
12.1.2. 
Demographics and Medical History ...........................................................................70 
12.1.3. 
Complete and Abbreviated Physical Examinations ....................................................70 
12.1.4. 
Detailed Neurological Examination ...........................................................................70 
12.1.5. 
Vital Sign Measurements ............................................................................................71 
12.1.6. 
Hematology, Serum Chemistries, Coagulation and Urinalysis ..................................71 
12.1.7. 
Pregnancy Test ............................................................................................................73 
12.1.8. 
Tumor Samples ...........................................................................................................73 
12.1.9. 
12-Lead Electrocardiogram (ECG) .............................................................................74 
12.1.10. 
Disease and Response Assessments .........................................................................74 
12.1.11. 
Tesevatinib Administration ........................................................................................75 


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12.1.12. 
Patient Reported Outcomes (MDASI-BT) .................................................................75 
12.1.13. 
Tesevatinib Plasma Concentrations ............................................................................76 
12.1.14. 
Pharmacodynamics .....................................................................................................76 
12.1.15. 
Prior and Concomitant Medications ...........................................................................76 
12.1.16. 
Adverse Event Assessments .......................................................................................76 
12.1.17. 
Study Diary .................................................................................................................77 
12.2. 
Schedule of Visits .......................................................................................................77 
12.2.1. 
Screening Visit ............................................................................................................77 
12.2.2. 
Cycle 1; Day 1 ............................................................................................................78 
12.2.3. 
Cycle 1; Day 15 ..........................................................................................................78 
12.2.4. 
Cycle 2; Day 1 ............................................................................................................79 
12.2.5. 
Cycle 3; Day 1 ............................................................................................................79 
12.2.6. 
Cycle 4; Day 1 ............................................................................................................80 
12.2.7. 
Cycle 5; Day 1 ............................................................................................................81 
12.2.8. 
Cycle 6; Day 1 ............................................................................................................81 
12.2.9. 
Cycle 7+; Day 1 ..........................................................................................................82 
12.2.10. 
Day 15 on Cycle 2 through Cycle 6 ............................................................................83 
12.2.11. 
End-of-Study Drug Treatment Visit (EOS) ................................................................83 
12.2.12. 
30-Day Follow-up .......................................................................................................84 
12.2.13. 
Follow-up Phone Contact ...........................................................................................85 
12.2.14. 
Unscheduled Visits: To Occur as Needed ..................................................................85 
13. 
STATISTICAL CONSIDERATIONS .......................................................................86 
13.1. 
General Design ...........................................................................................................86 
13.2. 
Sample Size Justification ............................................................................................86 
13.3. 
Interim Analysis ..........................................................................................................87 
13.4. 
Statistical Considerations ............................................................................................87 
13.4.1. 
Study Populations .......................................................................................................87 
13.4.2. 
Patient Accountability, Demographics, and Baseline Characteristics ........................88 
13.4.3. 
Tesevatinib Exposure ..................................................................................................88 
13.4.4. 
Concomitant Medications ...........................................................................................88 
13.4.5. 
Plasma Concentrations ................................................................................................88 


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13.4.6. 
Efficacy/Activity .........................................................................................................88 
13.4.6.1. 
Primary efficacy endpoint ...........................................................................................88 
13.4.6.2. 
Secondary efficacy endpoints .....................................................................................89 
13.4.6.3. 
Sensitivity analysis for primary and secondary PFS and OS endpoint 
analysis .......................................................................................................................90 
13.4.6.4. 
Exploratory endpoints .................................................................................................90 
13.4.6.5. 
Safety Data ..................................................................................................................91 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................93 
14.1. 
Monitoring the Study ..................................................................................................93 
14.2. 
Audits and Inspections ................................................................................................94 
15. 
ETHICAL ASPECTS .................................................................................................95 
15.1. 
Compliance Statement ................................................................................................95 
15.2. 
Good Clinical Practice ................................................................................................95 
15.3. 
Informed Consent .......................................................................................................95 
15.4. 
Institutional Review Board .........................................................................................96 
15.5. 
Future Use of Patient Samples ....................................................................................96 
16. 
PROTOCOL AMENDMENTS ..................................................................................98 
17. 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING .........................99 
17.1. 
Investigator’s Files and Retention of Documents .......................................................99 
17.2. 
Source Documents and Background Data ..................................................................99 
17.3. 
Electronic Case Report Forms ..................................................................................100 
17.4. 
Confidentiality of Trial Documents and Patient Records .........................................100 
18. 
PUBLICATION POLICY ........................................................................................102 
19. 
REFERENCES .........................................................................................................103 
APPENDIX 1.  KARNOFSKY PERFORMANCE STATUS CRITERIA ...............................105 
APPENDIX 2.  RANO CRITERIA ...........................................................................................106 
APPENDIX 3.  MD ANDERSON SYMPTOM INVENTORY-BRAIN TUMOR 
MODULE .................................................................................................................108 
APPENDIX 4.  CONCOMITANT DRUGS THAT SHOULD BE AVOIDED, 
SUBSTITUTED OR USED WITH CAUTION .......................................................110 
APPENDIX 5.  TOPICAL STEROID POTENCY CHART .....................................................112 
 


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LIST OF TABLES 
Table 1: 
Study Assessments ......................................................................................................19 
Table 2: 
Clinical Laboratory Panels .........................................................................................21 
Table 3: 
Dose Adjustments According to CTCAE Toxicity Grade for Related AEs ...............50 
Table 4: 
Median PFS and PFS-6 Distributions .........................................................................86 
Table 5: 
Assumptions for Distribution of EGFR Subpopulations ............................................87 
 
 
 


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LIST OF ABBREVIATIONS 
AE(s) 
adverse event(s) 
ADL 
activities of daily living 
ADPKD 
autosomal dominant polycystic kidney disease  
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
ANC 
absolute neutrophil count 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BBB 
blood-brain barrier 
BID 
twice-a-day 
BSA 
body surface area 
CNS 
central nervous system 
CPK 
creatine phosphokinase 
CR 
complete response 
CRF 
case report form 
CS 
clinically significant  
CSF 
cerebrospinal fluid 
CYP3A4 
cytochrome P450 
DOR 
duration of response 
ECG 
electrocardiogram 
EGFR 
epidermal growth factor receptor 
EGFRvIII 
epidermal growth factor receptor variant III 
eCRF 
electronic case report form 
EOS 
end of study 
FU 
follow-up 
GCP 
good clinical practice 
GI 
gastrointestinal 
Hb 
hemoglobin 
HER2 
human epidermal growth factor receptor 2 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 


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IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
intravenous  
KPS 
Karnofsky performance status 
LM 
leptomeningeal 
LTFU 
long-term follow-up 
MDASI-BT 
M.D. Anderson Symptom Inventory – Brain Tumor 
questionnaire 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NCS 
non-clinically significant  
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
OS-9 
overall survival at 9 months 
PCR 
polymerase chain reaction 
PCV 
procarbazine, lomustine, and vincristine 
PD 
progressive disease 
PE 
physical exam 
PFS 
progression-free survival 
PFS-6 
progression-free survival at 6 months 
PK 
pharmacokinetics 
PR 
partial response 
PRO 
patient reported outcome 
PT 
prothrombin time 
QTc(F) 
QT interval, corrected 
RANO 
Response Assessment in Neuro-Oncology 
SADR (or SAR) 
suspected adverse drug reactions  
SAE(s) 
serious adverse event(s) 
SD 
stable disease 


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SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SSRI 
selective serotonin re-uptake inhibitors 
SUSAR 
suspected unexpected serious adverse reactions 
TMZ 
temozolomide 
ULN 
upper limit of normal 
VEGFR2 
vascular endothelial growth factor receptor 2 
WHO 
World Health Organization 
 


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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 
EGFR, 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 and potentially other solid tumors. 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), which is registered in this indication. 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 activating EGFR 
mutations. The potential advantage of tesevatinib over erlotinib is that tesevatinib is far more 
efficient at crossing the blood-brain barrier. It is therefore a good candidate for therapy of brain 
metastases and primary brain cancers which are driven by EGFR mutations. 
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 
To date, the tesevatinib clinical program consists of eight completed trials using the tablet 
formulation (six Phase 1 and two Phase 2 studies). One of the Phase 1 trials (KD019-104) in 
healthy volunteers compared the tablet formulation to the liquid formulation.  Four additional 
trials of the tablet formulation are included, of which three are ongoing; KD019-101 in 
autosomal dominant polycystic kidney disease (ADPKD), KD019-204 in metastatic breast 
cancer, and KD019-206 in patients with NSCLC; and one (KD019-301 in NSCLC) which 
recently closed due to slow enrollment.  
In these studies, over 275 patients with solid tumor malignancies, ADPKD, and healthy 
volunteers have received tesevatinib. The MTD in patients with solid tumor malignancies was 
determined to be 300 mg once daily. 
Further details of the clinical studies are provided in the Investigator’s Brochure. 
5.2. 
Safety Profile of Tesevatinib 
Tesevatinib has been evaluated in 6 clinical studies in various solid tumors in more than 275 
patients, of whom at least 50 received the recommended dose of 300 mg daily. The safety profile 
is similar to that of other agents in this class, with predominantly GI and skin AEs. The most 
frequently reported AEs associated with tesevatinib use are diarrhea, skin rash, fatigue, nausea, 
cough, dyspnea, dry skin, vomiting, constipation, vomiting, anorexia and QTc prolongation (see 


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Investigators Brochure for further detail). The AEs of special interest are as follows (refer to 
Section 9.1.4 for instruction on management of these AEs):  
Diarrhea:  Diarrhea is an expected AE for agents like tesevatinib that have significant EGFR 
inhibitor activity. Grade 3 diarrhea was the dose-limiting toxicity. At doses below those that 
cause dose-limiting toxicity, diarrhea has been effectively managed by starting loperamide upon 
occurrence of grade 1. 
QTc Prolongation: In clinical trials of tesevatinib, cases of QTc prolongation have been 
observed.  
In patients with malignancies treated in the clinical program at ≥ 300 mg daily or 350 mg 
intermittently, the majority of whom had advanced metastatic NSCLC, approximately 20% were 
found to have QTc prolongation based on machine read ECGs at some time during treatment that 
met the CTCAE v3 definition of an AE. The majority of these were Grade 2 and 3 with no Grade 
4. There were no clinical findings associated with the ECG changes.  
No SAEs of syncope, convulsions, sudden death, ventricular tachycardia, fibrillation, flutter, or 
torsades de pointes have been received for the > 275 patients exposed to tesevatinib.  
PK data from the clinical program demonstrated that QTc prolongation increased with increasing 
tesevatinib plasma concentration which correlated with dose administered. 
Patients in this study will be monitored carefully for QTc prolongation, and a central  laboratory 
will review all ECGs.    
Skin Rash:  Acneiform skin rash is an expected adverse event 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.   
Clinical Chemistry:  Creatinine elevations have been observed up to Grade 3 in the absence of 
other indicators of renal failure. 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. This effect appears to be due to inhibition of MATE transporter proteins by tesevatinib. 
Elevations of creatinine have also been observed in patients with other concurrent causes of renal 
dysfunction such as dehydration due to diarrhea.  
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.  
Occasional elevation of amylase and CPK have been observed with tesevatinib treatment. These 
were asymptomatic and reversible.   
Interstitial Lung Disease: Non-fatal interstitial lung disease (ILD) has been reported in 
association with the use of tesevatinib in one patient with NSCLC out of >275 patients exposed 
to tesevatinib. 


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5.3. 
Rationale 
5.3.1. 
Study Rationale 
Gliomas account for 80% of primary malignancies of the CNS. Glioblastomas (WHO Grade IV 
astrocytic tumors) account for 60–70% of gliomas and remain the most aggressive subtype. 
Glioblastoma occurs mostly in adults (median age of 64 years at diagnosis) with an estimated 
incidence of 2–3 cases per 100,000 people in Europe and North America. With 1- and 5-year OS 
rates of 29% and 3%, respectively, the prognosis of glioblastoma remains poor [Central Brain 
Tumor Registry of the United States 2011] and there is a need to develop more effective 
therapeutic approaches. 
Standard treatment for newly diagnosed glioblastoma is surgical debulking followed by 
radiotherapy and TMZ with additional maintenance TMZ [Stupp 2005]. Despite the survival 
benefit associated with such treatment, almost all patients relapse following initial therapy.  
Patients with recurrent glioblastoma have a median PFS of about 4 months and OS of less than 10 
months. The optimal management for patients with recurrent glioblastoma remains unclear, as 
there have been no randomized trials directly comparing active intervention with supportive care. 
The most important prognostic factors for benefit from re-intervention are pre-treatment 
performance status and patient age [Kappelle 2001].  
Active interventions include repeated surgery, re-irradiation, or systemic therapy in order to 
improve or preserve neurological function and prolong PFS and OS. Chemotherapy with TMZ 
demonstrated an increase in survival as second-line therapy in initial trials. However, TMZ is now 
generally used as a component of first-line treatment and hence there is no established 
chemotherapy regimen available for recurrent glioblastoma [Stupp 2009; Stupp 2010]. 
Nitrosourea-based chemotherapy, either as single agents or in combination regimens such as PCV, 
have shown some activity in Phase 2 studies of patients who progressed after prior chemotherapy 
[Schmidt 2006; Fabrini 2009]. Systemic treatment with the anti-VEGF monoclonal antibody 
bevacizumab has also shown some activity in recurrent glioblastoma [Friedman 2009]. 
Bevacizumab is currently approved for use in patients with progressive disease following prior 
therapy in the United States but not in the European Union [Avastin® USPI 2015]. The label 
specifically mentions that there are no data demonstrating an improvement in disease-related 
symptoms or increased survival. 
EGFR gene abnormalities occur commonly in glioblastomas, suggesting that EGFR inhibition 
could be a useful clinical strategy. Studies indicate that EGFR gene amplification and /or 
mutation are present in approximately 57% of glioblastomas [Brennan 2013]. EGFR variant III 
(EGFRvIII), which leads to constitutive EGFR signaling, is seen in approximately 25% of 
glioblastomas [van den Bent 2009]. Clinical trials of EGFR inhibitors in patients with 
glioblastomas have produced disappointing results, perhaps because the available agents have 
poor BBB penetration. A Phase 2 trial of erlotinib, for instance, led to a 6-month PFS rate of 
11% with erlotinib, compared to 24% with physician’s choice of temozolomide or carmustine 
[van den Bent 2009]. In vitro data suggest that some EGFR abnormalities will correlate with 
clinical sensitivity to erlotinib [Sarkaria 2007]. In addition to inhibiting EGFR, tesevatinib also 


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has VEGFR2 inhibitory activity, and there may be advantages to the simultaneous inhibition of 
EGFR and VEGFR2 in glioblastomas. Thus, although the determinants of glioblastoma 
responsiveness to EGFR inhibitors remain poorly defined, further research on the role of 
tesevatinib in glioma could be a productive approach to improving glioma treatment.   
Unlike other agents in its class, tesevatinib effectively penetrates into the brain, with levels in 
mice and rats with intact BBBs the same or higher than plasma levels [Tonra 2015].  Tesevatinib 
has levels in the choroid plexus and meninges that are 10 times the plasma levels, suggesting that 
tesevatinib may penetrate well into CSF.  There is preliminary evidence of clinical benefit in 
patients with leptomeningeal metastases in NSCLC [Kadmon data on file]. Thus, there is a good 
biologic rationale to evaluate tesevatinib in patients with recurrent glioblastoma which has 
progressed on or after prior therapy. Its role in tumors with and without and EGFR activating 
mutations, EGFR protein overexpression and gene amplification also needs to be explored. 
Glioblastomas are inherently inaccessible and challenging to assess in terms of repeat biopsy for 
evaluation of treatment-related biomarkers. Circulating tumor DNA has shown promise as a 
peripherally accessible source of biomarker information in glioblastoma [Touat 2015, Best 
2015]. 
  
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 patients with EGFR mutations.  In one study, the 
confirmed PR rate in patients with EGFR mutations was 57% (8/14), and an additional 3 patients 
with EGFR mutations had unconfirmed PRs. 
Tesevatinib 300 mg daily was selected from the regimens tested in the early clinical program 
based on its benefit-risk profile. 


