A Phase I/II, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of YH25448 in Patients With EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer (NSCLC)
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Janssen Research & Development, LLC

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Clinical Protocol
YH25448-201
(Trial also known as:73841937NSC2001)
A Phase I/II, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability,
Pharmacokinetics and Anti-Tumor Activity of YH25448 in Patients with EGFR
Mutation Positive Advanced Non-Small Cell Lung Cancer (NSCLC)
Protocol Version: Final Eng Ver 11.0
(Formerly referred to in the United States of America as YH25448-201/USA-1)
24-hr Emergency Number
YUHAN Corporation
74 Noryangjin-ro, Dongjak-gu, Seoul 06927, Republic of Korea,
Janssen Research & Development, LLC
920 U.S. Route 202, Raritan, NJ, 08869, United States of America
EudraCT NUMBER: 2019-003106-28
This protocol contains information that is confidential and proprietary
to Yuhan Corporation and Janssen Research & Development, LLC
SOUTH KOREA
Telephone: +
Fax: +
OUTSIDE KOREA  US toll-free:
US local:
PPD
PPD
PPD
PPD
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DOCUMENT HISTORY
Document 
Date of Issue 
Summary of Change
Protocol Initial Eng ver.1.0 17-NOV-2016 
Not Applicable
Protocol ver. 2.0 
10-JAN-2017 
Exclusion of Korean patients for
Part C 1st line therapy cohort,
applying the comments from MFDS,
and others including word correction
etc.
Protocol ver. 3.0 
06-APR-2017 
Change the inclusion criteria for Part
A and clarification the meaning
according to the change of KOR
version 3.0.
Protocol ver. 4.0 
11-DEC-2017 
Change the Inclusion/Exclusion
criteria, detailed description of
analysis set and correct errors
according to the change of KOR
version 5.0.
Protocol ver. 5.0 
04-MAY-2018 
Deletion of Part C Dose Extension
Phase Brain Metastasis (BrM)
cohort, deletion  of ”except Korea”
and change in the patients’ number
for Part C 1st line therapy cohort, and
others according to the change of
KOR version 6.0.
Protocol ver. 6.0 
30-NOV-2018 
Change the inclusion criteria for Part
C 2nd line therapy cohort, detailed
description of withdrawal consent
procedure, clarification of SRC at
Part B & Part C and others according
to the change of KOR version 8.0.
Protocol ver. 6.0/USA-1 
15-Apr-2019 
Add study centers in United States
and description of Part D: US
patients, to enroll patients in the US,
according to the change of KOR
version 8.0(Eng version 6.0).
Protocol ver. 6.1/USA-1 
21-May-2019 
Add dose modification guideline of
YH25448 
for management 
of
toxicity for Part D.
Protocol ver. 7.0 
30-Jul-2019 
Change the standard for causality
assessment, time schedule for vital
sign and ECG assessment for Part D,
and reflect other changes to unify
protocol for Korea and outside
Korea. Sponsor name for Part D is
changed from Yuhan to Janssen.
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Protocol ver. 8.0 
25-Feb-2020 
Updated to allow collection of
optional whole blood samples for
pharmacogenetic 
analysis 
of
GSTM1 in Part D (ex-Korea PK
study), to clarify that central
confirmation of TnI+ is not required
in Part D (ex-Korea PK study), and
to clarify that treatment will not be
restarted after diagnosis of ILD, in
line with Korean HA guidance.
Protocol ver. 9.0 
08-Jan-2021 
Application of changes in visit
frequency 
and 
clinical 
trial
procedure following changes in data
collection after the primary data base
lock.
Protocol ver. 10.0 
13-Apr-2021 
To re-insert safety assessments for
Part 
D 
after 
primary 
DBL
(19 Apr 2021) to allow protocol
consistency across part D countries
following a request from the MHRA.
Protocol ver. 11.0 
19-Nov-2021 
Removed requirement for long-term
follow-up ofpatients in Part D.
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Amendment Protocol Ver 11.0 (19 Nov 2021)
Overall Rationale for the Amendment:The requirement for long-term follow-up of patients in Part D
was removed.
Section number and  
Name
Description ofChange 
BriefRationale
6.1 Study Plan for Flow 
Chart/Time and Events 
Schedule Table 11. Part D: 
Patients Outside Korea 
Added footnote 20 to indicate that, as of 
Protocol Amendment 11, follow-up visits will 
not be required for patients in Part D and 
overall survival and subsequent anticancer
therapy data will not be collected. Updated
footnote 17 to clarify that follow-up visits will
not be required for patients in Part D as of
Amendment 11.
Long-term follow-up
is no longer required
for patients in Part D.
6.2.6.4 Follow-up 
Added a statement that, as of Protocol 
Amendment 11, follow-up visits will not be 
required for patients in Part D and overall 
survival and subsequent anticancer therapy data
will not be collected.
Long-term follow-up
is no longer required
for patients in Part D
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SYNOPSIS
Clinical Protocol
YH25448-201
(Trial also known as: 73841937NSC2001)
Title of Study: A Phase I/II, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability,
Pharmacokinetics and Anti-Tumor Activity of YH25448 in Patients with EGFR Mutation
Positive Advanced Non-Small Cell Lung Cancer (NSCLC)
Study Sponsorship: Study Parts A, B, and C are sponsored by Yuhan Corporation under
protocol identifier YH25448-201, and Study Part D is sponsored by Janssen Research &
Development under protocol identifier 73841937NSC2001.
Estimated Number of Study Centers and Countries/Regions:Approximately 20 centers in
Korea and approximately 10 centers outside Korea.
Study Phase: Phase I/II
Study Design: Multicenter, Open-label trial. There are four parts to this study. Part A, Dose
escalation phase. Part B, Dose expansion phase. Part C, Dose extension phase. Part D, Safety,
tolerability, efficacy and PK evaluation in patients enrolled outside Korea, including the United
States of America (US). Note that Parts A through C are specific to Korean sites only and as of
26 Nov  2018, the safety tolerability, efficacy and PK of YH25448 have been evaluated in
approximately 127 patients enrolled in Korea in dose escalation (Part A) and expansion phase
(Part B) and 67 patients in dose extenstion phase at 240mg QD dose (Part C).
Primary Objective (Parts A, B, and C): To evaluate the safety, tolerability and efficacy of
YH25448 when given orally to patients with EGFRm+ locally advanced or metastatic NSCLC.
Secondary Objectives (Parts A, B, and C):
To define the maximum tolerated dose (MTD), if possible, a dose/exposure predicted to result
in anti-tumor activity and maximum absorbable dose (MAD).
To characterize the pharmacokinetic (PK) profiles of YH25448 and its potential metabolites,
including M7, following a single oral dose and at steady state.
Dose Escalation and Expansion phases: To obtain a preliminary assessment of the anti-tumor
activity of YH25448 by evaluation of objective response rate (ORR), duration of response
(DoR), disease control rate (DCR), tumor shrinkage and progression free survival (PFS) using
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Dose Extension phase: To obtain additional assessments of the anti-tumor activity of YH25448
by evaluation of DoR, DCR, tumor shrinkage and PFS using RECIST 1.1 as assessed by an
independent central review of radiological information and overall survival (OS).
Primary and Secondary Objectives of Part D: Applies to patients enrolled outside of
Korea only
Primary Objective:
To evaluate the safety, tolerability, and pharmacokinetics (PK) of YH25448 when given orally
to patients with EGFRm+ locally advanced or metastatic NSCLC.
Secondary Objectives:
To characterize the PK profiles of potential YH25448 metabolites in plasma, including M7,
following a single oral dose and at steady state.
To obtain additional assessments of the anti-tumor activity of YH25448 by evaluation of
objective response rate (ORR), duration of response (DoR), disease control rate (DCR), tumor
shrinkage and progression free survival (PFS) using RECIST 1.1 as assessed by investigator
review of radiological information and overall survival (OS).
Exploratory Objectives (Parts A, B, and C)
To collect and store plasma for potential exploratory research of blood born biomarkers into
factors that may  influence development of NSCLC and/or response to YH25448 (where
response is defined broadly to include efficacy, tolerability or safety).
To collect and store deoxyribonucleic acid (DNA) for future exploratory research into
genes/genetic variation that may influence PK or response (i.e. absorption, distribution,
metabolism, excretion, safety, tolerability and efficacy) to YH25448 treatment and or
susceptibility to cancers.
To collect and store diagnostic tumor sample and any fresh tumor biopsies for potential future
exploratory research into factors that may influence development of NSCLC and/or responses
to YH25448 (where response is defined broadly to include efficacy, tolerability or safety).
To collect patient reported outcomes (PRO) data to explore disease-related symptoms and
health related quality of life (HRQoL).
To assess the relationship between PK and selected efficacy, pharmacodynamic and/or safety
endpoints, where deemed appropriate.
To characterize the PK profiles of YH25448 and its potential metabolites, including M7, in
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cerebrospinal fluid (CSF).
To collect and store residual CSF for potential exploratory research of factors that may influence
development of NSCLC and/or response to YH25448 (where response is defined broadly to
include efficacy, tolerability or safety).
Exploratory Objectives (Part D)
To collect deoxyribonucleic acid (DNA) for exploratory research into genes/genetic variation
that may  influence PK or response (i.e. absorption, distribution, metabolism, excretion, safety,
tolerability and efficacy) to YH25448 treatment and or susceptibilityto cancers. The specific
objective of the pharmacogenetic assessment is to investigate genetic variants of the Glutathione
S-Transferase Mu 1 (GSTM1) genotypes affecting the disposition of YH25448 and to
understand the correlation of GSTM1 genetic variants with PK and safety and tolerability.
Overall Study Design (Parts A, B, and C)
This is a phase I/II, open-label, multicenter study of YH25448 administered orally in patients
with EGFRm+ NSCLC withor withoutasymptomatic brain metastasis. The study design allows
an escalation of dose with intensive safety monitoring to ensure the safety of the patients. It is
possible for additional dose levels to be added during the course of the study.
A cycle of study treatment will be defined as 21 days of continuous dosing and the
evaluation of measurable lesion as per RECIST 1.1 will be performed at every 2 cycles.
After the primary database lock, radiological disease evaluations are not required and may
be performed at the discretion of the investigator in accordance with local standard of care.
Part D: Overall Study Rationale and Design in patients outside Korea
This is a phase I/II, open-label, multicenter study of YH25448 administered orally in patients
with EGFRm+ NSCLC with or without asymptomatic brain metastasis. A PK study (Study
YH25448-101), using the current RP2D of 240 mg in 12 Caucasian (3 Russian, 4 Turkish, 4
Moroccan, and 1 French) and 12 Korean healthy volunteers all enrolled from Korea, showed
that the AUClast and Cmax  were respectively 40% and 30% lower in Caucasian compared to
Korean patients. Consequently, additional dose testing is required to support the RP2D in
Caucasians outside Korea, including the US. Based on current PK data from this study (Study
YH25448-201) of patients with EGFRm+ NSCLC, increasing the dose of YH25448 from 240
mg to 320 mg increases both the AUCss and Cmax,ss by about 20%. The 320 mg dose and has
been shown to be safe in 5 Korean patients with no dose limiting toxicity (DLT). As of the data
cutoff date of 26 Nov 2018, there were no treatment discontinutions due to adverse event at 320
mg cohort and the dose appears to be safe and tolerable. Comparing safety in the 320 mg (n 5)
vs 240 mg (n 24) cohort, all grade adverse drug reactions (ADRs) were similar in both dose
cohorts with pruritis, rash, decreased appetite and muscle spasms the most frequent. One patient
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with ADR of Grade 3 pneumonitis was reported in the 240 mg dose cohort. No ADR with Grade
≥3 was reported in the 320 mg cohort. In conclusion: 1) no DLT was observed at the 240 and
320 mg dose and 2) the overall safety profile was similar between 240 and 320 mg dose.
In Part D, YH25448 will be given to patients outside Korea, including Caucasians, at the current
RP2D of 240 mg and 320 mg in order to evaluate safety, tolerability, efficacy (including tumor
response) and PK in patients outside ofKorea.
A cycle of study treatment will be defined as 21 days of continuous dosing and the evaluation
of measurable lesion as per RECIST 1.1 will be performed at every 2 cycles. After the primary
database lock, radiological disease evaluations are not required and may be performed at the
discretion of the investigator in accordance with local standard of care.
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Study Design
RD : recommended dose
BrM : brain metastasis
Part A: Dose Escalation Phase
The part A will determine the MTD or MAD of YH25448 for max. 6 patients of each cohort
based upon assessment of the safety, tolerability and PK data collected during the first 21 days
of daily dosing in patients experienced clinical benefit from EGFR TKIs followed by
progression disease while on continuous treatment with the authorized EGFR TKIs prior to
enrolling in the study. At least 3 and up to 6 patients for evaluating DLT will be required for
each cohort. It is possible to be evaluated for additional dose cohort according to the necessary
of dose escalation or dose de-escalation.
For PK assessment of single and multiple doses, patients will receive a single dose on Day 1
Cycle 0 then after 7±2 days washout, multiple dosing, once daily will be initiated. PK blood
samples will be collected over 60 hours after single dose. In the first cohort administration of
the first dose will be separated from the start dosing of the subsequent patients by at least 7 days
for the first patient. Dosing frequency (e.g. bid) may be adjusted during the study on the basis
of emerging safety and PK data. Trough plasma concentrations will be measured at each visit
during Cycle 1, and PK evaluation at steady state will be performed over 24 hours after the first
administration in Cycle 2.
Dosing for cohort 1 will begin at 20 mg once daily.
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Dose escalation and de-escalation will follow the scheme below, according to the following
logic:
 
Dose limiting toxicity (DLT) will be assessed once the first three patients completed Cycle 1
(i.e. 21 days).
 