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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objectives 
6.1.1. 
Primary efficacy objective 
 To evaluate the efficacy of tesevatinib as measured by investigator-assessed PFS-6 
6.1.2. 
Primary safety objective 
 To evaluate the safety and tolerability of tesevatinib in all patients and in the 
subgroup of patients with EGFRvIIIpos and the subgroup of patients with EGFR 
amplificationpos tumors 
6.2. 
Secondary Objectives 
 To evaluate the efficacy of tesevatinib as measured by investigator-assessed PFS-6 in 
the subgroup of patients with EGFRvIIIpos glioblastoma  
 To evaluate the efficacy of tesevatinib as measured by investigator-assessed PFS-6 in 
the subgroup of patients with EGFR gene amplified glioblastoma 
 To evaluate the efficacy of tesevatinib as measured by the rate OS-9 and OS overall, 
in all patients and in those with EGFRvIIIpos and EGFR gene amplified glioblastoma 
 To evaluate the efficacy of tesevatinib as measured by PFS, ORR per RANO criteria, 
and DOR in all patients and in those with EGFRvIIIpos and EGFR gene amplified 
tumors 
 To evaluate the efficacy of tesevatinib as measured by PFS-6, OS-9, RANO OOR and 
DOR in: 
o EGFRvIIIpos vs EGFRvIIIneg 
o EGFR amplificationpos vs EGFR amplificationneg 
6.3. 
Exploratory objectives 
 To evaluate the plasma concentrations of tesevatinib in patients with and without 
systemic steroid treatment  
 To evaluate the potential association of exploratory tissue and blood biomarkers with 
response to tesevatinib and with adverse events. These include EGFRvIII mutation 
and gene amplification and may include circulating tumor DNA  
 To evaluate the correlation between patients with EGFRvIIIpos tumor and those 
patients with EGFR gene amplification 
 To evaluate and compare EGFRvIIIpos expression and/or other tissue biomarkers 
potentially associated with response with tesevatinib, in paired primary and recurrent 
glioblastoma specimens from the same patient, when these are available 


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 To evaluate patient-reported outcomes of disease and treatment-related symptom 
severity and interference as measured by the MDASI-BT questionnaire 
 To evaluate patient-reported outcomes of disease and treatment-related symptom 
severity and interference as measured by the MDASI-BT in the subgroup of patients 
with EGFRvIIIneg  and EGFR gene amplificationneg tumors as compared to those in 
patients with EGFRvIIIpos and EGFR gene amplificationpos tumors 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overview of Study Design 
This is a multicenter, Phase 2 study to assess the activity of tesevatinib in patients (n =40) with 
recurrent glioblastoma. This study will be conducted at up to 10 sites in the United States. 
The availability of paraffin-embedded tumor sample diagnostic of glioblastoma is mandatory for 
entry into the study. Tumor samples will be evaluated for the EGFRvIII mutation and for EGFR 
gene amplification. Tissue from recurrent surgery is preferred, but tissue from initial surgery is 
sufficient for study entry. Baseline MRI is mandatory.  
After completion of the screening assessments and confirmation of study eligibility by the 
Medical Monitor upon review of an inclusion package, tesevatinib will be orally administered to 
all patients at a dose of 300 mg once daily. A cycle will be considered as 28 days. Patients will 
be evaluated for efficacy according to the RANO criteria. 
Patients who develop ≥ Grade 3 adverse event(s) considered by the investigator to be related to 
study drug (with the exceptions noted in Section 9.1.3) will have study treatment interrupted 
until the drug-related toxicities have resolved to ≤ Grade 1. Once toxicities have resolved to ≤ 
Grade 1, the patient may resume study treatment at a reduced dose of 250 mg/day. No more than 
one dose reduction is permitted. Patients who require more than one dose reduction will have 
study drug discontinued and enter the Follow-up Period. 
Patients for whom toxicity persists beyond 21 days despite dose interruption may resume study 
treatment only with permission from the responsible Medical Monitor.   
If study treatment is withheld, the patient should be instructed not to make up the withheld doses. 
Section 9.1.3 provides detailed instructions concerning dose interruptions and reductions. 
Study treatment will continue until disease progression, unacceptable toxicity, patient or 
physician decision to discontinue, or death.  Assessments for disease response will occur at week 
4 and week 8 and then every 8 weeks thereafter using the RANO criteria (Appendix 2).  
Upon treatment discontinuation, patients will be followed every 8 weeks for survival. 
Tumor samples will be used for exploratory biomarker research including, but not limited to, 
evaluation of EGFRvIII expression by immunohistochemistry (IHC) or real-time Polymerase 
Chain Reaction (PCR).  An appropriate definition and cutoff for EGFRvIIIpos tumors will be 
established, and outcome in this subpopulation will be evaluated in addition to the overall study 
population.  
To characterize the safety and tolerability profile of tesevatinib, patients will be monitored 
throughout the study for adverse events (all grades), serious adverse events, and any adverse 
events requiring drug interruption or discontinuation.  Patients will undergo safety evaluations, 
including PE, KPS, vital sign measurements, hematology, serum chemistry, urinalysis and ECG.   
MRI will be used to evaluate the tumor at baseline. All MRIs taken on study patients will be 
submitted to the sponsor for possible retrospective analysis. 


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7.2. 
Discussion of Study Design 
The single arm design assessing PFS-6 in the overall population with the ability to detect a rate 
of 25% is appropriate as a preliminary test of activity in patients with glioblastoma, based on 
PFS-6 rates seen in randomized studies with bevacizumab [Weathers 2015; Taal 2014; Galanis 
2015]. The sample size of this study is also designed to permit the comparison of results with 
EGFR amplified and non-amplified tumors, as well as EGFRvIII mutated versus wild-type. The 
sample size is adequate to characterize the safety profile in patients with glioblastoma. 
7.3. 
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 patients’ 
interests. 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 patients.  
 Patient enrollment is unsatisfactory. 
 Drug supply issues. 
 Data recording is inaccurate or incomplete. 
 Excessive patient self-withdrawal. 
 Significant protocol deviations (e.g., violation of eligibility criteria, dosing errors, 
missing data for study endpoint analysis). 
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 patients. 
 Case Report Forms/Records.  Electronic case report forms (eCRFs) will be used in 
this study.  Records (including correction forms) for all enrolled patients 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. 


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 A summary of the study prepared by the principal investigator (IRB summary closure 
letter is an acceptable equivalent). 


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8. 
STUDY POPULATION 
8.1. 
Target Population 
This study will be conducted in up to 40 patients with recurrent glioblastoma. Tumor samples 
will be evaluated for the EGFRvIII mutation and EGFR gene amplification.   
8.2. 
Inclusion Criteria 
Patients will be included if they meet the following criteria: 
1. Willingness and ability to provide written informed consent and to comply with the study 
protocol as judged by the investigator. 
2. Age ≥ 18 years old. 
3. Karnofsky performance status ≥ 70% (see Appendix 1). 
4. Stable or decreasing dose of corticosteroids within 5 days prior to study enrollment. 
5. Female subjects of childbearing potential have a negative pregnancy test at screening. 
Females of childbearing potential are defined as sexually mature women without prior 
hysterectomy or who have had any evidence of menses in the past 12 months. However, 
women who have been amenorrheic for 12 or more months are still considered to be of 
childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-
estrogens, or ovarian suppression. 
 Women of childbearing potential (i.e., menstruating women) must have a negative 
urine pregnancy test (positive urine tests are to be confirmed by serum test) 
documented within the 24-hour period prior to the first dose of study drug.  
 Sexually active women of childbearing potential enrolled in the study must agree to 
use two forms of accepted methods of contraception during the course of the study 
and for 6 months after their last dose of study drug.  Effective birth control includes 
(a) IUD plus one barrier method; (b) on stable doses of hormonal contraception for at 
least 3 months (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. 
6. For male patients who are sexually active and who are partners of premenopausal 
women: agreement to use two forms of contraception as in criterion 5 above during the 
treatment period and for at least 6 months after the last dose of study drug. 
7. Histologically confirmed glioblastoma. A local pathology report constitutes adequate 
documentation of histology for study inclusion.  Patients with an initial diagnosis of a 
lower-grade glioma are eligible if a subsequent biopsy was determined to be 
glioblastoma. 


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8. First recurrence after concurrent or adjuvant chemoradiotherapy. Imaging confirmation of 
first tumor progression or regrowth as defined by the RANO criteria.  A minimum of 12 
weeks must have elapsed from the completion of radiotherapy to study entry to minimize 
the potential for MRI changes related to radiation necrosis that might be misdiagnosed as 
progression of disease, unless there is a new lesion outside the radiation field or 
unequivocal evidence of viable tumor on histopathological sampling. 
9. Prior treatment with TMZ for low grade glioma or glioblastoma. 
10. No more than one prior line of systemic treatment for glioblastoma.  Concurrent and 
adjuvant TMZ-based chemotherapy, including the combination of TMZ with an 
investigational agent, is considered one line of therapy. 
11. Prior therapy with gamma knife or other focal high-dose radiotherapy is allowed, but the 
patient must have subsequent histologic documentation of recurrence, unless the 
recurrence is a new lesion outside the irradiated field. 
12. Recovery from the toxic effects of prior therapy, with a minimum time of: 
a. ≥ 28 days elapsed from the administration of any investigational agent 
b. ≥ 28 days elapsed from the administration of any prior cytotoxic agents, except ≥ 14 
days from vincristine, ≥ 21 days from procarbazine, and ≥ 42 days from nitrosureas 
c. ≥ 14 days elapsed from administration of any non-cytotoxic agent (e.g., interferon, 
tamoxifen, thalidomide, cis-retinoic acid) 
13. Patients who have undergone recent surgery for recurrent or progressive tumor are 
eligible provided that: 
a. Surgery must have confirmed the recurrence 
b. There must be residual disease measurable per RANO criteria e.g. 1 cm x 1 cm 
c. A minimum of 28 days must have elapsed from the day of surgery to first dose of the 
study drug. For core or needle biopsy, a minimum of 7 days must have elapsed prior 
to study entry 
14. Availability of formalin-fixed paraffin-embedded tumor tissue diagnostic of 
glioblastoma. 
8.3. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Concurrent therapeutic intervention (including radiation therapy and NovoTTF). 
2. Prior exposure to EGFR inhibitors. 
3. Prior exposure to bevacizumab or other VEGF- or VEGF-receptor-targeted agent within 8 
weeks of study start. 
4. Prior treatment with prolifeprospan 20 with carmustine wafer. 
5. Prior intracerebral agent. 


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6. Evidence of recent hemorrhage on baseline MRI of the brain.  However, patients with 
clinically asymptomatic presence of hemosiderin, resolving hemorrhagic changes related 
to surgery, or presence of punctuate hemorrhage in the tumor are eligible. 
7. Need for urgent palliative intervention for primary disease (e.g., rapidly increasing 
intracranial pressure, impending herniation, uncontrolled seizures). 
8. ANC < 1.5 x109/L; platelet count < 100 x109/L; or Hb < 9.0 g/dL within 7 days prior to 
enrollment.  Note: The use of transfusion or other intervention to achieve Hb ≥ 9 g/dL is 
acceptable. 
9. Total bilirubin ≥ 1.5 x ULN (except in patients diagnosed with Gilbert’s disease). 
10. AST (SGOT), ALT (SGPT), or ALP ≥ 2.5 x ULN. 
11. Serum creatinine > 1.5 x ULN. 
12. Serum potassium or magnesium below lower limit of normal. 
13. INR, PT, or APTT as follows unless on anticoagulation that is expected to alter 
coagulation test results: 
 INR > 1.5 or PT > 1.5 xULN or aPTT > 1.5 xULN 
14. Known contraindication to MRI, such as cardiac pacemaker, shrapnel or ocular foreign 
body. 
15. Used any prescription medication during the prior 2 weeks that the investigator judges is 
likely to interfere with the study or to pose an additional risk to the patient in 
participating, specifically inhibitors or inducers of cytochrome P450 (CYP)3A4 (refer to 
Appendix 4).  A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class is 
allowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine, 
paroxetine, sertraline, and fluoxetine). 
16. Taking any drugs associated with torsades de pointes or known to moderately or severely 
prolong the QTc(F) interval (see Appendix 4). 
17. 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.  Patients with a history of atrial arrhythmias 
should be discussed with the Medical Monitor. 
18. Uncontrolled diabetes, as evidenced by fasting serum glucose level >200 mg/dL. 
19. NYHA Grade II or greater congestive cardiac failure. 
20. Has marked prolongation of QTc(F) interval at screening or baseline (QTc[F] interval 
> 470 msec) using the Fridericia method of correction for heart rate. 
21. History of myocardial infarction (within 12 months) or unstable angina (within 6 months) 
prior to study enrolment. 
22. History of stroke or transient ischemic attacks within 6 months prior to study enrolment. 


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23. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to study enrolment. 
24. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation). 
25. History of intracranial abscess within 6 months prior to study enrolment. 
26. History of another malignancy in the previous 3 years, with a disease-free interval of < 3 
years Patients with prior history of in situ cancer or basal or squamous cell skin cancer 
are eligible. 
27. Evidence of any active infection requiring hospitalization or IV antibiotics within 2 
weeks prior to study enrolment. 
28. Known hypersensitivity to any excipients of tesevatinib. 
29. Inability to swallow or absorb orally-administered medication. 
8.4. 
Removal of Patients from Study  
Withdrawal of a patient from the study means that no further study visits or procedures are 
performed and no further data are collected. Every reasonable effort will be made to keep the 
patient in the study; however, in the event that a patient 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/adverse events). Refer to Table 1 
and  
 


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Table 2b: Schedule of Study Assessments for Subjects Completing 24 Cycles of Tesevatinib 
Treatment 
Timepoint  
(Study Day) 
Cycle 26 Cycle 28
Cycle 30
Cycle 32
Cycle 34 Cycle 36+ 
EOS Tx i 
30-Day 
FU j 
(± 5d) 
UNS k
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1 (± 
3d) 
Day 1  
(± 3d) 
Physical Examination a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological Examination b 
X 
X 
X 
X 
X 
X 
 
 
X 
Vital Signs c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Labs d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG e 
X 
X 
X 
X 
X 
X 
X 
 
X 
Disease Assessment f 
X 
X 
X 
X 
X 
X 
X 
 
X 
Karnofsky performance 
status 
X 
X 
X 
X 
X 
X 
X 
 
X 
Corticosteroid use 
X 
X 
X 
X 
X 
X 
X 
 
X 
MRI tumor assessment 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tesevatinib Dispensing g 
X 
X 
X 
X 
X 
X 
 
 
X 
AE Monitoringh 
X 
X 
X
X
X
X
X 
X
d = day; ECG = electrocardiogram; EOS = end of study; FU = follow-up; KPS = Karnofsky Performance Status; LTFU = long-
term follow-up; MRI = magnetic resonance imaging; PK = pharmacokinetic; UNS = unscheduled; Tx = treatment 
l: 
Abbreviated PE is acceptable (to be completed in a targeted manner covering related body systems). 
m: Neurological exam should include full cranial nerve central and peripheral, motor and sensory assessments. 
n: 
Vital sign measurements (blood pressure, heart rate, respiratory rate, and temperature) to be obtained with patient in 
sitting position. 
o: 
To be drawn and analyzed locally.  Safety labs = hematology and clinical chemistry.  See Table 2b.   
p: 
Supine 12-Lead ECGs will be performed at each visit.   
q: 
The assessment should be performed every 8 weeks. Radiological assessment must be performed with a brain MRI 
scan and should be consistent throughout all visits.   
r: 
Study drug should be dispensed and accounted for from previous visit. 
s: 
AEs are to be collected from the time of informed consent through 30 days after last dose of study drug.   
t: 
The End-of-Study Drug Treatment visit is to occur as soon as possible after the patient’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.   
u: 
The 30-Day Follow-Up visit should occur 30 days (±5 days) after the patients’ 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.  Assessments for the 30-day follow up may be done by telephone. 
v: 
For unscheduled visits, study assessments are at the investigator’s discretion. 
 
 


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Table 3.  
A termination eCRF must be completed for all enrolled patients. 
The patient may be withdrawn from the study for any of the following reasons. 
 Voluntary withdrawal by patient 
 Patient lost to follow-up 
 Termination of the study by sponsor 
 Patient death 
If a patient dies, Kadmon will actively seek to determine the date and cause of death.  
If there is an ongoing toxicity associated with tesevatinib, patients must be followed with 
appropriate medical management until resolution or stabilization. 
A reasonable effort should be made to contact any patient who is lost to follow-up during the 
course of the study in order to complete assessments and retrieve any outstanding data. If a 
patient is unreachable by telephone after three (3) attempts, the minimum of a registered letter 
should be sent requesting that the patient make contact with the investigator. 
8.5. 
Replacement of Patients in Study 
Patients discontinued from the trial will not be replaced. 
 