If no DLT is observed in a cohort of 3-6 evaluable patients then dose escalation may occur
(see Table 1). Dose increases will be permitted after the review of safety data from a minimum
of 3 evaluable patients has been performed.
 
If one patient experiences a DLT in a group of 3 or more evaluable patients then the cohort
will be expanded to include 6 evaluable patients. If only one DLT is observed in the complete
cohort of 6 evaluable patients then dose escalation may occur.
 
If 2 or more patients experience a DLT in a group of at least 3 patients up to 6 patients, the
dose will be considered not tolerated and recruitment to the cohort and dose escalation will
cease. A lower dose or a lower intermediary dose (de-escalation, see Table 2) may be
considered to better define the MTD.
 
If 2 or more patients experience a DLT in a group of up to 6 patients at the starting dose of 20
mg then 10 mg would be investigated.
 
Prior to achieving MTD, the maximum absorbable dose is achieved (i.e. when no increase in
exposure with increasing dose is observed), the scheduling of dose escalation or dose de-
escalation can be changed.
 
Prior to a dose escalation or de-escalation decision, the Safety Review Committee (SRC) will
review all available safety and PK data.
 
Dose escalation will not exceed doubling of the dose in principle.
The provisional dose escalation and de-escalation scheme is described in Table 1 and 2,
respectively. All dose levels beyond cohort 1 may change in light of emerging safety, tolerability
and PK data.
Table 1. Provisional dose escalation scheme
Cohort
Dose (mg)
(to be administered once daily)
1 
20
2 
40
3 
80
4 
120
5 
160
X 
xxx
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Table 2. Dose de-escalation scheme
Dose at time of toxicity (mg) 
(to be administered once daily) 
Lower intermediary dose* (mg)
(to be administered once daily)
320 
260
240 
200
160 
140
120 
100
80 
60
40 
30
20 
10
* Lower intermediary dose: The middle dose between assigned dose level and lower dose level.
Part B: Dose Expansion Phase
Part B will be conducted to assess safety, tolerability, efficacy and PK of YH25448 for
approximately 20 evaluable patients per each cohort with T790M+ on the basis of central
confirmed T790M mutation result who have experience in the authorized EGFR TKIs therapy
followed by progression disease prior to enrolling in the study regardless of whether BrM has
occurred or not (See Figure 1).Trough plasma concentrations will be measured at each visit
during Cycle 1, and PK evaluation at steady state will be performed over 24 hours after the first
administration in Cycle 2.
Each dose cohort of part B will be started to enroll the patient after confirmation of safety data
for each corresponding dose cohort of part A. SRC will determine the change of dose level and
decide to quit patients enrollment based on emerging data from expansion phases.
Part C: Dose Extension Phase
Once MTD or RD is reached for Part C as a result of the overall evaluation of the results of Part
A and B and after the reflection of this result in the protocol or IB, additional 2 cohorts of 100
evaluable patients will be enrolled to assess the efficacy, safety and tolerability of YH25448.
Trough plasma concentrations for PK evaluation will be measured at each visit during Cycle 1.
1) 2nd  line therapy Cohort
The efficacy and the tolerability of YH25448 will be assessed for approximately 60
patients with T790M+ who have received the authorized EFGR TKIs treatments and
whose progression of the disease has been confirmed after recent treatment regardless of
BrM occurrence. 
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2) 1st line therapy Cohort
Approximately 40 patients with EGFRm+ NSCLC who are EGFR TKI-naïve regardless
of BrM occurence will be enrolled to assess the efficacy and tolerability of YH25448.
Part D: Patients outside Korea
As of 26 Nov 2018, the safety tolerability, efficacy and PK of YH25448 have been evaluated in
approximately 127 patients enrolled in Korea in dose escalation (Part A) and expansion phase
(Part B) and 67 patients in dose extension phase at 240 mg QD dose (Part C). YH25448 was
found to be well tolerated with no dose limiting toxicity up to a maximum of 320 mg per day.
The recommendend Phase 2 dose, based on an assessment of safety, efficacy and PK, is 240 mg
per day.
The goal of Part D is to evaluate the safety, tolerability, efficacy and PK of YH25448 at the 240
mg and 320 mg dose levels in patients enrolled outside Korea. Approximately 12-15 patients
outside Korea will be enrolled at each dose level to provide a minimum of 6 Caucasian patients
with evaluable PK. Although enrollment will not be based on race, it is expected that
approximately 80% of patients will be Caucasian.
Patients outside Korea will be enrolled into the 240 mg and 320 mg Cohort on an alternating
basis, Management of individual patient toxicity will be according to Section 5.4.1.3.
Main Inclusion Criteria
1) For Parts A, B and C only:Histologically or cytologically (i.e., pleural effusion, ascites
cases) confirmed diagnosis of NSCLC patients with single activating EGFR mutations
(L858R or Exon19Del or G719X or L861Q).
A. In Part D: Patients outside Korea with histologically or cytologically (ie, using
pleural effusion, ascites) confirmed NSCLC with previously diagnosed EGFRm+,
and who have had progressive disease on prior EGFR-TKI therapy.
2) Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 patients with no
deterioration over the previous 2 weeks and a minimum life expectancy of 3 months.
3) Patients who have at least one measurable extracranial lesion, not previously irradiated
and not chosen for biopsy during the study screening period or one measurable lesion that
has passed 14 days or more after biopsy, that can be accurately measured at baseline as ≥
10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm)
with computerized tomography (CT) or magnetic resonance imaging (MRI), are suitable
for accurate repeated measurement.
4) In Part A, patients who had experienced clinical benefit from EGFR TKIs followed by
systemic objective progression while on continuous treatment with the authorized EGFR
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TKIs. Prior to enrolling in the study, patients must have central confirmation of T790M+/-
mutation status from a sample taken after progression disease on the EGFR TKIs therapy.
5) In Part B, patients who have been treated with the authorized EGFR TKIs and must be
confirmed progression disease prior to enrolling in the study. Patients must have central
confirmation of T790M mutation positive(+) from a sample taken after progression
disease on the therapy recently.
6) In Part C-2nd  line therapy cohort, patients who have been treated with the authorized
EGFR TKIs and must be confirmed progression disease prior to enrolling in the study.
Patients must have T790M mutation positive(+) from a sample taken after progression
disease on the recent therapy which is confirmed by local or central lab using the method
approved by MFDS. However, if the T790M mutation is confirmed locally, the collected
tumor sample must be submitted for central confirmation before the enrollment.
7) In Part C-1st line therapy cohort, patients must have not received any EGFR-TKIs prior
to enrolling in the study, and EGFR mutation status must be confirmed as positive by a
qualified institutional laboratory or a central laboratory.
Main Exclusion Criteria
1) Symtomatic spinal cord compression (if steroid treatment is not required within at least 2
weeks prior to the start ofthe study treatment then the patient may be enrolled)
2) Brain metastases with symptomatic and/orrequiring emergency treatment (e.g. Steroid for
at least 2 weeks prior to start of study treatment).
3) Intracranial hemorrhage with symptomatic and/or requiring treatment
4) CNS complications that require urgent neurosurgical intervention (e.g. resection or shunt
placement).
5) Leptomeningeal metastasis prior to study treatment.
6) Past medical history of interstitial lung disease (ILD), drug-induced IDL, radiation
pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
7) EGFR TKIs administration to treat T790M resistance mutation (For Parts A, B, and C
only).
8) Any cardiovascular disease as followed,
a) History of symptomatic CHF or serious cardiac arrhythmia requiring treatment
b) History of myocardial infarction or unstable angina within 6 months of the first dose
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of study treatment
c) 
LVEF <50%
Efficacy Endpoints
Primary Endpoints (Parts A, B, and C)
 
Safety and tolerability (primary for dose escalation and expansion phase)
 
Objective response rate (ORR) (primary for dose extension, secondary for dose escalation and
expansion phases)
Secondary Endpoints (Parts A, B, and C)
 
PK parameters of YH25448 and its metabolites following a single oral dose and multiple oral
doses.
 
Duration of response (DoR), disease control rate (DCR), tumor shrinkage
 
Progression free survival (PFS) (secondary for dose expansion and extension phases)
 
Overall survival (OS) (secondary for the selected extension dose in expansion phase and
extension phase)
For the BrM patients only (secondary for dose expansion and extension phases): objective
intracranial response rate (OIRR), duration of intracranial response (DoIR), intracranial
progression free survival (IPFS)
Primary and Secondary Efficacy Endpoints for Part D
Primary Endpoints
 
Safety, tolerability, and PK of YH25448
Secondary Endpoints
 PK profiles of potential YH25448 metabolites in plasma, including M7, following a single
oral dose and at steady state.
 Overall response rate (ORR)
 Duration of response (DoR)
 Disease control rate (DCR)
 Tumor shrinkage
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 Progression free survival (PFS)
 Overall survival (OS)
Exploratory Endpoints (Parts A, B, and C)
 
Patient Reported Outcome: EORTC QLQ LC-13, QLQ C-30, QLQ BN-20 (BrM patients only)
 
Metabolite identification
 
Biomarker data
 
Pharmacogenetics
 
Diagnostic tumor samples
Exploratory Endpoints (Part D)
 
Pharmacogenetic assessment of variants that encode GSTM1
Safety Variables
AEs, physical examination, clinical laboratory information, vital signs, ECOG performance
status, ECG parameters, and concomitant medications/procedures
Statistical Analyses
The analyses of data will be based on different anaylsis population according to the purpose of
the analyses. Analysis populations are described below:
 
Safety analysis population: All patients who received at least one dose of investigational
product (IP)
 
Evaluable for response population: All patients in the safety analysis population who has a
baseline RECIST 1.1 assessment whose tumor EGFR mutation status was confirmed via a
central testing. Central testing results must match the cohort to which they were assigned. For
Part D, all patients in the safety analysis population who have a baseline RECIST 1.1
assessment (no central testing of EGFR mutation status is required).
 
Brain metastatic full analysis population: All patients in the evaluable for response population
who have a measurable and/or unmeasurable intracranial lesion at baseline.
 