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9. 
STUDY DRUG 
9.1. 
Tesevatinib 
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. 
Patients will be provided with either a weekly or monthly supply of study drug and instructions 
for taking the study drug at home. Subjects who have completed 24 cycles of treatment without 
disease progression or unacceptable toxicity will receive a 2-month supply of tesevatinib at each 
bimonthly visit.  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: 
Kadmon Corporation, LLC 
KD019 Tablets 100-mg – 32 tablets/bottle 
Lot Number:  XXXXX.XXX   ____bottles/box 
Direction: Take as directed by physician 
Caution: Federal law prohibits the transfer of this drug to any person other than the 
patient for whom it was prescribed. 
Caution:  New Drug-Limited by Federal Law to Investigational Use 21 CFR 
312.6(a). 
Keep out of reach of children and pets. 
Store at USP controlled room temperature of 20°-25°C (68°-77°F).  Brief excursions 
permitted to 15°C-30°C (59°-86°F) 
Kadmon Corporation, LLC New York, NY 10016 USA 
 
Kadmon Corporation, LLC 
KD019 Tablets 150-mg – 32 tablets/bottle 
Lot Number:  XXXXX.XXX   ____bottles/box 
Direction: Take as directed by physician 
Caution: Federal law prohibits the transfer of this drug to any person other than the 
patient for whom it was prescribed. 
Caution:  New Drug-Limited by Federal Law to Investigational Use 21 CFR 
312.6(a). 
Keep out of reach of children and pets. 
Store at USP controlled room temperature of 20°-25°C (68°-77°F).  Brief excursions 
permitted to 15°C-30°C (59°-86°F) 
Kadmon Corporation, LLC New York, NY 10016 USA 


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9.1.1. 
Randomization and Blinding 
This is an open-label, non-randomized study. 
9.1.2. 
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). Patients 
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. 
Patients must be instructed not to make up missed doses unless the missed dose can be taken 
within 12 hours of the normal dosing time.  Patients should not re-take study drug doses in the 
event of vomiting. 
Patients will be treated with study drug until disease progression or unacceptable toxicity occurs.   
Subjects who have completed 24 cycles of treatment without disease progression or unacceptable 
toxicity will be eligible to receive tesevatinib until disease progression or unacceptable toxicity 
occurs.   
All patients also will be followed for a period of 30 days following their last dose of tesevatinib.   
9.1.3. 
Dose Modifications and Delays for Toxicity Related to Study Drug 
Patients who develop ≥ Grade 3 adverse event(s) considered by the investigator to be related to 
study drug (with the exceptions noted below) will have study treatment interrupted until all drug-
related toxicities have resolved to ≤ Grade 1. Once these toxicities have resolved to ≤ Grade 1, 
the patient may resume study treatment at a reduced dose of 250 mg/day. No more than one dose 
reduction is permitted. Patients who require more than one dose reduction will have study drug 
discontinued and enter the Follow-up Period. 
The exceptions are: 
 asymptomatic Grade 3 elevations of amylase or lipase,  
 Grade 3 elevation of alkaline phosphatase in a patient known to have bone 
metastases,  
 Grade 3 elevation of glucose in a patient receiving systemic corticosteroids,  
 Grade 3 creatine phosphokinase [CPK] elevation in the absence of muscle symptoms,  
 Grade 3 sodium values ≥126 mmol/L in a patient with diarrhea) 
Patients for whom toxicity persists beyond 21 days despite dose interruption may resume study 
treatment at a reduced dose of 250 mg/day only with permission from the responsible Medical 
Monitor.   


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If study treatment is withheld, the patient should be instructed not to make up the withheld doses.  
Table 5: 
Dose Adjustments According to CTCAE Toxicity Grade for Related AEs 
Occurrence 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
First appearance 
No action with study 
drug 
 For diarrhea start 
loperamide, 
monitor for 
dehydration 
 For rash start 
topical steroids 
(see 
Section 9.1.4.2)  
 For QTc 
prolongation no 
action 
No action with study 
drug 
 For diarrhea 
start/increase  
loperamide, 
monitor for 
dehydration 
 For rash topical 
steroids ± 
doxycycline (see 
Section 9.1.4.2) 
 For QTc check 
con-meds and 
electrolytes, 
correct as 
indicated  
 For confirmed 
pneumonitis 
interrupt and 
consult Medical 
Monitor 
Interrupt treatment 
until resolved to 
Grade 0-1. If 
interruption < 21 days 
restart at 250 mg/day. 
If interruption ≥ 21 
days, check with 
Medical Monitor. 
 In addition, for 
QTc check con-
meds, 
electrolytes and 
consult Medical 
Monitor (see 
Section 9.1.4.3.1 
for restarting and 
monitoring 
instructions). 
 For creatinine in 
absence of renal 
dysfunction no 
interruption. 
Discontinue. Consult 
Medical Monitor if 
continuation is in 
patient’s best interest. 
 In addition, for 
QTc hospitalize 
patient and 
perform 
cardiology 
evaluation (see 
Section 9.1.4.3.1)
. 
Second 
appearance 
Discontinue study 
drug 
Discontinue study 
drug 
9.1.3.1. 
Requirements for Continuation of Treatment Post Cycle 1 
Patients must fulfill the following criteria in order to commence a new cycle of treatment: 
 all related ≥ Grade 3 AEs have resolved to ≤ Grade 1 
 serum potassium and magnesium above the lower limit of normal 
 no arrhythmias, pathologic bradycardia, or associated symptomology 
 QTcF ≤ 470 msec and increase from baseline ≤ 60 msec unless Medical Monitor has 
given permission to continue 
 no concurrent medications that prolong QTc (see Appendix 4) 
 no evidence of progressive disease  
 no additional therapeutic interventions for glioblastoma 
 no strong inhibitors or inducers of CYP3A4, CYP2C8, CYP2D6 or CYP1A2 (see 
Appendix 4)  


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9.1.3.2. 
Study Drug Discontinuation 
Withdrawal of a patient from study treatment means that no further tesevatinib is administered 
but the remaining study visits or procedures are performed and follow-up data are collected.  
A patient’s study drug may be prematurely discontinued for any of the following reasons:  
 Progression of disease 
 An AE requires permanent discontinuation of study drug 
 Voluntary withdrawal by patient 
 Protocol deviation 
 Patient lost to follow-up 
 Patient death 
 Termination of study by sponsor 
Patients that have study drug discontinued due to toxicity are to be followed until there is either: 
 Resolution or stabilization to baseline or Grade 1 
 The patient is lost to follow-up 
 The event is otherwise explained 
9.1.4. 
Management of Adverse Events of Special Interest 
AEs of special interest include the following:  diarrhea, skin rash, QTc(F) prolongation, elevated 
serum creatinine, elevated serum amylase and ILD.  Unless otherwise specified, study drug may 
be held for up to 21 days at the discretion of the investigator.   
9.1.4.1. 
Diarrhea 
Diarrhea should be managed with loperamide. On first occurrence of Grade 1 diarrhea initiate 
loperamide and monitor patient’s electrolytes and hydration status. Patients with severe diarrhea 
who are unresponsive to loperamide or other anti-diarrheals or who become dehydrated require 
interruption of study drug until resolution to ≤ Grade 1 in severity. If Grade 4 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 interrupted, and appropriate measures should be taken to rehydrate the 
patient intensively via intravenous fluid administration. In addition, renal function and serum 
electrolytes, including potassium and magnesium, should be monitored in patients at risk of 
dehydration. 
9.1.4.2. 
Skin Rash  
Skin rash should be managed according to locally accepted clinical recommendations. Study 
drug may be held up to 21 days for Grade 3 rash.  
 


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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: 
 Patient 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 5 for steroid potency chart): 
 Ongoing use of treatments from ‘preventative treatments’ above 
 Grade 1 (<10 % BSA involved, without pruritus or tenderness) 
 Topical steroids (refer to Appendix 5 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 


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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 QD for 1 week or equivalent 
 
Suggestions for once a rash reappears: 
 Over the course of treatment rash may come and go 
 Hydrocortisone 1% cream with moisturizer and sunscreen twice daily, in 
combination with doxycycline 100 mg BID 
 May need to follow guidelines above if rash worsens 
If unacceptable rash recurs on reintroduction of tesevatinib at the same dose, then dose reduction 
of tesevatinib should be discussed with the Medical Monitor.  
9.1.4.3. 
QT Interval Prolongation 
Patients 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 range and may require additional monitoring or adjustment if patients develop 
diarrhea. Medications with potential for QTc(F) prolongation should not be used concurrently or 
started within 24 hours of tesevatinib administration (see Appendix 4). 
9.1.4.3.1. Management of QTc(F) Interval Prolongation 
The following guidelines should be used in the management of QTc(F) prolongation.  Patients 
will have ECGs performed at times designated by the protocol (refer to Table 1).     
Grade 2 QTc(F) Prolongation: 
If the QTc(F) interval increases to an absolute value of  ≥ 60 msec above baseline (predose on 
Day 1) but < 500 msec and the patient is asymptomatic (does not have palpitations, dizziness, 
syncope, orthostatic hypotension, or a significant ventricular arrhythmia on ECG), the following 
actions should be taken: 


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 Re-check and confirm concomitant medications for any medications that may be 
contributing to QTc(F) prolongation.  Consult the Medical Monitor for 
discontinuation of any medication found. 
 Check electrolytes, especially magnesium and potassium; correct abnormalities as 
clinically indicated. 
Grade 3 QTc(F) Prolongation: 
If the QTc(F) interval increases to an absolute value of ≥ 500 msec at any evaluation and if the 
patient 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 
 Contact Medical Monitor to discuss appropriate management 
 QTc(F):  When QTc(F) is within 30 msec of baseline 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. 
Grade 4 QTc(F) Prolongation: 
If the QTc(F) interval increases to an absolute value of ≥ 500 msec at any evaluation, and if the 
patient 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: 
 The patient should be hospitalized and undergo a thorough cardiology evaluation 
 Do not dose with study drug again   
 Consult with Medical Monitor  
 Check electrolytes especially magnesium and potassium; correct abnormalities as 
clinically indicated 


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 ECGs should be monitored until the QTc(F) returns to within 30 msec above the 
average baseline 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.  
However, if the patient has objective tumor response, consideration will be given to continuing 
treatment with tesevatinib at a reduced dose after discussion with the Medical Monitor. 
9.1.4.4. 
Elevated Serum Creatinine 
Patients 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.  Dose interruptions and reductions are not necessary in the 
absence of renal dysfunction. 
9.1.4.5. 
Elevated Serum Amylase 
In the event of asymptomatic increase of serum amylase to > 1.5 × ULN, lipase, fasting 
triglycerides, and amylase isoenzymes should be monitored.  Treatment should only be 
interrupted if clinical pancreatitis develops, corresponding to Grade 3 CTCAE per Table 5.  
9.1.4.6. 
Interstitial Lung Disease 
New or worsening respiratory symptoms suspicious of pneumonitis in patients in the study 
should be evaluated with high-resolution CT of the chest to determine whether ILD is present.  
Tesevatinib should be discontinued if interstitial lung disease is suspected, and further 
management discussed with the Medical Monitor. 
9.2. 
Study Drug Accountability and Patient Treatment Compliance 
Drug accountability and patient treatment compliance will be assessed using drug dispensing and 
return records, and the patient’s study diary. 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 patient dispensing records and returned study product 
documentation.  Dispensing records will document quantities received from Kadmon and 
quantities dispensed to patients, including lot number, date dispensed, patient identification 
number, patient 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.  
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 


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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. 
9.3. 
Concomitant Medication and Treatment 
If the patient 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. 
Patients should avoid ingesting grapefruit, pomelo or Seville orange fruits (and juice) with 
tesevatinib or at any time during the study.  Patients should not take medications that are 
associated with a risk of QTc interval prolongation and/or torsades de pointes. Additionally, 
patients are not permitted to take concomitant medications that strongly 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 (see Appendix 4). 
Other prohibited treatments include the following: 
 Other investigational drugs 
 Concurrent anti-tumor therapies such as chemotherapy, gene therapy, biologics, 
radiation therapy, or other immunotherapy 
 Warfarin or other anti-coagulant drugs (Low dose low molecular weight heparin 
given for deep vein thrombosis (DVT) prophylaxis is allowed) 
 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 
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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. 
9.3.1. 
Additional Therapy 
A patient should not receive additional therapeutic treatment for glioblastoma during the study 
period. 
9.3.2. 
Additional Anti-Cancer Treatment and Radiotherapy  
Patients should not receive additional therapeutic anti-cancer treatment until after PD has been 
documented on study and End of Treatment study assessments have been completed. If a patient 
requires additional anti-cancer treatment, study treatment will be discontinued and the patient 
will enter the Post-Treatment Period and followed every 8 weeks by phone call.  
9.3.3. 
Interaction of Tesevatinib with Other Medications 
Cytochrome P4503A4 is the major metabolic pathway of tesevatinib in humans. This suggests 
the potential for other drugs to significantly affect the biotransformation of tesevatinib in humans 
through drug-drug interactions. There is also a moderate potential to inhibit CYP2C8, CYP2D6 
and CYP1A2 although this is most likely to occur at higher concentrations than those expected in 
this study.  
Due to these interactions and potential interactions, inhibitors and inducers of CYP3A4, 
CYP2C8, CYP2D6, and CYP1A2 should be avoided if a substitute is available or otherwise used 
with caution in all patients while receiving study drug. In addition, patients must be closely 
monitored for the desired drug effect and potential AE. 
Substrates of isoenzymes CYP3A4, CYP2C8, CPY2D6 and CYP1A2 may be used with 
appropriate clinical monitoring. 
See Appendix 4 for a list of drugs that are clinically relevant inhibitors and inducers of CYP3A4, 
CYP2C8, CYP2D6, and CYP1A2.  
9.3.3.1. 
Management of Patients Requiring Concomitant Medications Associated with 
QT Interval Prolongation 
Tesevatinib has been associated with prolongation of the QT interval. Patients requiring 
treatment with drugs known to be associated with torsades de pointes or significant QT interval 
prolongation may not be enrolled into this study (see Appendix 4).  
Drugs associated with QT interval prolongation should be avoided in patients receiving study 
drug unless deemed clinically necessary. Should a patient develop a condition for which a 
medication known to affect QT interval is indicated, consideration should be given to the 


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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. 
As of Amendment 4 this will not be applicable—During long-term follow-up, patients 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 
held until the concomitant treatment course is complete.  The decision about whether the patient 
can continue on trial following this interruption will be determined by the Medical Monitor. 
During long-term follow-up, patients 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. 
 If the average QTc interval from these 3 ECGs is > 60 msec above the average 
baseline (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 interval is no more than 
60 msec above baseline 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 interval prolongation should be managed as noted in Section 9.1.4.3. 
 


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10. 
EFFICACY ASSESSMENTS 
Disease assessments will be based on the RANO criteria [Wen 2010] and will comprise 
radiological assessments (MRI), clinical assessments (KPS), and corticosteroid use.  Based on 
radiological assessments, clinical status, and corticosteroid use, an overall evaluation of CR, PR, 
SD, or PD should be made at each disease assessment after baseline according to the RANO 
criteria (Appendix 2).  
Disease assessment during the screening period is to be performed within 7 days before study 
drug administration and must be used as the baseline radiological assessment. Per the study’s 
schedule of assessments (see Table 1), disease assessment is intended to be done prior to starting 
cycle 2, 3, 5, 7+.  The corticosteroid dose should be kept stable for 5 days prior to the MRI scan. 
During the study, disease assessments should be performed at week 4 and week 8 after the date 
of first study treatment and then every 8 weeks (at Week 16, 24, etc.), regardless of treatment 
delays. For patients who discontinue treatment for other reasons than PD, disease assessment in 
the follow-up period should continue every 8 weeks (according to the original schedule) until 
disease progression. For patients with PD, disease assessment at the EOS is only required if not 
performed within the previous 8 weeks. 
Disease assessments as initially planned according to the schedule of assessments should be 
maintained regardless of treatment delays. Unscheduled disease assessments may be performed 
at the discretion of the investigator to allow a decision on further study treatment administration 
for individual patients. For patients who discontinue treatment for reasons other than progressive 
disease, disease assessment in the follow-up period should continue every 8 weeks (according to 
the original schedule) until disease progression. 
10.1. 
Radiological Assessment by Brain MRI 
The acquisition protocol for MRI (provided as a separate document) will provide further details 
for scan standardization. All efforts should be made to perform MRI scans according to the 
corresponding specification in order to ensure that quality of MRI will be standardized among all 
sites. Consistency of subsequent MRIs should be ensured during all assessments for each patient, 
with the same technique being used for evaluating lesions. Patients should be imaged on the 
same MRI scanner for the duration of the study. A 1.5T or 3T scanner must be used for this 
study. The use of IV contrast should, as long as clinically possible, be kept consistent.  
The following sequences of the entire brain must be acquired: 
 T1 pre-gadolinium 
 T2/FLAIR 
 T1 post-gadolinium 
Target Lesions: Lesions should be measured on the greatest size (bi-dimensional measurement of 
the longest cross-sectional diameters) observed either on axial, coronal, or sagittal slices, and the 
most representative observed chosen to be followed for response evaluation (i.e., once selected at 
baseline, the plane should be maintained across the study, to allow comparison). If there are 


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multiple contrast- enhancing lesions, a minimum of two of the largest lesions, and a maximum of 
five lesions, should be measured, and the sum of the products of the perpendicular diameters of 
these lesions should be determined. Occasionally, the largest lesions may not lend themselves to 
reproducible measurements, and the next largest lesions that can be measured reproducibly 
should be selected. For patients with recurrent disease who have multiple lesions of which only 
one or two are increasing in size, the enlarging lesions should be considered the target lesions for 
evaluation of response. 
Nontarget Lesions: All other lesions will be considered nontarget lesions and should also be 
recorded. Rarely, unequivocal progression of a nontarget lesion requiring discontinuation of 
therapy or development of a new contrast-enhancing lesion may occur, even in the setting of 
stable disease or partial response in the target lesions. These changes would qualify as 
progression.  
Tumor measurements should be made by the same investigator/radiologist for each patient 
during the study to the extent that this is feasible. 
A radiological assessment of complete response (CR) or partial response (PR) requires 
confirmatory imaging at least 4 weeks after the initial assessment of response was observed. In 
the event that the radiographic changes are equivocal and it is unclear whether the patient 
has stable or progressive disease, treatment should be continued and the patient should be 
closely observed. If subsequent imaging studies demonstrate that progression has occurred, the 
date of progression should be the date of the scan at which disease progression was first 
suspected. 
Sites should save all MRI images as DICOM files or other standard format with unique 
descriptive file names (e.g. study number, patient initials and number, date and image sequence 
number) on to anonymized DVD(s) and provide these to the Sponsor upon request. 
10.2. 
Clinical Status by Karnofsky Performance 
Clinical deterioration is defined as a decline in the Karnofsky performance status (Appendix 1) 
from 100% or 90% to ≤ 70%; a decline of ≥ 20% from 80% or less; or a decline from any 
baseline value to 50% or less, for at least 7 days, unless attributable to comorbid events (e.g., 
seizures, medication adverse effects, complications of therapy, cerebrovascular events, infection, 
etc.). Clinical status must be recorded as Improved, Stable, or Worsened. 
10.3. 
Corticosteroid Dose 
At the time of each disease assessment, the corticosteroid intake will be compared with 
corticosteroid intake at the time of the last disease assessment. The changes will be recorded as 
Increased, Unchanged, or Decreased. Increases or decreases in corticosteroid dose should be 
clinically justified. 
Note: Increases in corticosteroid dose for reasons other than disease control do not need to be 
taken into consideration when making this comparison. 


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10.4. 
Overall Disease Assessment 
Based on radiological assessments, clinical status, and corticosteroid use, an overall evaluation of 
CR, PR, SD, or PD should be made at each disease assessment after baseline according to the 
RANO criteria (Appendix 2). 


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11. 
SAFETY 
11.1. 
Safety Parameters 
The NCI-CTCAE; Version 4.03 will be used for grading toxicities unless otherwise specified.  
Patients 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 Karnofsky performance status.  
11.2. 
Adverse Event Definition 
An adverse event (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 patient is hospitalized for observation. 
 


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11.3. 
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. 
11.3.1. 
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 adverse event 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 patient 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 patient 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 
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 


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 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 patient 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) 
11.3.2. 
Suspected Unexpected Serious Adverse Reactions (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.  
11.3.3. 
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. 
11.3.4. 
Non-Serious Adverse Events 
All other AEs, not fulfilling the previous definitions, are classified as non-serious. 
11.3.5. 
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 patient is participating in the study.  For example, a protocol-related AE 


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may be an event that occurs during a washout period or that is related to a procedure required by 
the protocol. 
11.3.6. 
Relationships/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). 
11.3.7. 
Recording Adverse Events 
All AEs (including SAEs) are to be accurately recorded on the Adverse Event page of the 
patient’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). 
11.3.8. 
Adverse Event Monitoring and Follow-up 
The investigator will follow all patients who experience adverse events until there is a return to 
the patient’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.  
11.3.9. 
Laboratory and ECG Abnormalities 
For the purposes of grading creatinine, the upper limit of normal – not the patient’s baseline 
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. 
Non-Clinically Significant (NCS) Laboratory Abnormalities 
All laboratory results must be filed in the patient’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 


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 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 patient 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 patient experiences a serious toxicity or dies, the FDA 
will be notified within 24 hours, as required.   
11.3.10. 
Pregnancy 
If any patient becomes pregnant following the first dose of tesevatinib, the patient 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. 
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. 
11.3.11. 
Serious Adverse Event Reporting 
11.3.11.1. Governing Regulatory Requirements 
Compliance with this request for prompt reporting is essential in that the sponsor is responsible 
for informing the US Food and Drug Administration (FDA) as well as all other participating 
investigators of the event.  
Under FDA ruling (US Code of Federal Regulations, Title 21 CFR Part 312.32) and the 
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  


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 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. 
11.3.11.2. Time-Frame for Reporting 
Any death, pregnancy, or SAE experienced by a patient from the time of informed consent until 
30 days after receiving the last dose of study drug, regardless of relationship to study drug, or 
any death that occurs more than 30 days after receiving study drug, and is believed to be study 
drug-related, must be promptly reported (within 24 hours of the investigator becoming aware of 
the event) by fax to the sponsor (or designee). Fax: 646-430-9549. 
In the event of an issue with the fax line, forward the SAE form via email to 
ClinicalSAEReporting@kadmon.com. 
The investigator will be able to contact the safety Medical Monitor at all times: 
Sanjay Aggarwal, MD 
Vice President Clinical Development 
Kadmon Corporation 
55 Cambridge Parkway 
Cambridge, MA 02142 
Phone:  
857-253-8642 
 
E-mail:   sanjay.aggarwal@kadmon.com 
11.3.11.3. 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, patient 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. 


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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 National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 
 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. 
11.3.12. 
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. 


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11.3.13. 
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. 
11.4. 
Other Safety Considerations 
11.4.1. 
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 patient is hospitalized for observation, will not 
constitute an AE but will be recorded as a protocol deviation.  
11.4.2. 
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.  
11.5. 
Safety Monitoring 
Patients will be closely monitored for adverse events of interest and potential drug-drug 
interactions through standard safety reporting as well as a regular medical review of safety data 
outputs from both the clinical and pharmacovigilance databases. Particular attention will be paid 
to the success of diarrhea and rash management strategies and the use of concomitant 
medications which have a risk of drug-drug interaction or QTc prolongation. SAEs, including 
deaths, and withdrawals due to adverse events will also be closely monitored. A central 
laboratory will be used to monitor for QTc prolongation, and any study drug reintroduction in the 
case of QTc prolongation will only be performed with the agreement of the Medical Monitor. 
A Data Monitoring Committee will not be used for this study. 


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12. 
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 patient takes the first dose of study drug, with subsequent 
study days numbered sequentially thereafter.  
If significant changes from baseline 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). 
12.1. 
Procedures to be Performed 
12.1.1. 
Informed Consent 
All patients must take part in the informed consent process. Adequate time must be allowed for 
the patient 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 patient has signed and dated an IRB/IEC-approved ICF. 
12.1.2. 
Demographics and Medical History 
A complete medical history will be taken.  Medical history includes clinically significant 
diseases, surgeries, history of glioblastoma (including date of diagnosis, history of prior low-
grade astrocytoma, location of disease, prior cancer therapies and procedures), and all 
medications (e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, 
nutritional supplements) used by the patient within 28 days prior to randomization. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
12.1.3. 
Complete and Abbreviated 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 pulse, lungs, abdomen 
(liver/spleen), kidneys, and neurological (symptom directed only). Interval history should be 
recorded at all study visits. 
12.1.4. 
Detailed Neurological Examination 
Neurological exam should include full cranial nerve central and peripheral, motor and sensory 
assessments. 


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12.1.5. 
Vital Sign Measurements 
Vital sign measurements will be collected after the patient 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).   
Please note that blood pressure measurements are to be performed using the appropriate 
technique (per guidelines of the American Heart Association). Specifically, patients 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 patient’s position (if not seated). 
12.1.6. 
Hematology andSerum Chemistries. 
Samples for laboratory assessments (hematology andserum chemistries) are to be collected.  A 
Local laboratory will perform hematology andserum chemistry tests and results will be provided 
to the investigator.  Blood and urine samples for hematology, serum chemistry will be prepared 
using standard procedures. Laboratory panels are defined as listed in  
 


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Table 2b: Schedule of Study Assessments for Subjects Completing 24 Cycles of Tesevatinib 
Treatment 
Timepoint  
(Study Day) 
Cycle 26 Cycle 28
Cycle 30
Cycle 32
Cycle 34 Cycle 36+ 
EOS Tx i 
30-Day 
FU j 
(± 5d) 
UNS k
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1 
(± 3d) 
Day 1 (± 
3d) 
Day 1  
(± 3d) 
Physical Examination a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological Examination b 
X 
X 
X 
X 
X 
X 
 
 
X 
Vital Signs c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Labs d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG e 
X 
X 
X 
X 
X 
X 
X 
 
X 
Disease Assessment f 
X 
X 
X 
X 
X 
X 
X 
 
X 
Karnofsky performance 
status 
X 
X 
X 
X 
X 
X 
X 
 
X 
Corticosteroid use 
X 
X 
X 
X 
X 
X 
X 
 
X 
MRI tumor assessment 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tesevatinib Dispensing g 
X 
X 
X 
X 
X 
X 
 
 
X 
AE Monitoringh 
X 
X 
X
X
X
X
X 
X
d = day; ECG = electrocardiogram; EOS = end of study; FU = follow-up; KPS = Karnofsky Performance Status; LTFU = long-
term follow-up; MRI = magnetic resonance imaging; PK = pharmacokinetic; UNS = unscheduled; Tx = treatment 
w: Abbreviated PE is acceptable (to be completed in a targeted manner covering related body systems). 
x: 
Neurological exam should include full cranial nerve central and peripheral, motor and sensory assessments. 
y: 
Vital sign measurements (blood pressure, heart rate, respiratory rate, and temperature) to be obtained with patient in 
sitting position. 
z: 
To be drawn and analyzed locally.  Safety labs = hematology and clinical chemistry.  See Table 2b.   
aa: Supine 12-Lead ECGs will be performed at each visit.   
bb: The assessment should be performed every 8 weeks. Radiological assessment must be performed with a brain MRI 
scan and should be consistent throughout all visits.   
cc: Study drug should be dispensed and accounted for from previous visit. 
dd: AEs are to be collected from the time of informed consent through 30 days after last dose of study drug.   
ee: The End-of-Study Drug Treatment visit is to occur as soon as possible after the patient’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.   
ff: The 30-Day Follow-Up visit should occur 30 days (±5 days) after the patients’ 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.  Assessments for the 30-day follow up may be done by telephone. 
gg: For unscheduled visits, study assessments are at the investigator’s discretion. 
 
 


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Table 3.  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 2 with the 
exception of Cystatin C. 
Subjects who have completed 24 cycles of treatment without disease progression or unacceptable 
toxicity will have safety laboratory assessments collected at each bi-monthly visit.  The local 
laboratory will perform hematology and serum chemistry tests.  Laboratory panels are defined as 
listed in Table 2b.    
Abnormalities in clinical laboratory tests that lead to a change in patient 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 11.3). 
12.1.7. 
Pregnancy Test 
Urine pregnancy tests are to be performed for females of childbearing potential. Positive urine 
tests are to be confirmed by a serum test.  
12.1.8. 
Tumor Samples 
The availability of paraffin-embedded tumor sample diagnostic of glioblastoma is mandatory for 
entry into the study. Samples from the original tumor and any subsequent biopsies will be 
required. Tissue from recurrent surgery is preferred, but tissue from initial surgery is sufficient 
for study entry. 
Twenty (20) slides cut as recently as possible and sections must contain adequate tumor. See the 
study laboratory manual for definition of adequate tumor sample.   
If the archival tissue is neither sufficient nor available, the patient may still be eligible, upon 
discussion with the Medical Monitor, with the assumption that the patient: 
 Can provide sufficient tissue; OR 
 Is willing to consent to and undergo a pre-treatment biopsy of the tumor 
A detailed description of tissue quality requirements and procedures for collection, handling, 
preparation and shipping of the samples to the central laboratory will be provided in a separate 
laboratory manual. 
For enrolled patients, part of the available tumor tissue from the tissue submitted will be used to 
assess EGFRvIII mutation and for EGFR gene amplification biomarkers. Other tissue 
assessments may include testing of protein expression, activation status, somatic mutations, and 
other exploratory markers related to tesevatimib and to glioblastoma biology. These assessments 
will be performed by the Sponsor, at a Sponsor-selected vendor. The remaining tumor tissue 
block will be returned to the site. 


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12.1.9. 
12-Lead Electrocardiogram (ECG) 
Supine 12-Lead ECGs will be performed at screening; predose, and once within 4 – 8 hours 
postdose on Days 1 and 15 of Cycle 1; pre-dose on Day 1 of Cycles 2 and beyond; and at the 
End of Study Drug Treatment visit.  ECGs will be read by a central laboratory. 
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 central ECG laboratory 
vendor. 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. Although ECGs will be read by a central laboratory, sites 
should take action if clinically significant abnormalities are detected at time of ECG. 
Subjects who have completed 24 cycles of treatment without disease progression or unacceptable 
toxicity will have ECG assessments performed at each bi-monthly visit.  These ECG assessments 
will be performed locally and read by qualified site personnel.   
Prior to enrollment, all patients must demonstrate an average screening QTc(F) value of 
≤ 470 msec by central digital analysis. Immediate clinical management of patients will initially 
be based on results of machine-read ECGs at the sites. However, the central digital analysis will 
prevail as it becomes available. In addition, the central digital analysis will be used for any AE 
and SAE documentation. 
An increase in QTc(F) interval (by central digital analysis) to a value > 60 msec above baseline 
or to the level of ≥ 500 msec requires further monitoring. After discussion with the Medical 
Monitor (if ≥ 500 msec) on appropriate management, the patient may be removed from the trial 
(see guidelines in Section 9.1.4.3.1). 
Abnormalities in the ECG that lead to a change in patient 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 abnormalities meet criteria defining them as serious, they must be reported as SAE (see 
Section 11.3). 
12.1.10. 
Disease and Response Assessments 
Disease assessments will be based on the RANO criteria [Wen 2010] and will comprise 
radiological assessments (MRI), clinical assessments (KPS), and corticosteroid use.  Based on 
radiological assessments, clinical status, and corticosteroid use, an overall evaluation of CR, PR, 
SD, or PD should be made at each disease assessment (see Section 10) after baseline according 
to the RANO criteria (Appendix 2).  