Brain metastatic evaluable for response population: All patients in the brain metastatic full
analysis population who have at least one measurable intracranial lesion at baseline.
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 
Pharmacokinetic analysis population: All patients who have at least one measurable
concentration collected post-dose.
Primary Analyses
Parts A and B (Dose Escalation and Dose Expansion Phases)and Part D (Patients outside
Korea)
Safety and tolerability will be assessed in terms of AEs, physical examination, laboratory data,
vital signs and ECG assessments. All patients who receive at least one dose of YH25448 will
be included in the assessment of the safety profile (safety analysis population). These safety
measures will be listed and summarized descriptively in the safety analysis population, as
appropriate.
Part C (Dose Extension Phase)
Objective response rate (ORR)
ORR is defined as the percentage of patients who have at least one confirmed partial or
complete response (PR or CR), according to RECIST 1.1 and appendix F  prior to disease
progression or recurrence.
The analysis population for ORR will be the evaluable for response population.
ORR will be presented with two-sided 95% confidence intervals using the normal
approximation.
Analyses will be performed using both the assessments by independent central review (ICR) as
well as by investigator, but the primary analysis for ORR will be based on ICR.
Secondary Analyses
Duration of Response (DoR)
DoR is defined as the time from the date of first documented responses (that is subsequently
confirmed) until date of documented progression or death (same as PFS event time) whichever
comes first. The time of the initial response will be defined as the latest of the dates contributing
towards the first visit response of PR or CR. If a patient does not progress following a response,
then their duration of response will use the PFS censoring time.
DoR in responding patients will be summarized and the number of responding patients with a
duration of response (>3; >6; >9; >12 months) will be presented. A Kaplan-Meier plot and
median DoR with 95% CI (calculated from the Kaplan-Meier plot) will be presented by dose
level and total.
Progression Free Survival (PFS)
PFS is defined as the time from first dosing date until documented disease progression or death
from any cause whichever first based on ICR as well as investigator assessment using
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RECIST 1.1 or appendix F. Patients who have not progressed or died at the time of analysis
will be censored at the time of the latest date of assessment from their last evaluable
RECIST 1.1 assessment. In general, the PFS censoring rules and the definition of progression
date follow the Food and Drug Administration (FDA) “Guidance for Industry Clinical Trial
Endpoints for the Approval of Cancer Drugs and Biologics (2007)”.
PFS will be summarized based on the safety analysis population for the expansion and
extension phases. PFS will be displayed using Kaplan-Meier plot. The number of events,
median (calculated from the Kaplan-Meier plot), and proportion of patients without an event
at 6, 12, and 18 months will be summarized.
Disease Control Rate (DCR)
DCR is defined as the proportion of patients with a best overall response (BOR), extracranial
and intracranial response ofCR, PR or SD.
Two-sided 95% confidence intervals DCR will be calculated using asymptotic normal
approximation by dose level and total.
Tumor shrinkage
Percentage change in tumor size will be determined for patients with measurable disease at
baseline and is derived at each visit by the percentage change in the sum of the diameters of
target lesions compared to baseline.
For brain metastatic patients, change in tumor size will be reported separately for extracranial
disease and intracranial.
The analysis population for change in tumor size will be the evaluable for response population.
Summaries and waterfall plots (bar charts) indicating percentage change from baseline in the
sum of the diameters of target lesions at week 6 and week 12 will be produced.
Objective Intracranial Response Rate (OIRR)
OIRR is defined as the percentage of patients who have at least one confirmed PR or CR in
intracranial lesion, according to RECIST 1.1 or appendix F prior to disease progression or
recurrence in the brain metastatic patients.
The OIRR will be analyzed by the brain metastatic full analysis population and brain metastatic
evaluable for response population.
OIRR will be presented with two-sided 95% confidence intervals (Clopper-Pearson interval)
by dose level and total.
Duration of Intracranial Response (DoIR)
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DoIR is defined as the time from the date of first documented responses (that is subsequently
confirmed) in intracranial disease until date of documented progression or death (same as
intracranial PFS event time according to appendix F) whichever comes first in brain metastatic
patients.
DoIR will be analyzed by brain metastatic evaluable for response population.
DoIR in intracranial responding patients will be summarized and the number of responding
patients with a duration of response (>3; >6; >9; >12 months) will be presented. A Kaplan-
Meier plot and median DoIR with 95% CI (calculated from the Kaplan-Meier plot) will be
presented by dose level and total.
Intracranial Progression Free Survival (IPFS)
IPFS is defined as the time from first dosing date until documented disease progression or death
from any cause whichever first based on ICR as well as investigator assessment using
RECIST 1.1 or appendix F in brain metastatic patients. Patients who have not progressed or
died at the time of analysis will be censored at the time of the latest date of assessment from
their last evaluable RECIST 1.1 assessment.
IPFS will be analyzed by the brain metastatic full analysis population.
IPFS will be presented in the Kaplan-Meier plot. The number of events, median (calculated
from the Kaplan-Meier plot), and proportion of patients without an event at 6, 12, and 18
months will be summarized.
Overall Survival (OS)
OS will be assessed based on the date of first dose and vital status at the time of data cutoff date.
OS is defined as the interval between the date of first dose and the date of patient death due to
any cause. The analysis population for OS will be the safety analysis population. OS will be
summarized for the selected extension dose in expansion phase and extension phase. OS will
be displayed using Kaplan Meier plots. The number of events, median (calculated from the
Kaplan Meier plot), and proportion of patients without an event at 6, 12 and 18 months will be
summarized. As appropriate, summaries of the number and percentage of patients who have
died, are still in survival follow-up, are lost to follow-up and have withdrawn consent will be
presented.
Pharmacokinetic Analyses
Plasma concentrations of YH25448 and its metabolites will be summarized by nominal
sampling time. Plasma concentrations, CSF concentrations and PK parameters will be
summarized according to dose. Parameters following single and multiple dosing will be
summarized separately. The dose proportionality of YH25448 will be assessed using a power
model with ln-transformed AUCt, Cmax, AUCss, Cmax,ss values as dependent variables and the
ln-transformed dose as an independent variable.
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Comparison of PK profiles and parameters for patients outside Korea and Korean patients after
administration of single dose and multiple dose of 240 and 320 mg will be conducted. Log-
transformed primary parameters for each dose, Cmax, AUClast, Cmax,ss and AUCss, will be
analyzed by analysis of variance, and point estimates and 90% confidence intervals of the
geometric mean ratio (patients outside Korea/Korean patients) will be calculated.
Sample Size Determination
Part A: Dose Escalation Phase
Approximately 30 patients with EGFRm+ NSCLC who had progressed following prior EGFR
TKIs therapy will be enrolled in dose escalation phase. The total number of patients will depend
upon the number of dose escalations necessary. At least 3 and up to 6 evaluable patients will be
required for each dose cohort.
Part B: Dose Expansion Phase
Approximately 20 evaluable patients with T790M+ mutation NSCLC on the basis of central
confirmed T790M mutation result regardless of brain metastasis (2nd line expansion
with/without BrM) who had progressed following prior EGFR TKIs therapy will be enrolled
per dose cohort.
Part C: Dose Extension Phase
2nd line therapy cohort
A total of 60 evaluable patients is required for the 2nd line therapy cohort in Part C. This sample
size will provide 88% power to test a difference of 45% (not considered clinically compelling)
versus 65% (ORR of minimal clinically meaningful) using a one-sided 0.025 alpha level.
1st line therapy cohort
A total of 40 evaluable patients is required for the 1st line therapy cohort in Part C. This sample
size will provide 93% power to test a difference of 55% (not considered clinically compelling)
versus 80% using a one-sided 0.025 alpha level.
Part D: Patients outside Korea
Approximately 12-15 patients outside Korea will be enrolled at each 240 mg and 320 mg dose
level to provide a minimum of 6 Caucasian patients with evaluable PK. Although enrollment
will not be based on race, it is expected that approximately 80% of patients will be Caucasian.
All patients will have progressed following prior EGFR TKI therapy.
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TABLE OF CONTENTS
SIGNATURE PAGE ....................................................................................................................2
DOCUMENT HISTORY.............................................................................................................3
SYNOPSIS.....................................................................................................................................6
TABLE OF CONTENTS...........................................................................................................21
LIST OF TABLES......................................................................................................................25
LIST OF FIGURES....................................................................................................................25
LIST OF APPENDIXES............................................................................................................25
1. 
INTRODUCTION and STUDY RATIONALE.........................................................26
1.1. Investigational Product Development Rationale .......................................................26
1.2. Summary of pre-clinical studies................................................................................26
1.3. 
Study Rationale..........................................................................................................29
1.4. Overall Risk/Benefit Assessment..............................................................................31
1.4.1. 
Potential benefits ...............................................................................................31
1.4.2. 
Potential risks ....................................................................................................31
1.4.3. 
Overall benefit-risk and ethical assessment ......................................................35
2. 
STUDY OBJECTIVES................................................................................................36
2.1. Primary Objective (Parts A, B, and C) ......................................................................36
2.2. Secondary Objectives (Parts A, B, and C).................................................................36
2.3. Primary and Secondary Objectives of Part D: Applies to patients enrolled outside
Korea 36
2.4. Exploratory Objectives..............................................................................................37
3. 
ETHICAL CONSIDERATIONS ................................................................................37
3.1. 
Good Clinical Practice...............................................................................................37
3.2. Institutional Review Board/Ethics Committee..........................................................38
3.3. 
Informed Consent ......................................................................................................38
4. 
INVESTIGATIONAL PLAN......................................................................................39
4.1. Study Design and Rationale.......................................................................................39
4.1.1. 
Rationale for dose regimen, dose escalation scheme ........................................39
4.1.2. 
Study Design .....................................................................................................40
4.1.3. 
Definition of dose-limiting toxicity...................................................................44
4.1.4. 
Definition of maximum tolerated dose..............................................................45
4.1.5. 
Definition of evaluable patients for DLT..........................................................45
4.1.6. 
Duration of therapy............................................................................................45
4.2. Study Population........................................................................................................46
4.2.1. 
Inclusion Criteria...............................................................................................46
4.2.2. 
Exclusion Criteria..............................................................................................48
4.2.3. 
Restrictions........................................................................................................51
4.2.3.1. 
Concomitant treatments...............................................................................51
4.2.3.2. 
Prohibited Treatments..................................................................................52
4.2.4. 
Discontinuation of Investigational Product and withdrawal from Study..........52
4.2.4.1. 
Procedures for discontinuation of a patient from investigational product...53
4.2.4.2.
Procedures for handling patients incorrectly initiated on investigational pro
duct 
53
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4.2.4.3. 
Procedure for withdrawal from study..........................................................54
5. 
TREATMENTS............................................................................................................54
5.1. 
Study Treatment.........................................................................................................54
5.1.1. 
Investigational Product......................................................................................54
5.1.2. 
Non-investigational Product..............................................................................54
5.1.3. 
Identification......................................................................................................55
5.1.4. 
Packaging and Labeling ....................................................................................55
5.1.5. 
Handling and Dispensing ..................................................................................55
5.2. 
Method of Assigning Patients to a Treatment ...........................................................56
5.3. 
Safety Review Committee.........................................................................................56
5.4. Dose Modification.....................................................................................................57
5.4.1. 
Toxicity management and dose modifications to YH25448.............................57
5.4.1.1. 
Escalation and Expansion patients ..............................................................57
5.4.1.2. 
Extension patients........................................................................................59
5.4.1.3. 
Patients Outside Korea ................................................................................59
5.4.1.3.1. YH25448 dose reduction levels in response to toxicity..............................59
5.4.1.3.2. YH25448 dose modification guidelines for toxicities.................................59
5.4.1.4. 
All Patients ..................................................................................................61
5.4.1.4.1. Guidelines for the management of YH25448 induced corneal ulceration ..61
5.4.1.4.2. Guidelines for the management of YH25448 induced interstitial lung disease
61
5.4.1.4.3. Guidelines for the management of YH25448 induced cardiac dysfunction61
5.4.1.4.4.
Guidelines for the prevention, monitoring, and management of YH25448 in
duced rash-related adverse events..................................................................................62
5.4.1.4.5.
Guidelines for the monitoring, and management of YH25448 induced diarrh
ea 
63
5.4.2. 
Assessment timings if dosing is interrupted......................................................64
5.5. 
Treatment compliance and accountability.................................................................64
6. 
STUDY ASSESSMENTS AND PROCEDURES.......................................................66
6.1. Study Plan for Flow Chart/Time and Events Schedule.............................................66
6.2. Safety Procedures ......................................................................................................87
6.2.1. 
Enrollment and screening..................................................................................88
6.2.2. 
Physical examination.........................................................................................88
6.2.3. 
Vital signs..........................................................................................................89
6.2.4. 
ECG...................................................................................................................90
6.2.5. 
Laboratory safety assessment............................................................................92
6.2.6. 
Other Safety Assessment...................................................................................94
6.2.6.1. 
Ophthalmologic examination ......................................................................94
6.2.6.2. 
Echocardiography (or MUGA Scan)...........................................................94
6.2.6.3. 
Hepatitis screen, HIV screen .......................................................................95
6.2.6.4. 
Follow-up.....................................................................................................95
6.3. Pharmacokinetics.......................................................................................................96
6.3.1. 
Collection of pharmacokinetic samples.............................................................96
6.3.2. 
Determination of drug concentration in pharmacokinetic samples...................97
6.4. Exploratory Research.................................................................................................97
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6.4.1. 
Exploratory biomarker research........................................................................97
6.4.1.1. 
Collection of Tumor Samples......................................................................98
6.4.1.2. 
Collection of exploratory Blood-born biomarker........................................98
6.4.1.3. 
Collection of plasma for exploratory analysis of cfDNA............................99
6.4.1.4. 
Collection of cerebrospinal fluid.................................................................99
6.4.2. 
Collection of Pharmacogenetics samples..........................................................99
6.5. Patient Reported outcomes ......................................................................................100
6.6. Biological sampling procedures ..............................................................................101
6.6.1. 
Volume of blood..............................................................................................101
6.6.2. 
Handling, storage and destruction of biological samples................................102
6.6.3. 
Pharmacokinetic samples ................................................................................102
6.6.4. 
Samples for exploratory research....................................................................103
6.6.5. 
Labeling and shipment of biohazard samples .................................................103
6.6.6. 
Chain of custody of biological samples...........................................................104
6.6.7. 
Withdrawal of informed consent for donated biological samples...................104
6.7. Anti-tumor activity..................................................................................................104
6.7.1. 
Tumor assessments..........................................................................................104
7. 
ADVERSE EVENTS..................................................................................................106
7.1. 
Definitions of adverse events...................................................................................107
7.2. Definition of Serious Adverse Events .....................................................................107
7.3. 
Recording of adverse events....................................................................................108
7.4. Reporting of serious adverse events ........................................................................111
7.5. 
Contact Information for reporting SAE...................................................................112
7.6. Overdose..................................................................................................................112
7.7. 
Pregnancy ................................................................................................................113
7.7.1. 
Maternal exposure ...........................................................................................113
7.7.2. 
Paternal exposure.............................................................................................113
7.7.3. 
Requirements for Pregnancy Testing ..............................................................114
7.7.4. 
Reporting of Pregnancy...................................................................................114
8. 
STATISTICAL CONSIDERATIONS......................................................................115
8.1. 
Sample Size Determination .....................................................................................115
8.2. 
Populations for Analyses.........................................................................................116
8.3. 
Patient Disposition...................................................................................................117
8.4. Demographics and Other Baseline Characteristics..................................................117
8.5. 
Assessment of Treatment Compliance ....................................................................117
8.6. Endpoint Definition.................................................................................................117
8.6.1. 
Efficacy Endpoints ..........................................................................................118
8.6.1.1. 
Primary Endpoints (Parts A, B, and C)......................................................118
8.6.1.2. 
Secondary Endpoints (Parts A, B, and C)..................................................118
8.6.1.3. 
Primary and Secondary Efficacy Endpoints for Part D.............................118
8.6.2. 
Safety Variables...............................................................................................119
8.6.3. 
Pharmacokinetic Endpoints.............................................................................119
8.6.4. 
Exploratory Endpoints.....................................................................................120
8.7. 
Analyses...................................................................................................................120
8.7.1. 
Calculation or Derivation of Variables............................................................121
8.7.1.1. 
Tumor Response Variables ........................................................................121
8.7.1.2. 
Pharmacokinetic Variables.........................................................................122
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8.7.2. 
Efficacy Analyses............................................................................................122
8.7.2.1. 
Primary Analyses.......................................................................................122
8.7.2.2. 
Secondary Analyses...................................................................................123
8.7.3. 
Safety Analyses ...............................................................................................127
8.7.3.1. 
Adverse Events..........................................................................................128
8.7.3.2. 
Clinical Laboratory Parameters.................................................................128
8.7.3.3. 
Vital Signs..................................................................................................129
8.7.3.4. 
12-lead Electrocardiogram ........................................................................129
8.7.3.5. 
Physical Examination................................................................................129
8.7.4. 
Pharmacokinetic Analyses...............................................................................130
8.7.5. 
Exploratory Analyses ......................................................................................130
8.8. 
Other Analyses.........................................................................................................130
8.8.1. 
Subgroup Analyses..........................................................................................130
8.8.2. 
Analyses to Characterize the Exposure-Response Relationship.....................131
8.9. 
Interim Analyses......................................................................................................131
8.10. Sensitivity Analyses.................................................................................................131
9. 
ADMINISTRATIVE SECTION...............................................................................131
9.1. Compliance..............................................................................................................131
9.1.1. 
Compliance with the Protocol and Protocol Revisions...................................131
9.1.2. 
Monitoring.......................................................................................................132
9.1.3. 
Investigational Site Training ...........................................................................132
9.2. Records Retention....................................................................................................133
9.2.1. 
Case Report Forms ..........................................................................................133
9.2.2. 
Investigational Product Records......................................................................134
9.3. 
Return and Destruction of Investigational Product .................................................134
9.3.1. 
Return of Investigational Product....................................................................134
9.3.2. 
Destruction of Investigational Product............................................................135
9.4. Publications..............................................................................................................135
10. 
GLOSSARY OF TERMS ..........................................................................................136
LIST OF ABBREVIATIONS..................................................................................................137
REFERENCES .........................................................................................................................140
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LIST OF TABLES
Table 1. Provisional dose escalation scheme................................................................................11
Table 2. Dose de-escalation scheme.............................................................................................12
Table 3. Summary of tumor response (Independent central review) ...........................................31
Table 4. Provisional dose escalation scheme................................................................................42
Table 5. Dose de-escalation scheme.............................................................................................43
Table 6. Investigational Products Description..............................................................................55
Table 7. Stepwise Algorithm for Management of Rash...............................................................63
Table 8. Part A: Dose Escalation Phase .......................................................................................66
Table 9. Part B: Dose Expansion Phase .......................................................................................70
Table 10. Part C: Dose Extension Phase ......................................................................................74
Table 11. Part D: Patients Outside Korea.....................................................................................81
Table 12. Time and Events Schedule for Pharmacokinetic (PK), and ECG Assessments for Part
D ...................................................................................................................................87
Table 13. PK blood sample schedule............................................................................................96
Table 14. Blood Volume ............................................................................................................101
Table 15. Radiological assessment follow-up according to the response ..................................106
Table 16. The definition of outcome ..........................................................................................125
LIST OF FIGURES
Figure 1. Study Design.................................................................................................................41
Figure 2. Dose modifications for toxicity ofYH25448................................................................58
Figure 3. Dose modifications for toxicity of YH25448 in Part D................................................60
LIST OF APPENDIXES
Appendix A. Algorithm for Continuation, Dose Modification or Discontinuation of YH25448
Based on Increases of Liver Biochemistry (Hy’s Law17)...........................................143
Appendix B. Algorithm for Continuation and Discontinuation of YH25448 Based on LVEF and
TnI Assessments in Patients .......................................................................................145
Appendix C. International Airline Transportation Association (IATA) Guidance Document ..147
Appendix D. Ethical and regulatory requirements .....................................................................148
Appendix E. Data and study management..................................................................................151
Appendix F. Guidelines for Evaluation of Objective Tumor Response Using RECIST 1.1
(Response Evaluation Criteria in Solid Tumors) FOR ASSESSMENT OF
INTRACRANIAL AND EXTRACRANIAL DISEASE18 ........................................155
Appendix G. GUIDANCE REGARDING POTENTIAL INTERACTIONS WITH
CONCOMITANT MEDICATIONS ..........................................................................165
Appendix H. PATIENT REPORTED OUTCOMES (QLQ C-30) ............................................169
Appendix I. PATIENT REPORTED OUTCOMES (QLQ LC-13) ...........................................172
Appendix J. PATIENT REPORTED OUTCOMES (QLQ BN-20)...........................................173
Appendix K. Information for Sponsor and Principal Investigators............................................175
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1. INTRODUCTION and STUDY RATIONALE
1.1. Investigational Product Development Rationale
One-third of all cancer deaths worldwide are still caused by lung cancer and non-small-cell lung
cancer (NSCLC) constitutes approximately 80% of lung cancer patients. Only minor portion of
NSCLC patients can be cured by surgery and most of the patients are diagnosed with locally
advanced or metastatic disease.1 Treatment of advanced NSCLC is initially decided by
molecular subtypes of the tumor and if the patients harbour epidermal growth factor receptor
(EGFR) mutation, EGFR tyrosine kinase inhibitors (TKIs) are recommended as the first-line
therapy and the patients are highly sensitive to those agents.2 Most patients who initially
respond to gefitinib and erlotinib eventually become resistant and experience progressive
disease. T790M, the point mutation of the gatekeeper residue in EGFR tyrosine kinase domain
accounts for about 50-60% of these cases of acquired resistance. This had lead to the
development of third generation EGFR-TKIs targeting T790M mutation.3 Approximately half
of patients with NSCLC harboring EGFR mutations develop brain metastasis (BrM) within 3
years from diagnosis.6 Currently-available EGFR TKIs show limited efficacy for the treatment
of brain metastases probably due to limited blood brain barrier (BBB) penetration of current
EGFR inhibitors.4,5
YH25448 is an oral, highly potent, mutant-selective and irreversible EGFR TKIs targets both
the T790M mutation and activating EGFR mutations while sparing wild type-EGFR. YH25448
is expected to benefitial for the NSCLC patients with brain metastasis due to good BBB
penetratration property as well as for the treatment of primary lung lesion and extracranial
lesions. This study will be conducted to evaluate the safety, tolerability and efficacy of
YH25448 in locally advanced or metastatic NSCLC patients with EGFR mutations.
1.2. Summary of pre-clinical studies
YH25448 selectively and irreversibly inhibited EGFR single and double mutant kinase activity
with IC50 values of 2 nM for L858R/T790M against 76 nM for wild type-EGFR. In the cell
proliferation assays, GI50 values were 6 nM, 5 nM, and 711 nM for H1975 cells
(L858R/T790M), PC9 cells (del19) and H2073 cells (wild type), respectively. In primary cancer
cells from patients harboring EGFR mutations, YH25448 showed more potent inhibition of
cancer cell growth compared to osimertinib. YH25448 treatment at the once-daily doses of 0.3-
10 mg/kg resulted in dose-dependent tumor regression in subcutaneous tumors in mice
implanted with H1975 cells and most of the mice showed complete tumor regression at 10
mg/kg. In an intracranial tumor implantation model using H1975 cells in mice, YH25448
achieved more significant, complete tumor growth inhibition and longer overall survival
compared to same doses of osimertinib at the dose range of 1-50 mg/kg and EDmax of
YH25448 was 25 mg/kg.
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Plasma half life of YH25448 was 5.9-6.8 hr and tumor to plasma AUC0 last ratio was 3.0-5.1 in
the tumor-bearing mice. YH25448 also showed excellent penetration of the BBB with brain to
plasma AUC ratio of 4.0 and 0.8 in rats and mice after oral administration, respectively and
achieving CSF concentrations exceeding the IC50 value for pEGFR inhibition. Overall, the
strong in vitro potency and high selectivity of YH25448 for mutant EGFR translated into robust
in vivo efficacy. These findings indicate that YH25448 will be able to address the unmet needs
for EGFR mutant-positive patients with brain metastasis. YH25448 was rapidly absorbed after
oral administration in mice, rats and dogs with Tmax was between 0.5 and 4.0 hr. The systemic
exposure of YH25448 was generally dose proportional in dogs and less than dose proportional
in rodents. Oral bioavailability was 33.7% to 79.8% dependent on the species and dose levels.
The volume of distribution following intravenous administration was ranged 2.9-17.2 L/kg in
animals indicating extensive distribution into tissues. Plasma protein binding rate of YH25448
was 99.0 to 99.5% in animals and it was 99.1% in human. After oral administration of 14C-
YH25448 in rats, radioactivity was widely detected in tissues and highest radioactivity was
observed in the uveal tract followed by stomach, small intestine, liver, Harderian gland, and
lung.
In emerging in vitro metabolism studies, glutathione (GSH)-conjugation by GSTM1 was found
to be the most abundant metabolic pathway. The relatively minor oxidative metabolism of
lazertinib is mainly CYP3A4-mediated, although 2C9, 1A2, and 2A6 may also contribute. In
an excretion study in rats, biliary excretion of metabolites was the major route of elimination
of lazertinib following single oral administration of 14C-lazertinib, with only a small fraction (<
5%) of the dose excreted in urine. In  metabolite identification  studies using hepatocytes, no
humanspecificmetabolitewas detectedandonlya trace amountoftwo metabolites (M6 andM7)
was identifiedin the human hepatocytes.
The key findings in the safety pharmacology studies were as following:
YH25448 inhibited the function of the hERG channel with IC50 value of 5.3 μM using a manual
patch clamp technique. In a tissue bath assay using isolated rabbit heart, no relevant
electrocardiographic and electrophysiological changes were observed after exposure up to 30
µM of YH25448.
 
There were no notable effects on the cardiovascular system in dogs following administration
of single oral doses up to 20 mg/kg of YH25448.
 
A single oral gavage dose of up to 100 mg/kg YH25448 administered to rats caused no general
clinical effects or effect on assessed neurological parameters.
 
A single oral administration of 100 mg/kg YH25448 in rats resulted in no biologically relevant
effects on assessed respiratory parameters.
The key findings in the toxicity studies were as following:
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 
In both rat and dog toxicology studies almost all the observations and findings are consistent
with consequences of the pharmacological inhibition of EGFR by YH25448 or sequelae
secondary to primary effects. A wide range of organs and tissues containing epithelial cell
lineages were affected with changes spanning mild epithelial atrophy through to degenerative
erosions, inflammation and necrosis.
 
In a 2-week dose range finding (DRF) study in rats, animals daily administered with 0, 50,
100, or 150 mg/kg/day of YH25448. Animals given 150 mg/kg/day were sacrificed early due
to test article-related decreases in mean body weights and food consumption. In blood
chemistry analysis, the most prominent effects were correlated with decreased food
consumption (lower total protein and albumin), dehydration (higher urea nitrogen, higher
inorganic phosphorus), and hepatocellular alterations (higher aspartate aminotransferase
(AST) and alanine aminotransferase (ALT)). Evidence of possible mild inflammation (higher
white blood cells, neutrophils, and monocytes) and lower red blood cell mass were also
observed. Based on these findings, the dose levels of 100 mg/kg/day and 50 mg/kg/day were
considered as the maximum-tolerated dose (MTD), and the no observed adverse effect level
(NOAEL), respectively.
 