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Disease assessment during the screening period is to be performed within 7 days before study 
drug administration and must be used as the baseline radiological assessment. Per the study’s 
schedule of assessments (see Table 1), disease assessment is intended to be done prior to starting 
cycle 2, 3, 5, 7+.  The corticosteroid dose should be kept stable for 5 days prior to the MRI scan. 
During the study, disease assessments should be performed at week 4 and week 8 after the date 
of first study treatment and then every 8 weeks thereafter (at Week 16, 24, etc.), regardless of 
treatment delays. For patients who discontinue treatment for other reasons than PD, disease 
assessment in the follow-up period should continue every 8 weeks (according to the original 
schedule) until disease progression. For patients with PD, disease assessment at the EOS is only 
required if not performed within the previous 8 weeks. 
Disease assessments as initially planned according to the schedule of assessments should be 
maintained regardless of treatment delays. Unscheduled disease assessments may be performed 
at the discretion of the investigator to allow a decision on further study treatment administration 
for individual patients. For patients who discontinue treatment for reasons other than progressive 
disease, disease assessment in the follow-up period should continue every 8 weeks (according to 
the original schedule) until disease progression. 
12.1.11. 
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 patient-specific rationale to take it 
regularly at a different time of day) and can be administered without regard to food intake. 
12.1.12. 
Patient Reported Outcomes (MDASI-BT) 
PROs of disease- and treatment-related symptom severity and symptom interference will be 
assessed using the MDASI-BT questionnaire. 
The MDASI is a validated and reliable self-report measure that was developed to assess 
symptom severity and interference [Cleeland 2000; Armstrong 2006]. 
Thirteen items ask patients to rate how severe the symptoms were when “at their worst” in the 
last 24 hours with regard to pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, 
remembering things, lack of appetite, drowsy, dry mouth, sad, vomiting, and numbness or 
tingling. An additional six items ask patients to rate how much the symptoms have interfered 
with six areas of function (general activity, walking, work, mood, relations with other people, 
and enjoyment of life) in the last 24 hours. The MDASI-BT (see Appendix 3) contains an 
additional nine items that assess symptoms and concerns specific to primary brain tumor patients 
(difficulty understanding, difficulty speaking, difficulty concentrating, seizures, weakness, 
change in appearance, change in vision, change in bowel patterns, irritability), for a total of 28 
items. 
All patients will complete the self-administered questionnaire pre-dose on Day 1 of Cycles 1 and 
2; every 8 weeks after enrollment (i.e., coinciding with the schedule of disease assessments); and 


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at the End of Study Drug Treatment visit (EOS). Additionally, patients who discontinue study 
treatment for reasons other than disease progression will complete the questionnaire every 8 
weeks during follow-up until the time of documented disease progression. The questionnaire will 
take patients ~5–10 minutes to complete. Patients must complete the questionnaire prior to any 
other tests or assessments and prior to any discussion of the patient’s progress with their 
physician or any other healthcare personnel at the site. 
Subjects who have completed 24 cycles of treatment without disease progression or unacceptable 
toxicity will not be required to complete the MDASI-BT questionnaire at subsequent bi-monthly 
visits. 
12.1.13. 
Tesevatinib Plasma Concentrations 
Blood samples will be drawn to evaluate tesevatinib plasma concentrations. Plasma samples for 
tesevatinib concentration analysis will be drawn predose of tesevatinib on Days 15 of Cycle 1; 
and predose of tesevatinib on Day 1 of every subsequent cycle (up to cycle 6). Data from these 
samples will contribute to a population PK analysis, and will be used to explore exposure-
response relationships.    
12.1.14. 
Pharmacodynamics 
The tumor tissues submitted should be a formalin-fixed, paraffin-embedded tumor specimen that 
enables the definitive diagnosis of glioblastoma and determination of EGFR status, to permit 
stratification for the purposes of the efficacy analyses.           
A tissue block (preferred) or 20 serial, freshly cut, unstained slides accompanied by an associated 
pathology report is required for participation in this study. Tissue quality and adequate viable 
tumor cell content are specified in the accompanying lab manual. 
Cytological samples are not acceptable. 
For enrolled patients, part of the available tumor tissue from the tissue submitted will be used to 
assess exploratory biomarkers. Tissue assessments may include testing of protein expression, 
activation status, somatic mutations, and/or gene amplification of EGFR, and other exploratory 
markers related to tesevatinib and to glioblastoma biology. These assessments will be performed 
by the Sponsor, at a central laboratory, or by a Sponsor-selected vendor. The remaining tumor 
tissue block will be returned to the site. 
12.1.15. 
Prior and Concomitant Medications 
All concomitant medications will be recorded from the time the patient signs the informed 
consent form through 30 days after the last dose of study drug. 
12.1.16. 
Adverse Event Assessments 
Information regarding the occurrence of AEs and SAEs will be collected from the time the 
patient signs the informed consent form throughout their participation in the study, including a 
period of 30 days after the patient’s last dose of study drug, unless a new treatment has been 


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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. 
Note:   AEs resulting in a patient’s permanent discontinuation from the study, regardless of 
seriousness or relationship to study drug, MUST be promptly reported to the sponsor. 
12.1.17. 
Study Diary 
Patients 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. 
12.2. 
Schedule of Visits 
12.2.1. 
Screening Visit 
At the screening visit (Day -22 to -1), information will be collected and patients will have 
clinical evaluations as follows: 
 Informed consent 
 Medical history  
 Demographics  
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, 
temperature) 
 Neurological examination 
 Tumor sample; original tumor and any subsequent biopsies required 
 Inclusion/exclusion criteria 
 Complete physical examination, including height and weight 
 Hematology, cystatin-C, serum chemistry, coagulation, and urinalysis 
 Urine pregnancy test, if applicable. Subject must have a negative urine pregnancy test 
documented within the 24-hour period prior to the first dose of study drug. Positive 
results are to be confirmed with serum testing.  
 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) 
 Disease assessment (MRI, clinical status, and corticosteroid use) - within 7 days 
before study drug administration 
 Baseline AE assessment 
 Baseline concomitant medications 


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12.2.2. 
Cycle 1; Day 1 
Results of clinical and laboratory evaluations, including ECGs, must be reviewed prior to dosing 
to confirm that the patient continues to meet eligibility criteria.  At the Day 1 Visit, the following 
procedures and evaluations will be performed: 
 Vital sign measurements (predose and 1 and 4 hours postdose) (sitting blood pressure, 
heart rate, respiratory rate, temperature) 
 Complete physical examination, including weight   
 Clinical laboratory tests (hematology, cystatin-C, serum chemistry panel and 
urinalysis) (Need not be repeated if screening visit occurred within 4 days prior to 
Day 1 visit.) 
 Urine pregnancy test, if applicable. Positive results are to be confirmed with serum 
testing.  
 Supine 12-Lead ECG (to be performed predose, and 4 - 8 hours postdose 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  
 Completion of PRO – MDASI-BT 
 Concomitant medications 
 AE assessment 
 Issue study drug diary 
 Dispense study drug 
12.2.3. 
Cycle 1; Day 15 
At the Cycle 1, Day 15 visit (± 3 days), the following evaluations will be performed: 
 Vital sign measurements (predose and 1 and 4 hours postdose) (sitting blood pressure, 
heart rate, respiratory rate, temperature) 
 Limited physical examination   
 Clinical laboratory tests (hematology, cystatin-C, serum chemistry panel and 
urinalysis)  
 Supine 12-Lead ECG (to be performed predose, and 4 - 8 hours postdose 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  
 Plasma sample predose for tesevatinib concentration 


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 Concomitant medications 
 AE assessment 
12.2.4. 
Cycle 2; Day 1 
At the Cycle 2, Day 1 visit (± 3 days), the following procedures and evaluations will be 
performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, 
temperature) 
 Complete physical examination   
 Clinical laboratory tests (hematology, cystatin-C, serum chemistry panel and 
urinalysis)  
 Urine pregnancy test, if applicable. Positive results are to be confirmed with serum 
testing.  
 Supine 12-Lead ECG (to be performed predose, and 4 - 8 hours postdose 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]) 
 Completion of PRO – MDASI-BT 
 Disease assessment (MRI, clinical status, corticosteroid use and overall disease 
assessment)  
 Tesevatinib administration  
 Plasma sample predose for tesevatinib concentration 
 Concomitant medications 
 AE assessment 
 Issue study drug diary 
 Dispense study drug 
12.2.5. 
Cycle 3; Day 1 
At the Cycle 3, Day 1 visit (± 3 days), the following procedures and evaluations will be 
performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, 
temperature) 
 Complete physical examination   
 Clinical laboratory tests (hematology, cystatin-C, serum chemistry panel and 
urinalysis)  


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 Urine pregnancy test, if applicable. Positive results are to be confirmed with serum 
testing.  
 Supine 12-Lead ECG (to be performed predose, and 4 - 8 hours postdose 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]) 
 Neurological examination 
 Plasma sample predose for tesevatinib concentration 
 Disease assessment (MRI, clinical status, corticosteroid use and overall disease 
assessment) 
 Tesevatinib administration  
 PRO – MDASI-BT 
 Concomitant medications 
 AE assessment 
 Collect/Issue study drug diary 
 Dispense study drug 
12.2.6. 
Cycle 4; Day 1 
At the Cycle 4, Day 1 visit (± 3 days), the following procedures and evaluations will be 
performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, 
temperature) 
 Complete physical examination   
 Clinical laboratory tests (hematology, cystatin-C, serum chemistry panel and 
urinalysis)  
 Urine pregnancy test, if applicable. Positive results are to be confirmed with serum 
testing.  
 Supine 12-Lead ECG (to be performed predose, and 4 - 8 hours postdose 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]) 
 Plasma sample predose for tesevatinib concentration 
 Tesevatinib administration  
 Concomitant medications 
 AE assessment 


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 Collect/Issue study drug diary 
 Dispense study drug 
12.2.7. 
Cycle 5; Day 1 
At the Cycle 5, Day 1 visit (± 3 days), the following procedures and evaluations will be 
performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, 
temperature) 
 Complete physical examination   
 Clinical laboratory tests (hematology, cystatin-C, serum chemistry panel and 
urinalysis)  
 Urine pregnancy test, if applicable. Positive results are to be confirmed with serum 
testing.  
 Supine 12-Lead ECG (to be performed predose, and 4 - 8 hours postdose 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]) 
 Neurological examination 
 Plasma sample predose for tesevatinib concentration 
 Disease assessment (MRI, clinical status, corticosteroid use and overall disease 
assessment) 
 Tesevatinib administration  
 PRO – MDASI-BT 
 Concomitant medications 
 AE assessment 
 Collect/Issue study drug diary 
 Dispense study drug 
12.2.8. 
Cycle 6; Day 1 
At the Cycle 6, Day 1 visit (± 3 days), the following procedures and evaluations will be 
performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, 
temperature) 
 Complete physical examination   


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 Clinical laboratory tests (hematology, cystatin-C, serum chemistry panel and 
urinalysis)  
 Urine pregnancy test, if applicable. Positive results are to be confirmed with serum 
testing.  
 Supine 12-Lead ECG (to be performed predose, and 4 - 8 hours postdose 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]) 
 Plasma sample predose for tesevatinib concentration 
 Tesevatinib administration  
 Concomitant medications 
 AE assessment 
 Collect/Issue study drug diary 
 Dispense study drug 
12.2.9. 
Cycle 7-24; Day 1 
At the Cycle 7+, Day 1 visit (± 3 days), the following procedures and evaluations will be 
performed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, 
temperature) 
 Complete physical examination   
 Clinical laboratory tests (hematology, cystatin-C, serum chemistry panel and 
urinalysis)  
 Urine pregnancy test, if applicable. Positive results are to be confirmed with serum 
testing.  
 Supine 12-Lead ECG (to be performed predose, and 4 - 8 hours postdose 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]) 
 Neurological examination 
 Disease assessment (MRI, clinical status, corticosteroid use and overall disease 
assessment) 
 Tesevatinib administration  
 PRO – MDASI-BT 
 Concomitant medications 
 AE assessment 


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 Collect/Issue study drug diary 
 Dispense study drug 
12.2.10. 
Cycle 26+; Day 1 
At the Cycle 26+, Day 1 visit (± 3 days), the following procedures and 
evaluations will be performed: 
 Limited physical examination   
 Neurological examination 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory 
rate, temperature) 
 Clinical laboratory tests (hematology and serum chemistry panel  
 12-Lead ECG  
 Disease assessment (MRI, clinical status, corticosteroid use and overall 
disease assessment) 
 Karnofsky performance status 
 Concomitant medications 
 Tesevatinib dispensing  
 AE assessment 
 
12.2.11. 
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 evaluation will be 
performed: 
 Serum Chemistry (Cystatin C does not need to be tested) 
12.2.12. 
End-of-Study Drug Treatment Visit (EOS) 
As soon as possible after the last dose of study drug, patients are to return to the study site to 
complete all end-of-study drug treatment assessments as described below. This may occur at the 
visit at which disease progression is diagnosed.  
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, 
temperature) 


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 Complete physical examination   
 Clinical laboratory tests (hematology, cystatin-C, serum chemistry panel and 
urinalysis)  
 Urine pregnancy test, if applicable. Positive results are to be confirmed with serum 
testing.  
 Supine 12-Lead ECG (to be performed predose, and 4 - 8 hours postdose 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]) 
 Disease assessment (MRI, clinical status, corticosteroid use and overall disease 
assessment) if not done within the previous 8 weeks. If PD was not observed prior to 
the EOS visit, disease assessments should be performed until PD. 
 PRO – MDASI-BT 
 Concomitant medications 
 AE assessment 
 Collect study drug diary 
 Collect study drug 
12.2.13. 
30-Day Follow-up 
The 30-Day Follow-Up should occur 30 days (± 5 days) after the patients’ 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. 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, 
temperature) 
 Complete physical examination   
 Clinical laboratory tests (hematology, cystatin-C, serum chemistry panel and 
urinalysis)  
 Urine pregnancy test, if applicable. Positive results are to be confirmed with serum 
testing.  
 Concomitant medications 
 If PD was not observed prior to the 30-day follow-up visit, disease assessments 
should be performed until PD. 
 AE assessment 


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12.2.14. 
Follow-up Phone Contact 
Beginning 8 weeks after the 30-Day Follow-Up Visit, patients are to be contacted by telephone 
every 8 weeks to assess survival status and any subsequent anti-cancer treatment. If PD was not 
observed before the 30-day follow-up period patients will need to return for follow-up MRI until 
PD is demonstrated or they start a new anti-cancer treatment. In the case of a patient receiving a 
new anti-cancer treatment in the absence of PD, the date of the most recent MRI will be used as 
the date of PD. 
 
12.2.15. 
Unscheduled Visits: To Occur as Needed 
If additional visits are needed (e.g., for resolution of an adverse event), the following procedures 
and evaluations may be performed as needed: 
 Vital sign measurements (sitting blood pressure, heart rate, respiratory rate, 
temperature) 
 Complete physical examination, including weight 
 Hematology, cystatin-C, serum chemistry and urinalysis 
 Urine pregnancy test, if applicable. Positive results are to be confirmed with serum 
testing.  
 Supine 12-Lead ECG (repeat three times consecutively within 30 minutes [must have 
an interval of at least 1-2 minutes between ECGs]. 
 Disease assessment (MRI, clinical status, corticosteroid use and overall disease 
assessment) 
 Tesevatinib administration (if appropriate) 
 AE assessment 
 Concomitant medications 
 Perform drug accountability, review patient diary, and collect old and dispense new 
study drug (if appropriate) 
 
 


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13. 
STATISTICAL CONSIDERATIONS 
All descriptive and inferential statistical analyses will be performed using the most recently 
released and available SAS statistical software or the most recently released and available 
version of R, unless otherwise noted.  
Additional statistical details will be provided in a prospective statistical analysis plan (SAP). 
13.1. 
General Design 
This is an open-label phase 2, multicenter study of tesevatinib monotherapy in patients with 
recurrent glioblastoma.  
13.2. 
Sample Size Justification 
This phase 2 trial is designed primarily to allow a preliminary assessment of the efficacy and 
safety of tesevatinib in the overall population of 40 patients with recurrent glioblastoma as well 
as to permit exploratory comparisons between predefined subgroups (by EGFRvIII mutation 
status and by EGFR gene amplification status). The target PFS-6 rate in the overall study 
population is 25%. PFS-6 rates seen in randomized studies with bevacizumab [Weathers 2015; 
Taal 2014; Galanis 2015] are of the order of 15-18%. Bevacizumab is registered in this 
indication.  
With a sample size of 40 patients in the overall population, PFS-6 = 25% and median PFS-6 = 
4.5 months, the trial has 95% power of having an estimated PFS-6 >15%. Addressing uncertainty 
by the lower 90% confidence limit of the estimated PFS-6 – corresponding to a one-sided test on 
5% significance level, the trial has 95% power to show a significant difference above 7% and 
80% power to show a significant difference above 10%. 
The power calculation is based on simulations in the Weibull distribution to describe the 
progression and survival times. The median PFS and the PFS-6 and the corresponding shape and 
scale parameters from the Weibull distribution are shown in Table 6 below. 
Table 6: 
Median PFS and PFS-6 Distributions 
 
Median PFS 
(months) 
6 month PFS
Weibull 
shape 
parameter 
Weibull 
scale 
parameter 
Overall population 
4.5 
25% 
5.24 
2.41 
For the trial outcome, two subpopulations (A and B) are defined in Table 7. 
 