In a 4-week oral repeat dose toxicity study in rats, animals were administered a dose level of
0, 25, 50, or 100/75 mg/kg/day YH25448 via oral route for 4 weeks followed by a 2-week
recovery phase. Two YH25448-related deaths were noted in 100/75 mg/kg/day group. Test
article-related clinical observations included an increased incidence of skin lesions along with
a decrease in mean body weights and food consumption noted in animals administered
100/75 mg/kg/day. These findings showed evidence of reversibility during the recovery
phase. In clinical pathology examination, higher urea nitrogen and creatinine in animals
administered ≥50 mg/kg/day and higher AST and ALT in animals administered ≥25
mg/kg/day was correlated with microscopic findings of tubular dilatation and slight papillary
necrosis and minimal single cell hepatocellular necrosis in animals administered 100/75
mg/kg/day which exhibited reversibility during the recovery phase. YH25448-related
microscopic findings were observed in other tissues (eye, bone, bone marrow, duodenum,
testis, skin, epididymis, ovary, uterus, vagina and mandibular lymph node) and the severity of
these findings increased in a dose-dependent manner with no findings at 25 mg/kg/day. Some
of these findings exhibited partial or complete reversibility during recovery phase. Therefore,
the dose level of 100/75 mg/kg/day is considered severely toxic dose 10 (STD10) due to
mortality observed at this dose, and 50 mg/kg/day as the MTD, and 25 mg/kg/day as the
NOAEL.
 
In a 2-week DRF toxicity study in dogs, animals administered with vehicle or YH25448 at the
dose of 15, 30, or 50 mg/kg/day once daily for 2 weeks. Administration of 15 mg/kg for 14
days was well tolerated; dose levels of 30 and 50 mg/kg were not tolerated, and resulted in the
early sacrifice on Day 7 of all animals administered 50 mg/kg and one female administered
30 mg/kg. Clinical observations, including red conjunctiva, squinted eyes, hypoactivity,
and/or abdominal splinting, along with body weight loss and decreased food consumption,
were noted. Clinical pathology effects were predominantly consistent with inflammatory
response. These effects included mildly to moderately increased fibrinogen and globulin
concentrations and mildly to moderately decreased albumin concentration and albumin:
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globulin ratio, although these were considered not adverse. The NOAEL and MTD of
YH25448 was considered as 15 mg/kg/day.
 
In a 4-week repeated toxicity study in dogs, YH25448 was administered daily via oral gavage
to animals for 4 weeks and assessed the reversibility after a 2-week recovery phase. Oral
administration of 5, 10, or 20 mg/kg/day YH25448 to dogs for 28 days was tolerated in both
males and females administered 5 or 10 mg/kg/day, and in females administered 20
mg/kg/day. However, 20 mg/kg/day was not tolerated in males because of marked body
weight loss, decreased food consumption and the early sacrifice of one male. YH25448-
related microscopic findings (degeneration/ necrosis of the myocardium and vessel, mixed
cell inflammation, thrombus, and haemorrhage) present in the hearts of two males
administered 20 mg/kg/day resulted in the early sacrifice of one of the males. Markedly
increased cardiac troponin I concentration correlated microscopically with cardiac
degeneration/necrosis in two high dose males. YH25448 related microscopic observations
were also noted in the duodenum (blunting and fusion of villi), skin (epidermal atrophy), and
kidney (inflammation of the pelvis) in 20 mg/kg /day group. Mixed cell inflammation and
reduced luminal sperm in the epididymis, decreased secretion in prostate, and decreased
lymphocytes in multiple lymphoid organs were present in animals administered 10
mg/kg/day. Epithelial atrophy in the cornea and esophagus, testicular tubular degeneration,
bone marrow hypercellularity, and mononuclear cell infiltration in the liver were present in
animals administered 5 mg/kg/day. Some of these findings exhibited partial reversibility
during recovery phase. No abnormal ophthalmic observations were noted. Also, no YH25448-
related changes in PR interval, QRS duration, QT interval, corrected QT (QTc) interval, RR
interval, or heart rate were observed in all dose groups. The HNSTD of YH25448 was
10 mg/kg/day for males and 20 mg/kg/day for females.
 
There were no findings to indicate the potential for genotoxicity when YH25448 was assessed
in the in vitro Ames and chromosome aberration test and in the in vivo micronucleus study in
rats up to 2,000 mg/kg/day.
 
YH25448 was not considered phototoxic in the in vitro assay in 3T3 cells.
Further details for non-clinical study results are provided in the investigator brochure (IB) and
the results from the non-clinical studies support progression into clinical trials in patients with
advanced NSCLC including brain metastatic conditions.
1.3. Study Rationale
YH25448 is a mutant-selective irreversible EGFR TKIs targeting both T790M mutation and
activating mutations while sparing EGFRmutation. In the preclinical studies, YH25448 showed
excellent efficacy in brain metastases model with NSCLC cells carrying T790M mutation and
high BBB penetration profiles. Therefore, with improved penetration of the BBB and
equipotent activity against both T790M mutation and activating EGFR mutations, YH25448
has the potential to provide clinical benefit to patients with NSCLC with brain metastasis. Also,
it is expected that YH25448 would show low toxicity such as rash and diarrhea due to its good
selectivity against EGFR mutation.
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This is a first time in patient study primarily designed to evaluate the safety, tolerability, and
efficacy of YH25448 in patients with EGFR mutation positive (EGFRm+) advanced NSCLC
with or without asymptomatic brain metastasis who progressed following prior therapy with
an EGFR TKIs agent. This study is composed of 4 parts; part A is a dose escalation phase, part
B is a dose expansion phase, part C is a dose extension phase and part D is for patients outside
Korea. NOTE: Study Parts A, B, and C are sponsored by Yuhan Corporation under protocol
identifier YH25448-201, and Study Part D is sponsored by Janssen Research & Development
under protocol identifier 73841937NSC2001.
In dose escalation phase, YH25448 will be escalated to reach either a maximum tolerated or
absorbable dose in patients as defined by dose-limiting toxicity in NSCLC patients who
progressed following prior EGFR TKIs treatment to evaluate the safety and tolerability. In dose
expansion phase, further safety, tolerability, PK and efficacy will be evaluated at each dose
level(s) of dose escalation phase in NSCLC patients who progressed following prior EGFR
TKIs treatment and harbouring confirmed T790M mutation. In dose extension phase, additional
2 cohorts (2nd line therapy cohort and 1st line therapy cohort) will be enrolled to further assess
the efficacy, safety, tolerability, and PK of YH25448 at the MTD or recommended dose (RD)
defined through dose escalation phase and dose expansion phase. Results of these studies will
serve as the evidence for further clinical development.
This study will also characterize the metabolite(s) profile of YH25448 and determine PK of its
metabolite(s) in biological samples if necessary. Also, exploratory correlation between
biomarker profiles and pharmacokinetics/pharmacodynamics will be analyzed.
Part D: Overall Study Rationale and Design in Patients Outside Korea
This is a phase I/II, open-label, multicenter study of YH25448 administered orally in patients
outside Korea with EGFRm+ NSCLC with or without asymptomatic brain metastasis. An
ethnicity study (Study YH25448-101), using the current RP2D of 240 mg in 12 Caucasian (3
Russian, 4 Turkish, 4 Moroccan, and 1 French) and 12 Korean healthy volunteers all enrolled
from Korea, showed that the AUClast and Cmax  were respectively 40% and 30% lower in
Caucasian compared to Korean subjects. Consequently, additional dose testing is required to
support the RP2D in Caucasians outside Korea. Based on current PK data from this study (Study
YH25448-201) of patients with EGFRm+ NSCLC, increasing the dose of YH25448 from 240
mg to 320 mg increases both the AUCss and Cmax,ss by about 20%. The 320 mg dose and has
been shown to be safe in 5 Korean patients with no dose limiting toxicity (DLT). As of the data
cutoff date of 26 Nov 2018, there were no treatment discontinutions due to AE at 320 mg cohort
and the dose appears to be safe and tolerable. Comparing safety in the 320 mg (n 5) vs 240 mg
(n 24) cohort, all grade adverse drug reactions (ADRs) were similar in both dose cohorts with
pruritis, rash, decreased appetite and muscle spasms the most frequent. One patient with ADR
of Grade 3 pneumonitis was reported in the 240 mg dose cohort. No ADR with Grade ≥3 was
reported in the 320 mg cohort. In conclusion: 1) no DLT was observed at the 240 and 320 mg
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dose and 2) the overall safety profile was similar between 240 and 320 mg dose.
In Part D, YH25448 will be given to patients outside Korea, including Caucasians, at the current
RP2D of 240 mg and 320 mg in order to evaluate safety, tolerability, efficacy (including tumor
response) and PK in patients outside of Korea.
1.4. Overall Risk/Benefit Assessment
1.4.1. Potential benefits
Non-clinical data demonstrated that YH25448 exerts anti-proliferative and pro-apoptotic
activity in tumor models harboring EGFR single activating or T790M double mutations.
Therefore, YH25448 may have the potential to provide clinical benefit both in terms of
increased efficacy and decreased EGFR wild type toxicity in patients with advanced EGFRm+
NSCLC who are either treatment-naïve or who have had disease progression after treatment
with an EGFR TKIs agent (+/- additional chemotherapy) and are diagnosed with T790M+
NSCLC. In the first line treatment population, YH25448 may have the potential to delay the
development of EGFR TKIs resistance via the T790M mechanism.
Results from Part A and Part B of the current study as of 26 November 2018 in 127 Korean
patients with EGFRm+ NSCLC were determined by independent central review, and are
presented in the table below.
Table 3. Summary of tumor response (Independent central review)
All Patients 
T790M+ Patients 
T790M- Patients
Number of evaluable 
patients
127 
108 
19
ORR  
54%  
57% 
37%
Median PFS (months) 
9.5 
9.7 
5.4
1.4.2. Potential risks
Section 1.2 of this protocol summarizes potential risks based upon non-clinical toxicity studies
with YH25448 in rats and dogs, and in vitro experiments, with further detailed information
available in the IB.
The monitoring and management of the potential risks is discussed below:
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Gastrointestinal tract effects
Patients with refractory nausea, vomiting and chronic gastrointestinal diseases are excluded
from participating in this study. Investigators will also be advised to follow the dose interruption
and reduction as detailed in Section 5.4.
Dermatological effects
No specific dermatological exclusion criteria are included in this study, however, patients with
any unresolved adverse event from prior therapy greater than CTCAE Grade 1 will be excluded
from participation. Dermatological treatment should be instituted for patients with any CTCAE
grade skin reactions, considered by the investigator to be causally related to
YH25448.Investigators will also be advised to follow the dose interruption and reduction as
detailed in Section 5.4. Photographs may be performed to record any clinically significant
findings. These photographs should be available for review by the Sponsor if necessary.
Ocular surface effects
Ophthalmic assessment, including slit lamp examination, fundoscopic examination, eye
examination and other tests by investigator’s judgement will be performed at screening and
should be repeated if a patient experiences any visual symptoms (including blurring of vision),
with additional tests if clinically  indicated by per investigator’s judgement. Any clinically
significant findings, including those confirmed by the ophthalmologist must be reported as an
AE. Photographs should be performed to record any clinically significant findings. These
photographs should be available for review by the Sponsor if necessary.
Ophthalmology examination results should be collected in the eCRF. Any patient developing
corneal ulceration will be permanently discontinued from study treatment and should be
followed regularly until resolution of the event.
Patients who wear contact lenses will be advised to discontinue wearing lenses if they have any
mild to moderate eye symptoms (CTCAE grade ≤2) while receiving treatment with YH25448
until at least one week after symptoms have resolved. If a patient has a recurrence of eye
symptoms or experiences any severe (CTCAE grade ≥3) ocular events they should discontinue
wearing their contact lenses until at least one week after treatment with YH25448 is
permanently discontinued. To monitor the progress, patients must not use any eye drops or
ointment for treatment of eye symptoms, unless agreed by a investigator, at any time during the
study until 1 week after YH25448 has been permanently discontinued. Patient will be advised
to consult the clinic promptly if they have any eye symptoms.
Cardiovascular effects
Patients who have unstable cardiac conditions and risk factors for QT prolongations will be
excluded from participation in this study. Concomitant use of regular medications that may
prolong the QT interval will be restricted whenever feasible (See appendix G), but patients may
receive any medication that is clinically indicated for the treatment of AEs. Electrolyte and vital
sign assessments, including pulse rate and blood pressure, will be monitored regularly
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throughout the study. A series of triplicate digital ECG assessments will be performed over a
24 hour period before/after the first single dose of YH25448, over a 24 hour after 22-day
multiple dosing (Day 1 Cycle 2) and at the time of presumed steady state (Day 8 and Day 15
Cycle 1), with single ECGs being recorded at the beginning of each subsequent treatment cycle,
as described in Section 6.2.4. The investigator or designated physician will review each ECG
prior to discharge from the clinic and may refer to a local cardiologist if appropriate for
immediate management of the patient. A paper copy should be filed in the patient’s medical
records. All digital ECG data will be transferred electronically for central analysis of heart rate,
PR, R-R and QT intervals by an external cardiologist. If an abnormal ECG finding at screening
or baseline is considered to be clinically significant by the investigator, it should be reported as
a concurrent condition.
Echocardiography (or Multiple Gated Acquisition Scan (MUGA)) and troponin I (TnI) test will
be performed regularly throughout the study until the primary  database lock  and with the
process described in detail in appendix B.
Respiratory effects
Patients with a past medical history of interstitial lung disease, drug-induced interstitial lung
disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically
active interstitial lung disease will be excluded from participation in this study. If new or
worsening pulmonary symptoms (eg, dyspnoea) or radiological abnormality suggestive of
interstitial lung disease is observed, an interruption in study treatment dosing is recommended,
and the Sponsor study team should be informed. Investigators should perform a full diagnostic
workup, to exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy,
cardiogenic edema, or pulmonary hemorrhage. In the presence of confirmatory HRCT scans
where other causes of respiratory symptoms have been excluded, a diagnosis of interstitial lung
disease should be considered and study treatment permanently discontinued.
In the absence of a diagnosis of interstitial lung disease study treatment may be restarted
following consultation with the Sponsor Study Physician.
Liver effects
Patients with any evidence of severe or uncontrolled systemic liver disease, including those
with known hepatitis B, hepatitis C, abnormal liver enzymes (defined as AST or ALT >2.5 x
upper limit of normal (ULN), total bilirubin >1.5 x ULN if no evidence of liver metastases;
AST or ALT >5 x ULN, total bilirubin >3 x ULN in the presence of liver metastases) at
screening are excluded from participating in the study. During the study, liver function tests will
be monitored regularly during the study and recorded at discontinuation. For Parts A, B and C:
After the primary database lock, Liver function tests will be performed as clinically indicated
per investigator discretion. The process described in detail in appendix A.
For Part D: After the primary database lock, please refer to the Schedule of Activities.
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Hematopoietic effects
Patients with inadequate bone marrow reserve as demonstrated by any of the following
laboratory values (absolute neutrophil count < 1.5 x 109/L; platelet count < 100 x 109/L;
haemoglobin <90 g/L) will be excluded from the study. Hematological parameters will be
monitored during the study and at permanent discontinuation. For Parts A, B and C: After the
primary database lock, hematology will be performed as clinically indicated per investigator
discretion.
For Part D: After the primary database lock, please refer to the Schedule of Activities.
Renal Effects
Patients with abnormal renal function as defined by creatinine >1.5 x upper limit of normal
(ULN) concurrent with creatinine clearance < 50 mL/min at screening are excluded from
participating in the study. During the study, kidney function tests (serum creatinine and blood
urea nitrogen) will be monitored regularly during the study and recorded at discontinuation. As
one case of suspected unexpected serious adverse reaction which is acute renal failure was
reported during the study, this will be closely monitored. For Parts A, B and C: After the
primary database lock, kidney function tests will be performed as clinically indicated per
investigator discretion.
For Part D: After the primary database lock, please refer to the Schedule of Activities.
Reproductive organ effects
No reproductive toxicology or teratogenicity studies have been conducted with YH25448 to
date, although the male and female reproductive tracts have been assessed as part of the 1 month
toxicology studies. Therefore women of child bearing potential and all men will be required to
use adequate contraceptive measures during the study and for an appropriate period thereafter.
Women of child bearing potential must have a negative pregnancy test prior to first dose of
study treatment. Women who are breast feeding will be excluded from participating in the study.
Male patients will be advised to arrange for the freezing of sperm samples prior to the start of
the study should they wish to father children, and not to donate sperm until 3 months after
discontinuation of study treatment.
Possible drug-drug interactions
In In vitro studies, the major biotransformation pathway of YH25448 is CYP3A4-mediated
metabolism. Hence, all patients must avoid concomitant use of medications, herbal supplements
and/or ingestions of foods with known potent inducer or inhibitory effects on CYP3A4 activity
whenever feasible. Such drugs must have been discontinued for an appropriate period before
they administer the first dose of study treatment and for a period of 1 week after the last dose
of YH25448. In vitro studies have shown that, YH25448 is an inhibitor of P-glycoprotein (P-
gp), MRP4 and Breast Cancer Resistance Protein (BCRP). Therefore, medications, herbal
supplements and/or ingestions of foods with known potent substrate of P-gp, MRP4 or BCRP
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recommended to be avoided whenever feasible. Guidance on medications to avoid, medications
that require close monitoring and on washout periods is given in appendix G. If medically
feasible, patients taking regular medication, with the exception of inhibitors or inducers of
CYP3A4 should be maintained on them throughout the study period. Patients may receive any
medication listed in appendix G that is clinically indicated for treatment of adverse events.
Part D: Potential Risk Evaluation
As of 26 Nov 2018, the safety tolerability, efficacy and PK of YH25448 have been evaluated in
approximately 127 patients enrolled in Korea in dose escalation (Part A) and expansion phases
(Part B) and 67 patients in the dose extension phase at 240 mg QD (Part C). YH25448 was
found to be well tolerated with no dose limiting toxicity up to a maximum of 320 mg per day.
For a review of safety please see the Investigator’s Brochure. The recommended Phase 2 dose,
based on an assessment of safety, efficacy and PK, is 240 mg per day.
Based on current PK data from this study (Study YH25448-201) of patients with EGFRm+
NSCLC, increasing the dose of YH25448 from 240 mg to 320 mg increases both the AUCss and
Cmax,ss by about 20%. The 320 mg dose and has been shown to be safe in 5 Korean patients with
no dose limiting toxicity (DLT). As of the data cutoff date of 26 Nov 2018, there were no
treatment discontinutions due to AE at 320 mg cohort and the dose appears to be safe and
tolerable. Comparing safety in the 320 mg (n 5) vs 240 mg (n 24) cohort, all grade adverse
drug reactions (ADRs) were similar in both dose cohorts with pruritis, rash, decreased appetite
and muscle spasms the most frequent. One patient with ADR of Grade 3 pneumonitis was
reported in the 240 mg dose cohort. No ADR with Grade ≥3 was reported in the 320 mg cohort.
In conclusion: 1) no DLT was observed at the 240 and 320 mg dose and 2) the overall safety
profile was similar between 240 and 320 mg dose. Therefore, based on the safety and
tolerability observed in Korean patients, as well as the lower systemic exposure observed in
Caucasian subjects, it is predicted that dosing Caucasian patients with YH25448 at 240mg and
320 mg (Part D) will have an acceptable benefit/risk profile.
1.4.3. Overall benefit-risk and ethical assessment
Non-clinical data of YH25448 support the notion that it will provide clinical benefit to the
NSCLC patients with  either activating EGFR mutations or T790M mutation. Especially,
YH25448 is expected to can satisfy unmet medical needs for the treatment of NSCLC with
brain metastasis. The non-clinical safety profile has not identified any risks that would preclude
investigation in this setting. An overall evaluation of the nonclinical data indicates an acceptable
risk/benefit profile for YH25448 to be further investigated in this study.
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2. STUDY OBJECTIVES
2.1. Primary Objective (Parts A, B, and C)
To evaluate the safety, tolerability and efficacy of YH25448 when given orally to patients with
EGFRm+ locally advanced or metastatic NSCLC.
2.2. Secondary Objectives (Parts A, B, and C)
To define the maximum tolerated dose (MTD), if possible, a dose/exposure predicted to result
in anti-tumor activity and maximum absorbable dose (MAD).
To characterize the pharmacokinetic (PK) profiles of YH25448 and its potential metabolites,
including M7, following a single oral dose and at steady state.
Dose Escalation and Expansion phases:  To obtain a preliminary assessment of the anti-
tumor activity of YH25448 by evaluation of objective response rate (ORR), duration of
response (DoR), disease control rate (DCR), tumor shrinkage and progression free survival
(PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Dose Extension phase: To obtain additional assessments of the anti-tumor activity ofYH25448
by evaluation of DoR, disease control rate (DCR), tumor shrinkage and PFS using RECIST 1.1
as assessed by an independent central review of radiological information and overall survival
(OS).
2.3. Primary and Secondary Objectives of Part D: Applies to patients enrolled
outside Korea
Primary Objective:
To evaluate the safety, tolerability and PK of YH25448 when given orally to patients with
EGFRm+ locally advanced or metastatic NSCLC.
Secondary Objectives:
To characterize the PK profiles of potential YH25448 metabolites in plasma, including M7,
following a single oral dose and at steady state.
To obtain additional assessments of the anti-tumor activity of YH25448 by evaluation of ORR,
DoR, DCR, tumor shrinkage and PFS using RECIST 1.1 as assessed by investigator review of
radiological information and OS.
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2.4. Exploratory Objectives
Parts A, B, and C
To collect and store plasma for potential exploratory research of blood born biomarkers into
factors that may influence development of NSCLC and/or response to YH25448 (where
response is defined broadly to include efficacy, tolerability or safety).
To collect and store deoxyribonucleic acid (DNA) for future exploratory research into
genes/genetic variation that may influence PK or response (i.e. absorption, distribution,
metabolism, excretion, safety, tolerability and efficacy) to YH25448 treatment and or
susceptibility to cancers.
To collect and store diagnostic tumor sample and any fresh tumor biopsies for potential future
exploratory research into factors that may influence development of NSCLC and/or responses
to YH25448 (where response is defined broadly to include efficacy, tolerability or safety).
To collect patient reported outcomes (PRO) data to explore disease-related symptoms and
health related quality of life (HRQoL).
To assess the relationship between PK and selected efficacy, pharmacodynamic and/or safety
endpoints, where deemed appropriate.
To characterize the PKprofiles of YH25448 and its potential metabolites, including M7, in CSF.
To collect and store residual CSF for potential exploratory research of factors that may influence
development of NSCLC and/or response to YH25448 (where response is defined broadly to
include efficacy, tolerability or safety).
Part D
To collect deoxyribonucleic acid (DNA) for exploratory research into genes/genetic variation
that may influence PK or response (i.e. absorption, distribution, metabolism, excretion, safety,
tolerability and efficacy) to YH25448 treatment and or susceptibility to cancers. The specific
objective of the pharmacogenetic assessment is to investigate genetic variants of the
Glutathione S-Transferase Mu 1 (GSTM1) genotypes affecting the disposition of YH25448 and
to understand the correlation of GSTM1 genetic variants with PK and safety and tolerability.
3. ETHICAL CONSIDERATIONS
3.1. Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by
the International Conference on Harmonization (ICH) and relevant local regulations
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The study is to be conducted in compliance with the protocol. The protocol and any
amendments and the Patient informed consent must receive Institutional Review Board (IRB)
approval prior to initiation of the study.
All potential serious violations must be reported to the Sponsorimmediately. A serious violation
is a violation  of the conditions and principles of GCP in connection with the study or the
protocol, which is likely to affect, to a significant degree, the safety or physical or mental
integrity of the patients of the study or the scientific value of the study.
Study personnel involved in the conduct of this study must be qualified by education, training,
and experience for the appropriate performance of their respective task(s).
This study will not use the services of study personnel where sanctions have been invoked or
where there has been scientific misconduct or fraud (e.g. loss of medical licensure, debarment).
Systems with procedures that assure the quality of every aspects of the study will be
implemented.
3.2. Institutional Review Board/Ethics Committee
Prior to study initiation, the investigator must obtain written and dated approval from the
IRB/EC  for the protocol, consent form, Patient recruitment materials/process (e.g.
advertisements), and any other written information to be provided to patients. The investigator
or Sponsor should also provide the IRB/EC with a copy of the IB, as well as updates and other
information (e.g. expedited safety reports, amendments, and administrative letters) in
accordance with regulatory requirements or institution procedures.
3.3. Informed Consent
Investigators must ensure that patients or in situations where consent cannot be given by
patients, their legally acceptable representatives are clearly and fully informed about the
purpose, potential risks, and other critical issues regarding clinical studies in which they
volunteer to participate. Freely given written informed consent must be obtained from every
patient (or in situations where consent cannot be given by patients, their legally acceptable
representative) prior to clinical study participation, including informed consent for any
screening procedures conducted to establish patient eligibility for the study. And investigators
ensure that each patient is notified that they are free to withdraw from the study at any time and
ensure a copy of each signed Informed Consent Form is given to the patient.
The rights, safety, and well-being of the study patients are the most important considerations
and should prevail over interests of science and society. 
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4. INVESTIGATIONAL PLAN
4.1. Study Design and Rationale
4.1.1. Rationale for dose regimen, dose escalation scheme
The predicted efficacious dose range (20-160 mg) for the dose escalation phase (Part A) of the
first-in-human study is based on the nonclinical PK and repeat-dose toxicology studies in
several animal species as well as the mouse efficacy study data in conjunction with in vitro
inhibition of ≥50% pEGFR signals in H1975 (L858R/T790M) cell lines; at which equivalent
exposure in mice, tumor regression was achieved in xenograft tumors both subcutaneously and
in the brain.
The international guidance for starting dose selection for agents in cancer patients (ICH S9)7
recommends that the starting dose should be either 1/10th of the severely toxic dose (STD10)
in rodent toxicity studies or 1/6th of the highest non-severely toxic dose (HNSTD) observed in
non-rodent studies. Based on the findings in non-clinical GLP tox studies, in which dogs are
defined as the most sensitive species, 10 mg/kg/day (HNSTD for male dogs) has been used in
the calculation for human dose prediction. In rats, the STD10 was 100/75 mg/kg/day from the
1-month study. Using the conversion factors published on the FDA website8 (FDA Guidance
2005), the maximum recommended starting dose (MRSD) derived from 1/10th of the rat STD10
was calculated to be 72 mg/day, whilst the MRSD derived from 1/6th of the dog HNSTD in
male was calculated to be 53 mg/day. As a result of using the most conservative data, a starting
dose of 53 mg/day is proposed for this study. Biologically active dose (BAD) which was
defined as dose exhibits 90% tumor growth regression in the NSCLC H1975 intracranial tumor
models in mice was 8.8 mg/kg/day for YH25448. This corresponds to human equivalent dose
(HED) of 42.8 mg in adults. Therefore, the 20 mg starting dose is anticipated biologically active
and covers pEGFR IC50 of H1975 cells for 24 hours. The proposed highest dose of 160 mg is
twofold lower than maximum tolerated dose determined in 4-week toxicity study in dogs as
the most sensitive species. The dose escalation scheme will not exceed doubling of the dose,
in principle. However, up to a quadrupling of the dose may be permitted in the first two
escalations only, if the drug concentrations from the first or second dose level are not
measurable or are below the predicted target drug exposure for biological effect. This will
ensure that the fewest possible cohorts are exposed to YH25448 below the presumed
therapeutic dose. Non-clinical modeling provides only an approximate prediction of human PK,
therefore the planned dose escalation scheme has the flexibility to be amended in light of
emerging data.
As this is the first administration of YH25448 in humans, in the first cohort the administration
of the first dose is separated by at least 7 days for the first 2 patients. This will ensure that any
acute toxic effects of the administration will have sufficient time to be identified before
additional patients are exposed. Once the completion of dosing of Cycle 1 in the last required
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evaluable patient from one cohort, the start of dosing in the subsequent cohort in order for the
SRC meeting to be called, and minutes of the dose escalation decisions to be distributed to all
participating centers.
Part D: Overall Study Rationale and Design in Patients Outside Korea
This is a phase I/II, open-label, multicenter study of YH25448 administered orally in patients
outside of Korea with EGFRm+ NSCLC with or without asymptomatic brain metastasis. An
ethnicity study (Study YH25448-101), using the current RP2D of 240 mg in 12 Caucasian
(3 Russian, 4 Turkish, 4 Moroccan, and 1 French) and 12 Korean healthy volunteers all enrolled
from Korea, showed that the AUClast and Cmax  were respectively 40% and 30% lower in
Caucasian compared to Korean patients. Consequently, additional dose testing is required to
support the RP2D in Caucasians outside Korea. Based on current PK data from this study (Study
YH25448-201) of patients with EGFRm+ NSCLC, increasing the dose of YH25448 from 240
mg to 320 mg increases both the AUCss and Cmax,ss by about 20%. The 320 mg dose and has
been shown to be safe in 5 Korean patients with no dose limiting toxicity (DLT). As of the data
cutoff date of 26 Nov 2018, there were no treatment discontinutions due to AE at 320 mg cohort
and the dose appears to be safe and tolerable. Comparing safety in the 320 mg (n 5) vs 240 mg
(n 24) cohort, all grade adverse drug reactions (ADRs) were similar in both dose cohorts with
pruritis, rash, decreased appetite and muscle spasms the most frequent. One patient with ADR
of Grade 3 pneumonitis was reported in the 240 mg dose cohort. No ADR with Grade ≥3 was
reported in the 320 mg cohort. In conclusion: 1) no DLT was observed at the 240 and 320 mg
dose and 2) the overall safety profile was similar between 240 and 320 mg dose.
In Part D, patients outside Korea, including Caucasians, will be dosed with the current RP2D
of 240 mg and 320 mg in order to test safety, tolerability, efficacy (including tumor response)
and PK in patients outside of Korea.
4.1.2. Study Design
This is a phase I/II, open-label, multicenter study of YH25448 administered orally in patients
with EGFRm+ NSCLC with or without asymptomatic brain metastasis. The study design allows
an escalation of dose with intensive safety monitoring to ensure the safety of the patients. It is
possible for additional dose levels to be added during the course of the study.
There are four parts to this study. Part A, Dose escalation phase, Part B, Dose expansion phase,
and Part C, Dose extension phase, and Part D, patients outside Korea.
A cycle of study treatment will be defined as 21 days of continuous dosing and the evaluation
of measurable lesion as per RECIST 1.1 will be performed at every 2 cycles. After the primary
database lock, radiological disease evaluations are not required and may be performed at the
discretion of the investigator in accordance with local standard of care.
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Figure 1. Study Design
RD : recommended dose
BrM : brain metastasis
Part A : Dose Escalation Phase
The part A will determine the MTD or MAD of YH25448 for max. 6 patients of each cohort
based upon assessment of the safety, tolerability and PK data collected during the first 21 days
of daily dosing in patients experienced clinical benefit from EGFR TKIs followed by
progression disease while on continuous treatment with the authorized EGFR TKIs prior to
enrolling in the study.
For the evaluating ofDLT, at least 3 and up to 6 patients will be required for each cohort. It is
possible to evaluate for additional dose cohort according to the necessity of dose escalation or
dose de-escalation.
For PK assessment of single and multiple doses, patients will receive a single dose on Day 1
Cycle 0 then after 7±2 days washout, multiple dosing, once daily will be initiated. PK blood
samples will be collected over 60 hours after single dose. In the first cohort administration of
the first dose will be separated from the start dosing of the subsequent patients by at least 7 days
for the first patient. Dosing frequency (e.g. bid) may be adjusted during the study on the basis
of emerging safety and PK data. Trough plasma concentrations will be measured at each visit
during Cycle 1, and PK evaluation at steady state will be performed over 24 hours after the first
administration in Cycle 2.
Dosing for cohort 1 will begin at 20 mg once daily.
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Dose escalation and de-escalation will follow the scheme below, according to the following
logic:
 