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Table 7: 
Assumptions for Distribution of EGFR Subpopulations 
 
Subpopulation 
Description 
Assumed 
proportion of 
subjects 
A 
Patients with an assumed beneficial mutation (EGFR gene 
amplified glioblastoma) 
57% 
B 
Patients with an assumed beneficial mutation (EGFRvIIIpos 
glioblastoma) 
27% 
 
The trial is not stratified to include a specific proportion of patients with the EGFR gene 
mutations and is not powered to show significant differences for the secondary endpoints that 
estimate differences in PFS-6 for the two subgroups compared to patients without the EGFR 
gene mutations.  
13.3. 
Interim Analysis 
An interim analysis is included with the possibility to stop for futility. The stopping rule is based 
on an unacceptable PFS-6 rate of 5% and a desirable PFS-6 rate of 20% or more. The trial will 
continue after the interim analysis if more than 1 responder is seen in 21 patients giving a 72% 
probability of stopping if the PFS-6 rate is ≤5%. 
13.4. 
Statistical Considerations 
For categorical variables, the number and percent of each category within a parameter will be 
calculated for observed data only. 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.  
13.4.1. 
Study Populations  
Adult patients with recurrent glioblastoma with availability of paraffin-embedded tumor samples 
diagnostic of glioblastoma will be enrolled. 
Two subgroups of patients are defined as having: EGFRvIIIpos and EGFR amplificationpos 
tumors. 
Primary and secondary efficacy analyses will include all patients who were included in the study. 
The same analysis methods for the primary and secondary analyses will be applied to both the 
ITT population and the EGFRvIIIpos and EGFR gene amplificationpos population. 
Safety analyses will include all patients who enrolled and received at least one dose of study 
treatment (the safety population). 


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All patients who take at least one dose of study drug will be evaluable for safety and efficacy 
assessments. 
Patients 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.   
For statistical purposes completion of the study will be defined as six months after the last 
patient starts study treatment.  
The plasma concentration analysis population will consist of all patients who receive at least one 
dose of tesevatinib, and who have at least one sample analyzed for plasma concentrations. 
13.4.2. 
Patient Accountability, Demographics, and Baseline Characteristics  
Patient disposition, demographic information and baseline characteristics will be tabulated for 
the overall population as well as by subgroups. Minimal data for screen failures, pertaining to 
why they failed to qualify to enroll will also be collected and listed. 
13.4.3. 
Tesevatinib Exposure  
The amount of tesevatinib administered by visit and overall (total dose) will be tabulated and 
presented by patient in data listings.  The distribution of the number of cycles achieved per 
patient will also be summarized. In addition, delays and all other alterations in tesevatinib 
administration will be presented.  
13.4.4. 
Concomitant Medications  
Concomitant medications will be coded using the current WHO Drug Dictionary and the data 
will be summarized and presented in tables and listings.  
13.4.5. 
Plasma Concentrations 
Plasma samples for tesevatinib concentration analysis will be drawn predose of tesevatinib on 
Day 15 of Cycle 1; and predose of tesevatinib on Day 1 of every subsequent cycle (up to cycle 
6). Due to the sparse number of time points data are summarized using descriptive statistics by 
time points, systemic steroid treatment and subgroup. 
These data, pooled with data from other studies, may be analyzed in a population PK analysis 
using nonlinear mixed effects modeling. 
13.4.6. 
Efficacy/Activity 
13.4.6.1. Primary efficacy endpoint 
Progression-Free Survival at 6 months (PFS-6).  
PFS is defined as the time between date of first dose and the date of first documented disease 
progression or death, whichever occurs first. The PFS-6 is defined as a patient being alive and 
progression free at 6 months (24 weeks). Disease progression will be determined based on 
investigator assessment with use of radiological assessments, clinical status, and corticosteroid 


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use. The specific criteria for disease progression is defined in Appendix 2. Patients without a 
date of disease progression or death will be analyzed as censored observations on the date of the 
last disease assessment; if no post-baseline disease assessment is available, PFS will be censored 
at the date of 1st dose. 
The analysis of the primary endpoint and the estimation of PFS-6 is performed with a Cox 
model. Karnofsky performance status is included as a covariate. Study center is included as a 
random effect assumed to follow a gamma distribution. Thus, this is a shared Cox gamma frailty 
model. The model is used to estimate PFS-6 with 2-sided 95% and 90% confidence intervals. 
Furthermore, Kaplan-Meier methodology will be used to estimate median PFS with 95% CI and 
the Kaplan-Meier curve will be constructed to provide a visual description of the PFS over time.  
Descriptive statistics overall and for each parameter (radiological assessment, clinical status and 
corticosteroid dose) in the disease progression assessment are presented for the entire assessment 
period as well as for 3, 6 and 9-month time points. 
13.4.6.2. Secondary efficacy endpoints 
The following subgroup PFS-6 endpoints: 
 Investigator-assessed PFS-6 in the subgroup of patients with EGFRvIIIpos 
glioblastoma 
 Investigator-assessed PFS-6 in the subgroup of patients with EGFR gene amplified 
glioblastoma 
are evaluated using the same methodology as for the primary endpoint. The analysis is 
performed by including a subgroup factor as fixed effect in the model used to analyze the 
primary endpoint. PFS-6 with 95% confidence intervals are estimated for each subgroup as well 
as for the residual population. 
Comparison of the efficacy between the subgroups and the residual group is performed by 
estimating the hazard ratio (HR) with 2-sided 95% and 80% confidence intervals and the p-value 
for the null hypothesis: HR=1. 
Furthermore, Kaplan-Meier methodology will be used to estimate median PFS with 95% CI 
using Greenwood’s formula and the Kaplan-Meier curves will be constructed to provide a visual 
description of the PFS for the subgroups over time.  
Descriptive statistics overall and for each parameter in the disease progression assessment are 
presented for the entire assessment period as well as for 3, 6 and 9-month time points by 
subgroup. 
The secondary endpoint: 
 OS rate at 9 months (OS-9) and OS overall, in all patients and in those with 
EGFRvIIIpos and EGFR gene amplified glioblastoma 
where OS is defined as the time between date of first dose of study drug and the date of death 
due to any cause. OS-9 is defined as the percentage of patients who are alive at 9 months.  


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Patients who are not reported as having died at the time of analysis will be censored at the date 
when they were last known to be alive; if no post-baseline data are available, OS will be 
censored at the date of first study drug. The analysis methods will be the same as for the PFS. 
The secondary endpoints: 
 ORR per RANO criteria, and DOR in all patients and in those with EGFRvIIIpos and 
EGFR gene amplified tumors 
where ORR is defined as a CR or PR. Patients without a post-baseline disease assessment will be 
considered as non-responders. The analysis population for ORR will be all enrolled patients with 
measurable disease at baseline. An estimate of ORR and its 95% CI will be calculated using the 
Blyth-Still-Casella method for each treatment arm. CIs for the difference in ORRs between the 
subgroups will be determined using the normal approximation to the binomial distribution. In 
addition, ORR is analyzed with a generalized logistic regression analysis. Subgroup is included 
as fixed effect, KPS as a covariate and study center as random effect. The adjusted odds ratio for 
being a responder is estimated and the two-sided 95% confidence interval presented. 
DOR is defined as the time from the initial response to disease progression or death among 
patients who have experienced a CR or PR during study. Patients who have not progressed or 
died at the time of analysis will be censored at the last disease assessment date. DOR will be 
estimated using Kaplan- Meier methodology. Comparisons between subgroups through use of 
the unstratified log-rank test will be made for descriptive purposes only. 
 To evaluate the efficacy of tesevatinib as measured by PFS-6, OS-9, RANO ORR and 
DOR in the subgroups: 
 EGFRvIIIpos vs EGFRvIIIneg 
 EGFR amplificationpos vs EGFR amplificationneg 
The statistics for these subgroup comparisons are described at each of the endpoints. 
In addition, statistics for the change and percent change from baseline tumor measurements will 
be presented. These analyses will be done after each two cycles of therapy. Summary statistics 
will be produced for PFS and OS. The percentage of patients without disease progression after 3 
and 6 months of dosing will also be presented separately by local (investigator) and potentially 
by central radiography results. Sites will provide copies of all MRI image sets for central 
retention in case central radiology review is required. 
13.4.6.3. Sensitivity analysis for primary and secondary PFS and OS endpoint analysis 
As a sensitivity analysis for the primary and secondary PFS and OS analysis the estimation of 
PFS-X, medium PFS, OS-X and median OS is performed with parametric survival analysis 
models, the models are compared to the Cox model based on the AIC-value. For each model the 
PFS-X, medium PFS, OS-X and median OS confidence intervals are estimated. 
13.4.6.4. Exploratory endpoints 
The analysis of the exploratory endpoints will be further detailed in the SAP. 


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 To evaluate the potential association of exploratory tissue and blood biomarkers with 
response to tesevatinib (PFS-6) and with adverse events. These include EGFRvIII 
mutation and gene amplification and may include circulating tumor DNA expression 
of these and other factors 
 To evaluate the correlation between patients with EGFRvIIIpos tumor and those 
patients with EGFR gene amplification with respect to survival and safety 
 To evaluate and compare EGFRvIIIpos expression and/or other tissue biomarkers 
potentially associated with response with tesevatinib, in paired primary and recurrent 
glioblastoma specimens from the same patient, when these are available 
 To evaluate patient-reported outcomes of disease and treatment-related symptom 
severity and interference as measured by the MDASI-BT questionnaire  
The MDASI-BT score is analyzed using a repeated measurement analysis with the MDASI-
BT score as dependent variable, baseline score as covariate and cycle as fixed effect. Patient 
and center as included as random effects. 
The data are summarized as scores and as change from baseline, as well as the categorical 
variables severe, moderate and mild cognitive impairment. 
 To evaluate patient-reported outcomes of disease and treatment-related symptom 
severity and interference as measured by the MDASI-BT questionnaire in the 
subgroup of patients with EGFRvIIIneg  and EGFR gene amplificationneg tumors as 
compared to those in patients with EGFRvIIIpos and EGFR gene amplificationpos 
tumors 
Comparisons will be performed by using the mixed model and including subgroup and a 
subgroup-cycle interaction.  
Data will be modelled with the MDASI-BT score as dependent variable and with a categorical 
response (binary or three categories). 
13.4.6.5. Safety Data  
Safety analyses will be performed on all patients 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 overall results and results by subgroups. 
Safety observations and measurements include AEs, safety laboratory tests, vital sign 
measurements, physical examinations, ECG assessments, and plasma levels.  
Treatment-emergent AEs will be summarized using MedDRA® (Version 18.1 or higher) System 
Organ Class (SOC) and preferred term, classified from verbatim terms. The incidence and 
percentage of patients with at least 1 occurrence of a preferred term will be included, according 
to the most severe grade using the NCI-CTCAE; Version 4.03. The number of events per 


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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 subgroup 
and tesevatinib overall according to SOC and preferred terms.  All AEs will be 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. 
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 baseline to highest grade post-baseline 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.  Karnofsky 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 
patient visit and dose cohort and/or as appropriate. QTc prolongation results will be summarized 
separately. Covariate analyses will be employed as necessary. 
 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
 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 patient 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. 
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 patient 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 patient’s medical records, assess drug 
accountability, and ensure that the study is being conducted according to pertinent regulatory 
requirements. 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. 
Electronic CRF entries will be verified with source documentation. The review of medical 
records will be performed in a manner to ensure that patient confidentiality is maintained.  
Checking the eCRFs for completeness, clarity and cross checking with source documents is 
required to monitor the progress of the study. 
The monitor will visit the sites 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 patient 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 should be completed within seven (7) days of the patient’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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14.2. 
Audits and Inspections 
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the Kadmon Quality Assurance Unit (or 
designee), or to health authority inspectors after appropriate notification.  
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 protocol, the principles of GCP 
and any applicable regulatory requirements.  A regulatory authority or IRB may also wish to 
conduct an inspection (during the study or even after its completion).  If a regulatory authority or 
IRB 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 patient data will be treated confidentially.  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 patient 
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. 
Initial IRB approval, and all materials approved by the IRB for this study including the patient 
consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
 
 


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15. 
ETHICAL ASPECTS 
15.1. 
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. 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 Patients”, and Part 56, “Institutional Review Boards”. 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 patient informed consent form (ICF) prior to implementation.  
Voluntary written informed consent must be obtained from every patient prior to participation in 
this clinical study. The rights, safety, and well-being of participating patients are the most 
important considerations and should prevail over interests of science and society. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s). This study will not use the services of study 
personnel where sanctions have been invoked based upon scientific misconduct or fraud (e.g., 
loss of medical licensure, debarment). 
15.2. 
Good Clinical Practice 
The principal investigator will ensure that the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50 (1998) and 21 CFR, part 56, (1998) are followed. Since this is a covered clinical 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 
patient to this part that the applicant or FDA relies on to establish that the product is effective 
(including studies that show equivalence to an effective product) or that make a significant 
contribution to the demonstration of safety.”  This requires that investigators and all sub-
investigators must provide documentation of their financial interest or arrangements with 
Kadmon or proprietary interests in the drug being studied. This documentation must be provided 
prior to the participation of the principal investigator and any sub-investigator. The principal 
investigator and sub-investigator agree to notify Kadmon of any change in reportable interests 
during the study and for one year following completion of the study. Study completion is defined 
as the date that the last patient has completed the protocol-defined activities. 
15.3. 
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 
patient before the patient is entered into the study and before any study screening procedure is 


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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 
Patients (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 patient (or the patient’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 patient is unable to read, an impartial 
witness should be present during the entire informed consent discussion. After the patient 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 patient or to the patient’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 patient 
candidates. 
The eCRF for this study contains a section for documenting informed patient consent, and this 
must be completed appropriately. Signed ICFs must remain in each patient’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 patients (including those already being treated) should be informed of 
the new information, should be given a copy of the revised form, and should give their written 
consent to continue in the study. 
15.4. 
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 
patient enrollment and whenever subsequent modifications to the protocol are made. 
15.5. 
Future Use of Patient 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 patient response to 
treatment. The use of the samples for internal research will be done according to the guidelines 


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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 patient 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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16. 
PROTOCOL AMENDMENTS 
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 patients, 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 patients. 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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17. 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
17.1. 
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) patient 
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. 
Patient clinical source documents (usually predefined by the project to record key efficacy and 
safety parameters independent of the eCRFs) may include patient 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 patient 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 
patient 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 patient, appropriate copies should be made for storing outside of the study site. 
17.2. 
Source Documents and Background Data 
Investigators must maintain adequate and accurate source documents on which the eCRFs for 
each patient 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 patient candidate as a standalone document 
 Description of the complete consenting process 
 The basic identifying information that linked the patient’s medical record with the 
eCRFs 


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 The results of all diagnostic tests performed, diagnoses made, therapy provided, and 
any other data on the condition of the patient 
 The medical condition of the patient during their involvement in the study 
 All AEs 
 The patient’s exposure to the study medication 
 The patient’s exposure to any concomitant therapy 
 All relevant observations and data on the condition of the patient throughout the trial 
 Justification for all entries in the patient’s eCRF 
 Radiology images (hard copy and digital), and reports if required 
 Death information and any available autopsy data 
A patient log of all potentially eligible patients considered, but not consented, for obvious 
deviations from the entry criteria, will be kept at each site. The log will contain patients’ initials, 
diagnosis, eligibility, or, if not eligible, reason for not consenting.  All consented patients 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 patient confidentiality is protected. 
17.3. 
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 patient who receives any amount of study drug.  
This includes submission of retrievable data on patients 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 patient stops treatment or terminates from the study, the dates and reasons must be 
noted on the eCRF. 
17.4. 
Confidentiality of Trial Documents and Patient Records 
The investigator must ensure that patients’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On eCRFs or other documents submitted to Kadmon 


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and the IRB, patients should be identified by an identification code and/or initials and not by 
their names. The investigator should keep a patient enrollment log showing codes, names, and 
addresses. The investigator should maintain documents not for submission to Kadmon 
(e.g. patients’ 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, patient 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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18. 
PUBLICATION POLICY 
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. 
This study will be posted to clinicaltrials.gov to permit publication in appropriate peer reviewed 
journals. 


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19. 
REFERENCES 
Armstrong TS, Mendoza T, Gning I, et al. Validation of the M.D. Anderson Symptom Inventory 
Brain Tumor Module (MDASI-BT). J Neurooncol 2006;80:27–35. 
Best MG, Sol N, Zijl S, et al. Liquid biopsies in patients with diffuse glioma. Acta Neuropathol 
2015;129:849-865. 
Brennan CW, Verhaak RGW, McKenna A et al. The Somatic Genomic Landscape of 
Glioblastoma. Cell 2013; 155(2):462-477. 
[CBTRUS] Central Brain Tumor Registry of the United States 2011. 
Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom distress in cancer patients: the 
M.D. Anderson Symptom Inventory. Cancer 2000;89:1634–46. 
Fabrini MG, Silavano G, Lolli I, et al. A multi-institutional phase II study on second-line 
Fotemustine chemotherapy in recurrent glioblastoma. J Neurooncol 2009;92:79–86. 
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan 
in recurrent glioblastoma. J Clin Oncol 2009; 27:4733–40. 
Galanis E, Anderson SK, Anastasiadis P, et al. NCCTG N0872 (Alliance): A randomized 
placebo-controlled phase II trial of bevacizumab plus dasatinib in patients with recurrent 
glioblastoma (GBM). J Clin Oncol 2015; 33(suppl):abstr 2004. 
Kappelle AC, Postma TJ, Tahoorn MJ, et al. PCV chemotherapy for recurrent glioblastoma 
multiforme. Neurology 2001;56:118–20.  
Kiyohara Y, Yamazaki N, Kishi A. Erlotinib-related skin toxicities: treatment strategies in 
patients with metastatic non-small cell lung cancer. J Am Acad Dermatol. 2013;69(3):463–472. 
Lacouture ME, Anadkat MJ, Bensadoun RJ et al. Clinical practice guidelines for the prevention 
and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 
2011;19(8):1079–1095. 
www.psoriasis.org 
Sarkaria JN, Yang L, Grogan PT, et al.  Identification of molecular characteristics correlated 
with glioblastoma sensitivity to EGFR kinase inhibition through use of an intracranial xenograft 
test panel.  Mol Cancer Ther 2007; 6:1167-1174. 
Schmidt F, Fischer J, Herrlinger U, et al. PCV chemotherapy for recurrent glioblastoma. 
Neurology 2006;66:587–9. 
Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant 
temozolomide for glioblastoma. N Engl J Med 2005;352:987–96. 
Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant 
temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III 
study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459–66. 