Dose limiting toxicity (DLT) will be assessed once the first three patients completed Cycle 1
(i.e. 21 days).
 
If no DLT is observed in a cohort of 3-6 evaluable patients then dose escalation may occur
(see Table 4). Dose increases will be permitted after the review of safety data from a minimum
of 3 evaluable patients has been performed.
 
If one patient experiences a DLT in a group of 3 or more evaluable patients then the cohort
will be expanded to include 6 evaluable patients. If only one DLT is observed in the complete
cohort of 6 evaluable patients then dose escalation may occur.
 
If 2 or more patients experience a DLT in a group of at least 3 patients up to 6 patients, the
dose will be considered not tolerated and recruitment to the cohort and dose escalation will
cease. A lower dose or a lower intermediary dose (de-escalation, see Table 5) may be
considered in order to better define the MTD.
 
If 2 or more patients experience a DLT in a group of up to 6 patients at the starting dose of 20
mg then 10 mg would be investigated.
 
Prior to achieving MTD, the maximum absorbable dose is achieved (i.e. when no increase in
exposure with increasing dose is observed), the scheduling of dose escalation or dose de-
escalation can be changed.
 
Prior to a dose escalation or de-escalation decision, the Safety Review Committee (SRC) will
review all available safety and PK data.
 
Dose escalation will not exceed doubling of the dose in principle.
The provisional dose escalation and de-escalation scheme is described in Table 4 and 5,
respectively. All dose levels beyond cohort 1 may change in light of emerging safety, tolerability
and PK data.
Table 4. Provisional dose escalation scheme
Cohort
Dose (mg)
(to be administered once daily)
1 
20
2 
40
3 
80
4 
120
5 
160
X 
Xxx
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Table 5. Dose de-escalation scheme
Dose at time of toxicity (mg) 
(to be administered once daily) 
Lower intermediary dose* (mg)
(to be administered once daily)
320 
260
240 
200
160 
140
120 
100
80 
60
40 
30
20 
10
* Lower intermediary dose: The middle dose between assigned dose level and lower dose level.
Part B: Dose Expansion Phase
Part B will be conducted to assess safety, tolerability, efficacy and PK of YH25448 for
approximately 20 evaluable patients per each cohort with T790M+ who have experience in the
authorized EGFR TKIs therapy followed by progression disease prior to enrolling in the study
regardless of whether BrM has occurred or not (See Figure 1).
Trough plasma concentrations will be measured at each visit during Cycle 1, and PK evaluation
at steady state will be performed over 24 hours after the first administration in Cycle 2.
Each dose cohort of part B will be started to enroll the patient after confirmation of safety data
for each corresponding dose cohort of part A. SRC will determine the change of dose level and
decide to stop patients enrollment based on emerging data from expansion phases.
Part C: Dose Extension Phase
Once the MTD or RD is determined for Part C as a result of the overall evaluation of the results
of Part A and B and after reflection of this result in the protocol or IB, additional 2 cohorts of
100 evaluable patients will be enrolled to assess the efficacy, safety and tolerability of YH25448.
Trough plasma concentrations for PK evaluation will be measured at each visit during Cycle 1.
1) 2nd  line therapy Cohort
The efficacy and the tolerability of YH25448 will be assessed for approximately 60
patients with T790M+ who have received the authorized EGFR TKIs treatments and
whose progression of the disease has been confirmed after recent treatment regardless of
BrM occurence.
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2) 1st line therapy Cohort
Approximately 40 patients with EGFRm+ NSCLC who are EGFR TKI-naïve regardless
of BrM occurence will be enrolled to assess the efficacy and tolerability of YH25448. 
Part D:Patients Outside Korea
As of 26 Nov 2018, the safety tolerability, efficacy and PK of YH25448 have been evaluated in
approximately 127 patients enrolled in Korea in dose escalation and expansion phases.
YH25448 was found to be well tolerated with no dose limiting toxicity up to a maximum of
320 mg per day. The recommended Phase 2 dose, based on an assessment of safety, efficacy
and PK, is 240 mg per day.
The goal of Part D is to test the safety, tolerability, efficacy and PK of YH25448 at the 240 mg
and 320 mg dose levels in patients enrolled outside Korea. Approximately 12-15patients will
be enrolled at each dose level to provide a minimum of 6 Caucasian patients with evaluable PK. 
Although enrollment will not be based on race, it is expected that approximately 80% of patients
will be Caucasian.
Patients outside Koreawill be enrolled into the 240 mg and 320 mg Cohort on an alternating
basis, Management of individual patient toxicity will be according to Section 5.4.1.3.
4.1.3. Definition of dose-limiting toxicity
A DLT is defined as an adverse event or abnormal laboratory value that occurs from the first
dose of study treatment (Day1, Cycle 0) up to the last dose of Cycle 1 (21 days from the start
of multiple dosing) assessed as unrelated to disease progression, intercurrent illness, or
concomitant medications that despite optimal therapeutic intervention meets any of the
following criteria:
1) Hematological toxicity that is:
- ≥ CTCAE grade 4 present for more than 4 days.
- 
Febrile neutropenia.
2) Non-hematological toxicity ≥ CTCAE grade 3 including:
- QTc prolongation (>500msec or 60msec above baseline).
3) Any other toxicity that :
- Is greater than that at baseline, is clinically significant and/or unacceptable, and is judged
to be a DLT by the SRC.
- Is a protocol defined in  toxicity management, see Section  5.4 (e.g. confirmed corneal
ulceration).
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- Result in a disruption of dosing schedule more than 14 days.
A DLT excludes:
1) Alopecia of any grade.
2) Isolated laboratory changes of any grade without clinical sequelae or clinical significance.
The incidence and type of DLT-type toxicity from Cycle 2 and beyond will be taken into
account by SRC in determining dose escalation and de-escalation.
4.1.4. Definition of maximum tolerated dose
A dose will be considered non-tolerated and dose escalation will cease if 2 or more of up to 6
evaluable patients experience a DLT at a dose level. Once the non-tolerated dose is defined the
MTD will be confirmed at the lower dose or the lower intermediary dose level below the non-
tolerated dose may be investigated. Six evaluable patients are required to determine the MTD.
4.1.5. Definition of evaluable patients for DLT
For decision of dose escalation, an evaluable patient is defined as a patient that has received
YH25448 and either:
 
has completed safety evaluation requirement during the single dose period and over the first
21 days of continuous dosing or has experienced a DLT during the single dose period or the
first 21 days of continuous dosing.
 
has taken study drugs over 14 days during the first 21 days of continuous dosing.
4.1.6. Duration of therapy
Patients should continue on treatment with YH25448 until RECIST 1.1 defined progression or
until treatment discontinuation criteria is met. There is no maximum duration of treatment as
patients may continue to receive YH25448 beyond RECIST 1.1 defined progression as long as
they are continuing to show clinical benefit, as judged by the investigator.
However, tumor assessment will not be performed if patients continuously take YH25448
without dose escalation after progression. If patients continue to receive the study drug after
intracranial lesion has shown clinical benefit regardless of progression for extracranial lesion,
tumor assessment will be continued every 2 cycles until progression for intracranial lesion is
confirmed. After the primary database lock, radiological disease evaluations are not required
and may be performed at the discretion of the investigator in accordance with local standard of
care.
There will be no intra-patient dose escalation for each cohort, but if the dose escalation is
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required for the patients as judged by the investigator in the dose escalation and expansion
phase, the dose escalation must be determined by both the Sponsor Study Physician and the
investigator in advance. Tumor assessment can be performed until progression is confirmed
after dose escalation.
Dose increase is available only if disease is progressing after showing clinical benefit and the
escalated dose will be permitted within the range which is determined after the review of safety
and toxicity data. If YH25448 is discontinued for reasons other than disease progression, the
patient must continue RECIST  1.1 assessments every 2 cycles until disease progression  or
further lines of anticancer therapy are administered (with exception of Part A) After the primary
database lock, radiological disease evaluations are not required and may be performed at the
discretion of the investigator in accordance with local standard of care.
4.2. Study Population
Each patient must meet all of the inclusion criteria and none of the exclusion criteria for this
study at the time of starting study treatment. Under no circumstances can there be exceptions
to this rule.
4.2.1. Inclusion Criteria
For inclusion in the study, patients must fulfill all of the following criteria.
1. Signed Written Informed Consent
1) Provision of signed and dated, written informed consent prior to any study specific
procedures, sampling and analyses. For inclusion in optional genetic and/or biomarker
research, patients must provide informed consent for the research.
2. Age and Sex
1) At least 20 years of age and older or adult men and women for each country.
2) Females should agree to use adequate contraceptive measure (as defined in Section 4.2.3),
should not be breast feeding and must have a negative pregnancy test prior to start of
dosing if of child-bearing potential or must have evidence of non-child-bearing potential
by fulfilling one of following criteria at screening:
 
Post-menopausal defined as aged more than 50 years and ameorrhoeic for at least 12
months following cessation of all exogenous hormonal treatments.
 