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Stupp R, Tonn JC, Brada M, et al. High-grade malignant glioma: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21 Suppl 5:v190–3. 
Taal W, Oosterkamp HM, Walenkamp AM, et al. Single-agent bevacizumab or lomustine versus 
a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB 
trial): a randomised controlled phase 2 trial. Lancet Oncol 2014;15(9):943-53.  
Touat M, Duran-Pena A, Alentorn A, et al. Emerging circulating biomarkers in glioblastoma: 
promises and challenges. Exp Rev Mol Diagnost 2015;15(10):1311-1323. 
Tonra JR, Poyurovsky M, Liu KG et al.. KD019: Blood brain barrier penetrant HER2/neu, Src, 
and EGFR inhibitor. Cancer Res 2015;75(15 Suppl):A2590. 
van den Bent MJ, Brandes AA, Rampling R, et al.  Randomized Phase II trial of erlotinib versus 
temozolomide or carmustine in recurrent glioblastoms: EORTC Brain Tumor Group study 
26034.  J Clin Onc 2009; 27:1268-1274. 
Weathers SPS, Han SX, Liu DD, et al. A randomized phase II trial of standard dose bevacizumab 
versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma. J 
Clin Oncol 2015; 33(suppl):abstr 2005. 
Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade 
gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010;28:1963–72. 
 


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APPENDIX 1. KARNOFSKY PERFORMANCE STATUS CRITERIA 
Score (%) 
Criteria 
100 
Normal, no complaints, no signs of disease 
90 
Capable of normal activity, few symptoms or signs of disease 
80 
Normal activity with some difficulty, some symptoms or signs 
70 
Caring for self, not capable of normal activity or work 
60 
Requiring some help, can take care of most personal requirements 
50 
Requires help often, requires frequent medical care 
40 
Disabled, requires special care and help 
30 
Severely disabled, hospital admission indicated but no risk of death 
20 
Very ill, urgently requiring admission, requires supportive measures 
or treatment 
10 
Moribund, rapidly progressive fatal disease processes 
0 
Death 
 


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APPENDIX 2. RANO CRITERIA 
Response 
Criteria 
Complete 
response 
(CR) 
Requires all of the following: 
 Complete disappearance of all enhancing measurable and nonmeasurable disease 
sustained for at least 4 weeks 
 No new lesions 
 Stable or improved non-enhancing (T2/FLAIR) lesions 
 Patients must be off corticosteroids (or on physiological replacement doses only) 
 Clinical status is stable or improved 
Partial 
response 
(PR) 
Requires all of the following: 
 ≥ 50% decrease compared with baseline in the sum of products of perpendicular 
diameters of all measurable enhancing lesions sustained for at least 4 weeks 
 No progression of nonmeasurable T1enhancing disease 
 No new lesions 
 Stable or improved non-enhancing (T2/FLAIR) lesions on the same or lower dose of 
corticosteroids compared to baseline 
 Clinical status is stable or improved 
Note: Patients with nonmeasurable disease only cannot have a partial response; the best response 
possible is stable disease 
Stable 
disease 
(SD) 
Requires all of the following: 
 Patient does not qualify for complete response, partial response, or progression 
 Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline 
 Clinical status is stable or improved 
Note: In the event that the corticosteroid dose was increased for new symptoms and signs without 
confirmation of disease progression on neuroimaging, and subsequent follow-up imaging shows 
that this increase in corticosteroids was required because of disease progression, the last scan 
considered to show stable disease will be the scan obtained when the corticosteroid dose was 
equivalent to the baseline dose. 
Progression 
(PD) 
Defined by any of the following: 
 ≥25% increase in sum of the products of perpendicular diameters of enhancing lesions 
compared with the smallest tumor measurement obtained either at baseline (of no 
decrease) or best response, on a stable or increasing dose of corticosteroids 
 Significant increase in T2/FLAIR non-enhancing lesions on stable or increasing doses of 
steroids compared with baseline scan or best response after initiation of therapy, not caused 
by comorbid events (e.g., radiation therapy, demyelination, ischemic injury, seizures, 
postoperative changes, or other treatment effects) 
 Presence of any new lesions 
 Clear clinical deterioration not attributable to other causes apart from the tumor 
(e.g., seizures, medication adverse effects, complications of therapy, cerebrovascular 
events, infection, and so on) or decreases in corticosteroid dose 
 Failure to return for evaluation due to death or deteriorating condition 
 Clear progression of nonmeasurable disease 


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FLAIR = fluid-attenuated inversion recovery, RANO = Response Assessment in Neuro-Oncology (adapted from 
Wen 2010) 
 
 
 


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APPENDIX 3. MD ANDERSON SYMPTOM INVENTORY-BRAIN 
TUMOR MODULE  
 


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APPENDIX 4. CONCOMITANT DRUGS THAT SHOULD BE AVOIDED, SUBSTITUTED OR USED 
WITH CAUTION 
Drugs with QTc risk should be avoided per Section 9.3.3.1 of the protocol. Drugs that inhibit or induce the CYP isoenzymes 3A4, 2C8, 
2D6, 1A2 should be substituted when possible or used with caution in view of their potential to alter tesevatinib exposure. Drugs that are 
secreted by the kidney proximal tubule cells into the renal tubule by MATE transporter proteins should be used with caution. This list is not 
comprehensive, and all concomitant medications should be evaluated for possible interactions with tesevatinib. See the Indiana 
University P450 drug interaction table for complete information (http://medicine.iupui.edu/clinpharm/ddis/main-table/). 
 


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Drug Type 
Drugs with QTc Risk: AVOID 
Drugs with CYP or MATE Interaction Risk: CAUTION 
Anti-anginal 
bepridil 
 
Anti-arrhythmics 
amiodarone, disopyramide, dofetilide, ibutilide, 
procainamide, quinidine, sotalol 
amiodarone, quinidine, dofetilide, procainamide  
Antibiotics/anti-fungals 
clarithromycin, erythromycin, azithromycin, 
sparfloxacin, gatifloxacin, moxifloxacin, 
troleandomycin,  pentamidine 
fluoroquinolones, clarithromycin, erythromycin, rifampin, 
rifabutin, terbinafine, itraconazole, ketoconazole, cephalexin, 
pyrimethamine 
Anti-depressant 
 
fluvoxamine, bupropion, fluoxetine, paroxetine, duloxetine, 
clomipramine, doxepin, nefazodone 
Anti-epileptics 
 
carbamazepine, phenytoin, phenobarbital 
Anti-malarial 
chloroquine, halofantrine, quinidine 
quinidine,  
Anti-nausea/emetics 
domperidone, droperidol 
 
Anti-platelet 
 
ticlopadine, 
Anti-psychotic 
haloperidol, mesoridazine, thioridazine, chlorpromazine, 
pimozide 
aripiprazole, haloperidol,  
Anti-viral 
 
efavirenz, indinavir, nelfinavir, ritonavir, nevirapine 
Asthma and allergy 
 
chlorpheniramine, diphenhydramine, montelukast, fexofenadine 
Calcium channel blockers 
 
verapamil, diltiazem 
CNS depressants  
 
barbiturates  
GI stimulant/heartburn/GERD 
cisapride 
cimetidine 
Glucose lowering agents 
 
Pioglitazone, troglitazone, metformin 
Immune modulators 
 
cyclosporine, tacrolimus 
Lipid lowering 
 
gemfibrazole,  
Miscellaneous 
 
St John’s Wort, grapefruit juice, Seville oranges,  
Opiates/dependence 
levomethadyl, methadone 
Suboxone, methadone 
 
 


Tesevatinib 
Protocol Number KD019-208 
 
 
 
  
Kadmon Corporation 
 
 
Page 112 of 113 
Confidential and 
Proprietary 
03 Apr 2019
 
APPENDIX 5. 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 


Tesevatinib 
Protocol Number KD019-208 
 
 
 
  
Kadmon Corporation 
 
 
Page 113 of 113 
Confidential and 
Proprietary 
03 Apr 2019
 
Brand Name 
Generic Name 
Elocon Cream/Lotion, 0.1% 
Mometasone furoate 
Kenalog Cream/Spray, 0.1% 
Triamcinolone acetonide 
Synalar Ointment, 0.025% 
Fluocinolone acetonide 
Westcort Ointment, 0.2% 
Hydrocortisone Valerate 
Class 5 - Lower Mid-Strength 
Capex Shampoo, 0.01% 
Fluocinolone acetonide 
Cordran Cream/Lotion, 0.05% 
Flurandrenolide 
Cutivate Cream/Lotion, 0.05% 
Fluticasone propionate 
Dermatop Cream, 0.1% 
Prednicarbate 
DesOwen Lotion, 0.05% 
Desonide 
Locoid Cream/Lotion/Ointment/ 
Solution, 0.1% 
Hydrocortisone butyrate 
Pandel Cream, 0.1% 
Hydrocortisone probutate 
Synalar Cream, 0.025/ 
Fluocinolone acetonide 
Westcort Cream, 0.2% 
Hydrocortisone valerate 
Class 6 – Mild 
Aclovate Cream/Ointment, 0.05% 
Alclometasone dipropionate 
Derma-Smoothe/FS Oil, 0.01% 
Fluocinolone acetonide 
Desonate Gel, 0.05% 
Desonide 
Synalar Solution, 0.01% 
Fluocinolone acetonide 
Verdeso Foam, 0.05% 
Desonide 
Class 7 - Least Potent  
Cetacort Lotion, 0.5%/1% 
Hydrocortisone 
Cortaid Cream/Spray/Ointment, 1% 
Hydrocortisone 
Hytone Cream/Lotion, 1%/2.5% 
Hydrocortisone 
Micort-HC Cream, 2%/2.5% 
Hydrocortisone 
Nutracort Lotion, 1%/2.5% 
Hydrocortisone 
Synacort Cream, 1%/2.5% 
Hydrocortisone 
Abstracted from:  National Psoriasis Foundation. Topical treatments for Psoriasis. 2013. 
http://www.psoriasis.org/document.doc?id=164 (accessed 24 February 2014). 
 
 

SAP_001.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN COVER LETTER 
 
A Phase 2, Multicenter Study of Tesevatinib Monotherapy in 
Patients with Recurrent Glioblastoma 
 
 
Protocol Number: 
KD019-208 
IND Number: 
129323 
NCT Number: 
NCT02844439 
Document Date:  
Version 1.0 30 June 2020 
 


Kadmon Corporation 
 
 
KD019-208                                                                                           Statistical Analysis Plan 
SAP Version 1.0: 23-Jun-2020  
 
 
                        Page 1 of 19 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 2, Multicenter Study of Tesevatinib Monotherapy in 
Patients with Recurrent Glioblastoma  
Protocol Number: KD019-208 
 
 
 
Statistical Analysis Plan Version: 
Date of Statistical Analysis Plan: 
 
 
Version 1.0 
 
30-June-2020 
  
 
 
 
 
 
 


Kadmon Corporation 
KD019-208
    Statistical Analysis Plan 
SAP Version 1.0: 23-Jun-2020 
      Page 2 of 19 
SIGNATURE PAGE 
Date 
Revised by: Ben Wang 
Senior Principal Statistician 
Tigermed BDM. 
Date 
Reviewed by: Linghui Li 
Senior Director, Clinical Development 
Kadmon Holdings, Inc.  
07/01/2020


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DOCUMENT HISTORY 
Version 
Author 
Description 
1.0  
Ben Wang 
23-Jun-2020  New Document 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1 
INTRODUCTION .............................................................................................. 8 
2 
STUDY SUMMARY ........................................................................................... 8 
2.1 
Study Objectives ............................................................................................ 8 
2.1.1 
Primary Objectives.................................................................................. 8 
2.1.2 
Primary Safety Objective ........................................................................ 9 
• 
To evaluate the safety and tolerability of tesevatinib in all treated subjects. . 9 
2.1.3 
Secondary Objectives.............................................................................. 9 
2.2 
Study Design .................................................................................................. 9 
2.3 
Visit Schedule and Study Assessment ........................................................... 9 
3 
STATISTICAL METHODS .............................................................................. 9 
3.1 
General Methods .......................................................................................... 10 
3.1.1 
Computing Environment ....................................................................... 10 
3.1.2 
Changes from protocol .......................................................................... 10 
3.1.3 
Sample Size Justification and power calculations: ............................... 10 
3.1.4 
General Considerations ......................................................................... 10 
3.1.5 
Study Day.............................................................................................. 11 
3.1.6 
Baseline ................................................................................................. 12 
3.1.7 
Handling of Incomplete or Missing Data .............................................. 12 
3.2 
Analysis Populations .................................................................................... 13 
3.3 
Subject Disposition and Evaluability ........................................................... 14 
3.4 
Protocol Deviations ...................................................................................... 14 
3.5 
Demographics and Baseline Characteristics ................................................ 14 


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3.5.1 
Demographics ....................................................................................... 14 
3.5.2 
Medical History .................................................................................... 15 
3.5.3 
Baseline GBM Disease Characteristics ................................................ 15 
3.5.4 
Other Baseline Characteristics .............................................................. 15 
3.6 
Prior and Concomitant Medications ............................................................. 15 
3.6.1 
Medications and procedures for GBM .................................................. 15 
3.6.2 
Other Prior and Concomitant Medications ........................................... 15 
3.7 
Treatment Compliance and Exposure .......................................................... 16 
3.8 
Primary Endpoint Analysis .......................................................................... 16 
3.8.1 
Progression-Free Survival Rate at 6 Month (PFS-6) ............................ 16 
3.8.2 
Secondary Endpoint Analyses .............................................................. 16 
3.9 
Patient-Reported Outcomes (PRO) .............................................................. 17 
3.10 
Safety Analysis ......................................................................................... 17 
3.10.1 Adverse Events ..................................................................................... 17 
3.10.2 Clinical Laboratory Evaluation ............................................................. 18 
3.10.3 Vital Signs ............................................................................................. 18 
3.10.4 ECG....................................................................................................... 18 
3.11 
Pharmacokinetic and Pharmacodynamic Analysis ................................... 19 
4 
LIST OF TABLES, FIGURES, AND LISTINGS .......................................... 19 
  
 


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


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Abbreviation 
Full Term 
SAP 
Statistical Analysis Plan 
SOC  
System Organ Class 
STB 
Stable 
TEAE 
Treatment-emergent adverse event 
 
 
 


Kadmon Corporation 
 
 
KD019-208                                                                                           Statistical Analysis Plan 
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1 INTRODUCTION 
Gliomas account for 80% of primary malignancies of the central nervous system 
(CNS). Glioblastomas (World Health Organization (WHO) Grade IV astrocytic 
tumors) account for 60–70% of gliomas and remain the most aggressive subtype. 
Glioblastoma occurs mostly in adults (median age of 64 years at diagnosis) with an 
estimated incidence of 2–3 cases per 100,000 people in Europe and North America. 
With 1- and 5-year overall survival (OS) rates of 29% and 3%, respectively, the 
prognosis of glioblastoma remains poor [Central Brain Tumor Registry of the United 
States 2011] and there is a need to develop more effective therapeutic approaches. 
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), Src, and vascular endothelial growth factor receptor 
2 (VEGFR2). 
This Statistical Analysis Plan (SAP) describes detailed statistical procedures to be 
used for study KD019-208 as specified in the protocol (Amendment No. 4, 03-Apr-
2019): A Phase 2, Multicenter Study of tesevatinib Monotherapy in Patients with 
Recurrent Glioblastoma.  
The SAP was written in accordance with the recommendations outlined in the 
International Conference on Harmonisation (ICH) E9 Guideline entitled “Guidance 
for Industry: Statistical Principles for Clinical Trials” and the most recent ICH-E3 
Guideline, entitled “Guidance for Industry: Structure and Content of Clinical Study 
Reports.”  
2 STUDY SUMMARY 
2.1 Study Objectives  
2.1.1 Primary Objectives 
• To evaluate the efficacy of tesevatinib as measured by investigator-assessed 
progression-free survival rate at 6 months (PFS-6) in mITT population.  


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2.1.2 Primary Safety Objective 
• To evaluate the safety and tolerability of tesevatinib in all treated subjects.  
2.1.3 Secondary Objectives  
The secondary objectives of this study are: 
• To evaluate the efficacy of tesevatinib as measured by investigator-assessed 
progression-free survival rate at 6 months (PFS-6) in Subpopulations A and B.  
• To evaluate the efficacy of tesevatinib as measured by the OS-9 rate, in all 
patients and in those in Subpopulations A and B 
• To evaluate the efficacy of tesevatinib as measured by the PFS, in all patients and 
in those in Subpopulations A and B 
• To evaluate the efficacy of tesevatinib as measured by the OS, in all patients and 
in those in Subpopulations A and B 
• To evaluate the efficacy of tesevatinib as measured by ORR and DOR per RANO 
criteria, and DOR in all patients and in Subpopulations A and B  
• To evaluate the efficacy of tesevatinib as measured by PFS-6, OS-9, ORR and 
DOR in: 
o EGFRvIIIpos vs EGFRvIIIneg 
o 
EGFR amplificationpos vs EGFR amplificationneg 
 
2.2 Study Design 
This is an open-label, single dose arm, multicenter, Phase 2 study to assess the 
activity of tesevatinib in patients (n =40) with recurrent glioblastoma. This study will 
be conducted at up to 10 sites in the United States. 
Subjects meeting inclusion/exclusion criteria receive tesevatinib at the dose of 300 
mg once daily. One cycle will be defined as 28 days of treatment.  Subjects will be 
treated with study drug until disease progression or unacceptable toxicity occurs.  
All patients also will be followed for a period of 30 days following their last dose of 
tesevatinib or until the patient starts a new treatment.   
  
2.3 Visit Schedule and Study Assessment 
The flow chart of visit schedule and study assessments is given in Table 1 of the 
KD019-208 Protocol. 
3 STATISTICAL METHODS  


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3.1 General Methods 
3.1.1 Computing Environment 
All statistical programming and data analyses will be performed using SAS 
Version 9.4 on Windows platform. 
3.1.2 Changes from protocol  
Changes from protocol in statistical methods are made in both primary and secondary 
analyses wherever necessary. 
3.1.3 Sample Size Justification and power calculations: 
The power calculation is based on simulations in the Weibull distribution to describe 
the progression and survival times. The estimation of PFS-6 is done using the Cox 
model. Based on a one-stage design, with a sample size of 40 patients in the overall 
population, a PFS-6 of 25% and median PFS of 4.5 months, the trial has 95% power 
to demonstrate an estimated PFS-6 >15%. Based on a one-sided test on a 5% 
significance level, the trial has 95% power to show a significant difference above the 
null hypothesis of 7% and 80% power to show a significant difference above 10%. 
The study is not powered to detect differences in the secondary endpoints. 
3.1.4 General Considerations  
General considerations for descriptive statistics and presentation for continuous and 
categorical data are given below.  
3.1.4.1 Continuous variables 
Continuous data will be described using descriptive statistics: number of observations 
(n), mean, standard deviation, median, minimum, and maximum.   
Means, medians, standard deviations, and confidence intervals (CIs) will be reported 
to one decimal place more than the data reported on the case report form (CRF) or by 
the vendor. Minimum and maximum will be reported to the same number of decimal 
places displayed on the CRF or by the vendor. P-values will be reported to 4 decimal 
places. 
3.1.4.2 Binary Endpoint and Other Categorical Variables 
For endpoints with two possible outcomes such as alive/otherwise or 
response/otherwise within specific periods, the 95% confidence interval will be 
calculated with Clopper-Pearson method for survival rates or response rates.   For 


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other categorical variables, the counts and percent of each category within a 
parameter will be calculated for observed data only. The denominator for all 
percentages, unless otherwise specified, will be the number of subjects in the cohort 
or in the specified analysis population. 
3.1.4.3 Progression-Free Survival (PFS) Endpoints 
PFS is defined as the time from date of first dose to the date of disease progression or 
death, whichever happens first. For subjects who do not have an event (i.e. those who 
have not progressed, and are alive at the date of data cut-off or lost to follow-up), 
progression-free survival will be censored on that date.  
 PFS will be summarized using Kaplan-Meier methods for 25th percentile, median, 
and 75th percentile.  95% Confidence intervals will be calculated using Greenwood 
Formulation. Kaplan-Meier curves will be plotted for populations in the analysis.  
3.1.4.4 Overall Survival (OS) Endpoints 
OS is defined as the time from first dose until death due to any cause. In absence of 
confirmation of death, subjects will be censored either at the date that the subject was 
last known to be alive or the date of study cut-off, whichever comes earlier. 
OS will be summarized using Kaplan-Meier methods for 25th percentile, median, and 
75th percentile.  95% Confidence intervals will be calculated using Greenwood 
Formulation. Kaplan-Meier curves will be plotted for populations in the analysis.  
 
 
 
3.1.5 Study Day 
The Study Day for all assessments prior to the first study drug administration is 
calculated as the difference between the date of the event or measurement (e.g., 
adverse event [AE] onset date, assessment date, sample collection date) and the start 
date of study treatment. The day before the start of study treatment is Study Day -1. 
The Study Day for all post-assessments after the first study drug administration is 
calculated as the difference between the date of the event or measurement (e.g., AE 
onset date, assessment date, sample collection date) and the start date of study 
treatment plus one day. The first day of study treatment is Study Day 1 with 
subsequent study days numbered sequentially thereafter. 


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


Kadmon Corporation 
 
 
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                        Page 13 of 19 
 
not impute a date). If the AE/CM has stopped, then the last assessment date will 
be imputed. 
These data imputations are for categorization purpose only and will not be used in the 
listings. 
If the assessment of the relationship of the AE to  tesevatinib is missing, then it will 
be assumed that the AE is related to  tesevatinib and the AE considered as such in the 
frequency tables of possibly related AEs. No imputation should be done at the data 
level. 
Missing event dates  
Event date will be imputed only when day is missing, and the purpose of imputing an 
event date is to most conservatively calculate time to event.  
If the day is missing, the first (mid, last) day of the month will be imputed for 
undesired (neutral, desired) event. If the missing day is the same as the month of first 
dose of study drug, then the first dose date will be imputed for undesired event. 
These data imputations are for time to event calculation only and will not be used in 
the listings. 
3.2 Analysis Populations 
The following populations will be analyzed: 
Modified Intent-to-treat (mITT) Population: The primary population for efficacy 
analyses will be a Modified Intent-to-treat (mITT) Population defined as all subjects 
who receive at least 1 dose of study medication. The mITT Population will be used 
for tables of demography, baseline characteristics, and efficacy. 
Safety Population: The Safety Population is defined as all subjects who receive at 
least 1 dose of study medication. In this study, the Safety Population is equivalent to 
the mITT Population. 


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Subpopulation:  Two protocol defined subpopulations based on EGFR biomarkers 
EGFR at baseline are as follows 
 
Subpopulation 
 
Description 
A 
Patients with an assumed beneficial mutation (EGFR gene amplified 
glioblastoma) 
B 
Patients with an assumed beneficial mutation (EGFRvIIIpos 
glioblastoma) 
 
These two biomarkers are the targets for tesevatinib treatment. 
3.3 Subject Disposition and Evaluability 
Subjects who failed screening (i.e., subjects who signed the informed consent were 
screened but never started the study treatment, and their basic demographics and any 
AE after signing the informed consent may have been collected in the CRF) will be 
excluded from any populations defined in Section 3.2. Therefore, these subjects will 
be excluded from any summary tables or listings.  
The number of subjects discontinuing from the study and the primary reason for 
discontinuation will be summarized.  
3.4 Protocol Deviations 
All protocol deviations will be identified and classified as major or minor before 
clinical database lock and will be presented in a listing. 
Major Deviation: Protocol deviation that may impact the accuracy, and/or reliability 
of the study data or that may impact subject rights, safety or well-being. 
Minor Deviation: Protocol deviation that does not impact the accuracy, and/or 
reliability of the study data or subject rights, safety or well-being. 
3.5 Demographics and Baseline Characteristics 
3.5.1 Demographics 
Subject demographics and baseline characteristics will be summarized for the mITT 
Population. Descriptive statistics will be provided for age, height, and weight.  


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3.5.2 Medical History 
Medical history will be summarized by primary System Organ Class (SOC) and 
Preferred Term (PT). Medical history will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) Version 20.1 (or higher) terminology.   
3.5.3 Baseline GBM Disease Characteristics 
• Months since first GBM diagnosis 
• Months since recurrent GBM diagnosis  
• Tumor Measurement  
• Diagnosis of Prior Low Grade Astrocytoma 
  
3.5.4 Other Baseline Characteristics  
Other baseline values including Karnofsky Performance Scale (Appendix E; 
Karnofsky et al., 1949) and childbearing potential will also be summarized.  
3.6 Prior and Concomitant Medications 
3.6.1 Medications and procedures for GBM 
• Prior radiotherapy  
• Prior systemic therapy 
• Corticosteroid use at baseline 
3.6.2 Other Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary. Prior medications are defined as those medications that began and 
stopped before the start of study treatment. Concomitant medications are defined as 
medications taken after the start of study treatment and during the study period, 
including those began before but ongoing at the start of study treatment. If a 
medication start date is partially or fully missing and it is unclear as to whether the 
medication is prior or concomitant, it will be assumed that the medication is 
concomitant. 
Number and percentage of incidence of prior and CM will be summarized according 
to Anatomical Therapeutic Class (ATC) and preferred drug name. 


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3.7 Treatment Compliance and Exposure 
The amount of tesevatinib administered by visit and overall (total dose) will be 
tabulated and presented by patient in data listings. The distribution of the number of 
cycles achieved per patient will also be summarized. In addition, delays and all other 
alterations in tesevatinib administration will be presented 
3.8 Primary Endpoint Analysis 
3.8.1 Progression-Free Survival Rate at 6 Month (PFS-6)  
Proportion of patients who are alive and not progressed at 6 months (24 weeks) will 
be analyzed with method as described in3.1.4.2. This analysis is based on mITT 
population. Patients whose survival or response status at 6 months (24 weeks) are 
unknown are not considered alive or progression free.  Response Assessment in 
Neuro-Oncology (RANO) criteria are used to determine specific criteria for treatment 
response (Appendix 2 of the protocol.) in all endpoint analysis in this study.  
3.8.2 Secondary Endpoint Analyses  
3.8.2.1  PFS-6 in Subpopulations A and B, as well as combination of And B 
Progression-Free Survival rate at 6 months will be analyzed with method as described 
in 3.1.3.2 respectively in subpopulations A and B, and the combination of A and B.  
3.8.2.2 OS-9 in Subpopulations A and B, as well as in mITT 
Survival rate at 9 months will be analyzed with method as described in 3.1.4.2 
respectively in subpopulations A and B, and in mITT population. 
3.8.2.3 PFS in Subpopulations A and B, as well as in mITT 
PFS will be analyzed with method as described in 3.1.4.3 respectively in 
subpopulations A and B, and in mITT population. 
3.8.2.4 OS in Subpopulations A and B, as well as in mITT 
OS will be analyzed with method as described in 3.1.4.4 respectively in 
subpopulations A and B, and in mITT population. 
3.8.2.5 Objective Response Rate (ORR) and DOR per RANO 
ORR including CR or PR per RANO criteria will be analyzed with method as 
described in 3.1.4.2 respectively in subpopulations A and B, and in mITT population. 
This analysis will be performed in subpopulations A and B, and in mITT population. 
For responders in above analyses, corresponding Duration of response is calculated as 
the time from first documented evidence of CR or PR (whichever status is recorded 


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first) until the first documented sign of disease progression or death due to any cause 
(whichever is the first). DOR will be summarized  
It is defined for subjects with a confirmed CR or a confirmed PR. For subjects in the 
subset of responders who do not progress or die, duration of response will be 
analyzed with method as described in 3.1.4.3.  
3.8.2.6 PFS-6, OS-9, ORR and DOR comparisons in the following subgroups 
• EGFRvIIIpos vs EGFRvIIIneg 
• EGFR amplificationpos vs EGFR amplificationneg 
3.9 Patient-Reported Outcomes (PRO)  
Patient-reported outcomes in M.D. Anderson Symptom Inventory – Brain Tumor 
questionnaire (MDASI-BT) will be listed for teach subject.  
3.10 Safety Analysis 
Safety assessments will include AEs, serious adverse events (SAEs), vital sign 
measurements, clinical laboratory evaluations (hematology and chemistry), and 
electrocardiograms (ECGs). Unscheduled visits for safety assessments will not be 
presented in summary tables but will be in listings. All safety analyses will be 
performed using the safety population.  
3.10.1 Adverse Events 
AEs will be coded using the MedDRA dictionary (Version 20.1 or higher). 
Treatment-emergent AEs (TEAEs) are any AE occurring or worsening in severity 
after the first administration of study medication. All AEs (including SAEs) will be 
graded using the 5-point Common Terminology Criteria for Adverse Events 
(CTCAE) V4.03 scale (mild, moderate, severe, life-threatening, or death). Causality 
with tesevatinib will be classified as: definitely related; probably related; possibly 
related; unlikely related; or not related. 
 The investigator will further assess the relationship of AEs to tesevatinib or the 
underlying disease. 
The number and percentage of patients who experienced at least one TEAE as well as 
the number and percentage of patients who experienced AEs of each specific SOC 
and PT will be presented. For the presentation of AE incidences, the SOCs and the 
PTs within each SOC will be presented by decreasing total frequency. Tabulation by 


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maximum severity and relationship to tesevatinib will also be included by treatment 
group. 
The TEAEs, Grade ≥ 3 TEAEs, SAEs, and TEAEs leading to dose 
modification/discontinuation will be summarized by treatment arm, SOC, and PT. 
These analyses will be repeated for events considered related (definitely 
related/probably related/possibly related) to  tesevatinib.  
Subject listings will be provided for SAEs, AEs resulting in study drug 
discontinuation and deaths. 
Adverse events will also be presented in listings. Time to onset and duration of AEs 
will be included in listings, along with action taken and outcome. 
3.10.2 Clinical Laboratory Evaluation 
The summary statistics (including number, mean, standard deviation, median, 
minimum and maximum) of all laboratory variables and changes from baseline will 
be calculated for each visit or study assessment by treatment group. For parameters of 
white blood cell counts, neutrophils (absolute count), lymphocytes (absolute count), 
monocytes (absolute count), hemoglobin, platelets, ALP, ALT, aspartate 
aminotransaminase, gamma glutamyl transferase, total bilirubin, glomerular filtration 
rate, plots of mean/mean changes from baseline with the corresponding standard error 
will be displayed. 
For shift tables, laboratory results will be classified using the CTCAE Version 4.03. 
All graded laboratory parameters will be summarized separately for hematology and 
biochemistry. Corresponding shift tables comparing baseline to the worst 
post-baseline grade within the treatment period will be provided. 
3.10.3 Vital Signs 
Descriptive statistics for vital signs (weight, temperature, blood pressure, pulse rate, 
and respiratory rate) values and the change from baseline will be presented for each 
scheduled assessment time point.  
3.10.4 ECG 
Descriptive statistics for ECG parameters (i.e., PR interval, QRS interval, and QTcF 
interval) at each time point with triplicate ECGs will be presented for the values and 


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change from baseline scores. (QTcF is the QT interval using Fridericia’s correction 
which is calculated by QTcF = QT/RR1/3.)  
The number and percentage of subjects with observed QTcF values that satisfy the 
following conditions will be presented by treatment group and study visit and 
categorized as: ≤ 450 ms; > 450 to 480 ms; > 480 to 500 ms; and > 500 ms. 
The number and percentage of subjects having change from baseline QTcF values 
that satisfy the following conditions will be presented by treatment group and study 
visit and categorized as: ≤ 0 ms; > 0 to ≤ 30 ms; > 30 to ≤ 60 ms; and > 60 ms. 
3.11 Pharmacokinetic and Pharmacodynamic Analysis  
PK serum concentration and all biomarkers will be summarized at each collection 
time-point.     
   
4 LIST OF TABLES, FIGURES, AND LISTINGS 
List of tables, figures, and listings will be completed in a separate document.