Documentation of irreversible surgical sterilization by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy but not tubal ligation.
 
Women under 50 years old would be considered postmenopausal if they have been
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ameorrhoeic for at least 12 months following cessation of exogenous hormonal
treatment, and have serum follicle-stimulating hormone (FSH) and luteinizing
hormone (LH) levels in postmenopausal range for the institution.
3) Male patients who have not undergone a vasectomy must agree to use barrier
contraception i.e. condoms, and refrain from donating sperm until 3 months after last drug
is taken.
4) During the study, and for 3 months after receiving the last dose of study drug, female
patients must agree not to donate eggs (ova, oocytes) and male patients must agree not to
donate sperm for the purposes of assisted reproduction.
3. Target disease
1) Parts A, B and C only: Histologically or cytologically(i.e., pleural effusion, ascites cases)
confirmed diagnosis of NSCLC with single activating EGFR mutations (L858R or
Exon19Del or G719X or L861Q). EGFR mutation status should have been determined
using well-validated and robust methodology which has been approved by the regulatory
authority. In the country where diagnosis of EGFR mutation does not need to use
regularity approved kit, well-validated methodology will be used.
A. In Part D: Patients outside Korea with histologically or cytologically (ie, using
pleural effusion, ascites) confirmed NSCLC with previously diagnosed EGFRm+,
and who have had progressive disease on prior EGFR-TKI therapy.
2) Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no
deterioration over the previous 2 weeks and a minimum life expectancy of 3 months.
3) Patients who have at least one measurable extracranial lesion, not previously irradiated
and not chosen for biopsy during the study screening period or one measurable lesion that
has passed 14 days or more after biopsy, that can be accurately measured at baseline as ≥
10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm)
with computerized tomography (CT) or magnetic resonance imaging (MRI), are suitable
for accurate repeated measurement.
4) In Part A, patients who had experienced clinical benefit from EGFR TKIs followed by
systemic objective progression while on continuous treatment with the authorized EGFR
TKIs. Prior to enrolling in the study, patients must have central confirmation of T790M+/-
mutation status from a sample taken after progression disease on the EGFR-TKIs therapy.
5) In Part B, patients who have been treated with the authorized EGFR TKIs and must be
confirmed progression disease prior to enrolling in the study. Patients must have central
confirmation of T790M+ mutation from a sample taken after progression disease on the
therapy recently.
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6)
In Part C-1st line therapy cohort, patients must have not received any EGFR-TKIs prior
to enrolling in the study, and EGFR mutation status must be confirmed as positive by a
qualified institutional laboratory or a central laboratory.
7)
In Part C-2nd  line therapy cohort, patients who have been treated with the authorized
EGFR TKIs and must be confirmed progression disease prior to enrolling in the study.
Patients must have T790M mutation positive(+) from a sample taken after progression
disease on the recent therapy which is confirmed by local or central lab using the method
approved by MFDS. However, if the T790M mutation is confirmed locally, the collected
tumor sample must be submitted for central confirmation before the enrollment.
4.2.2. Exclusion Criteria
Patients must not enter the study if any of the following exclusion criteria are fulfilled.
1. Intervention with any the following:
1) An unapproved investigational product from another clinical study within 30 days of the
first dose of study treatment.
2) Treatment with an EGFR TKIs (e.g. erlotinib or gefitinib) within 8 days or approximately
5x half-life, whichever is the longer, of the first dose of study treatment or other
investigational products within approved indication of marketed product (if sufficient
wash-out time has not occurred due to schedule or PK properties, an alternative
appropriate wash-out time based on known duration oftime to reversibility of drug related
adverse events could be agreed upon by the Sponsor and the Investigator).
3) Any cytotoxic chemotherapy or other anticancer drugs for the treatment of advanced
NSCLC from a previous treatment regimen within 14 days of the first dose of study
treatment.
4) Major surgery (excluding for vascular access) within 4 weeks of the first dose of study
treatment, or have an anticipated need for major surgery during the study.
5) Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited
field of radiation for palliation within 1 week of the first dose of study treatment with the
exception of patients receiving radiation to more than 30% of the bone marrow which
must be completed within 4 weeks of the first dose of study treatment.
6) Patients currently receiving (or unable to stop use at least 1 week prior to receiving the
first dose of YH25448) medications or herbal supplements known to be inhibitors or
inducers of CYP3A4.
7) Any unresolved toxicities from prior therapy, greater than Common Terminology Criteria
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for Adverse Events (CTCAE) grade 1 at the time of starting 1st study treatment with the
exception of alopecia.
8) EGFR TKIs administration to treat T790M resistance mutant (For Parts A, B and C
only).
2.  Medical History and Concurrent Disease
1) Symptomatic spinal cord compression (if steroid treatment is not required within at least
2 weeks prior to the start of the study treatment then the patient may be enrolled).
2) Brain metastases with symptomatic and/or requiring emergency treatment (e.g. Steroid for
at least 2 weeks prior to start of study treatment).
3) Intracranial hemorrhage with symptomatic and/or requiring treatment
4) CNS complications that require urgent neurosurgical intervention (e.g. resection or shunt
placement).
5) Leptomeningeal metastasis prior to study treatment.
6) Past medical history of interstitial lung disease (ILD), drug-induced IDL, radiation
pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
7) Carcinoma besides NSCLC requiring treatment or any evidence of severe or uncontrolled
systemic diseases, including uncontrolled hypertension and active bleeding diatheses,
which in the investigator’s opinion makes it undesirable for the patient to participate in
trial or which would jeopardise compliance with the protocol. Screening for chronic
condition is not required.
8) Any cardiovascular disease as followed,
a) History of symptomatic CHF or serious cardiac arrhythmia requiring treatment
b) History of myocardial infarction or unstable angina within 6 months of the first dose
of study treatment
c) LVEF <50%
9) Active hepatitis with HbsAg+ or anti-HCV Ab+, confirmed positive HIV test results.
10) Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the
formulated product or previous significant bowel resection that would preclude adequate
absorption of study medication.
11) History of hypersensitivity to active or inactive excipients of YH25448 or drugs with a
similar chemical structure or class to YH25448.
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12) Clinically significant chronic infection or significant medical or psychiatric illness.
13) Judgment by investigators that the patient should not participate in the study if the patient
is unlikely to comply with study procedure, restrictions and requirements.
14) In addition, the following are considered criterion for exclusion from the exploratory
genetic research: Previous allogeneic bone marrow transplant, Non-leukocyte depleted
whole blood transfusion within 120 days of the date of the genetic sample collection.
3. 
Cardiac and Clinical Laboratory Criteria
1) Any of following cardiac criteria:
a) Mean resting corrected QT interval (QTc) > 470 msec obtained from 3
electrocardiograms (ECGs), using the screening ECG machine derived QTc value
b) Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG eg, complete left bundle branch block, third degree heart block, second
degree heart block, PR interval >250msec
c) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
such as heart failure, hypokalemia, congenital long QT syndrome, family history of
long QT syndrome or unexplained sudden death under 40 years of age in first
degree relatives or administration ofconcomitant medication known to prolong the
QT interval
2) Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values;
a) Absolute neutrophil count (ANC) < 1.5 x 109/L
b) Platelet count < 100 x 109/L
c) Hemoglobin <90g/L
d) Alanine aminotransferase (ALT) >2.5 times the upper limit of normal (UNL) if no
demonstrable liver metastases or 5 times ULN in presence of liver metastases
e) Aspartate aminotransferase (AST) >2.5 times the UNL if no demonstrable liver
metastases or 5 times ULN in presence of liver metastases
f) Total bilirubin >1.5 times ULN. If no liver metastases or >3 times ULN in the
presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or
liver metastasis
g) 
Serum creatinine >1.5 times ULN concurrent with creatinine clearance <50ml/min
measured by center’s standard method (e.g. Cockcroft and Gault equation).
Confirmation of creatinine clearance is only required when creatinine is >1.5 times
ULN
h) Unexplained inadequate liver function except ALP elevation which investigator can
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not determine on bone metastases
i)
In case of Troponin I test result finally confirmed by central lab exceeded ULN (TnI+).
In Part D, central laboratroy confirmation of TnI+ is not required.
4.2.3. Restrictions
The following restrictions apply while the patient is receiving study treatment and for the
specified times before and after:
1) Female patients of child-bearing potential should use reliable methods of contraception from
the time of screening until 3 months after discontinuing study treatment. Acceptable methods
of contraception include total and true sexual abstinence, tubal ligation, hormonal
contraceptives that are not prone to drug-drug interactions [IUS Levonorgestrel Intra Uterine
System (Mirena), Medroxyprogesterone injections (Depo-Provera)], copper-banded intra-
uterine devices and vasectomised partner. All hormonal methods of contraception should be
used in combination with the use of a condom by their male sexual partner for intercourse.
2) Female patients should not breast-feed during the trial and for at least 2 months after the last
dose of study treatment.
3) Male patients should be asked to use barrier contraceptives (i.e., by use of condoms) during
sex with all partners during the trial and for a washout period of 3 months. Patients should
avoid procreation for 3 months after completion of trial treatment. Patients should refrain from
donating sperm from the start of dosing until 3 months after discontinuing study treatment. If
male patients wish to father children they should be advised to arrange for freezing of sperm
samples prior to the start of study treatment.
4) Patients who wear contact lenses must discontinue wearing their lenses if they have any mild
to moderate eye symptoms (CTCAE grade ≤2) while receiving treatment with YH25448 until
at least one week after symptoms have resolved. If a patient has a recurrence of eye symptoms
or experiences any severe (CTCAE grade ≥3) ocular events such as corneal ulcer, they must
discontinue the administration of YH25448 permanently. To monitor the progress, patients
must not use any eye drops or ointment for treatment of eye symptoms, unless agreed by a
investigator, at any time during the study until 1 week after YH25448 has been permanently
discontinued. Patient should consult the clinic promptly if they have any concerns.
4.2.3.1. Concomitant treatments
Guidance on medicines to avoid, medications that require close monitoring and on washout
periods based on potential interactions with YH25448 are provided in appendix G.
Other anticancer agents, investigational agents and radiotherapy should not be given while the
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patient receiving study treatment. The patient may be allowed to take localized palliative
radiotherapy if it has been confirmed that there is no disease progression on the local lesion
excluding target lesion. Study drug interruption is not required in the case of local palliative
radiotherapy for pain control, but for local palliative radiotherapy to chest, study drug should
be interrupted during and up to 7 days post the palliative radiotherapy.
Blood transfusions are allowed at any time during the study.
Granulocyte colony stimulating factors shouldnot be used prophylactically during Cycle 1. Use
of prophylactic colony stimulating factors may be considered after Cycle 1 following discussion
with the Sponsor Study Physician.
Patients may receive treatment with corticosteroids and/or bisphosphonates for the treatment of
bone metastases.
Other medication, other than those described above, which is considered necessary for the
patient’s safety and well-being, may be given at the discretion of the investigator and recorded
in the appropriate sections of the eCRF. After the primary database lock, only concomitant
medications related to SAEs will be collected.
4.2.3.2. Prohibited Treatments
In In vitro studies, the major biotransformation pathway of YH25448 is CYP3A4-mediated
metabolism. Hence, all patients must prohibit concomitant use of medications, herbal
supplements and/or ingestion of foods with known potent inducer/inhibitory effects on
CYP3A4. Such drugs must have been discontinued for an appropriate period before they
administer the first dose of study treatment and for a period of 1 week after the last dose of
YH25448. In vitrostudies have shown that, YH25448 is an inhibitor of P-gp, MRP4 and Breast
Cancer Resistance Protein (BCRP). Therefore, medications, herbal supplements and/or
ingestion of foods with known potent substrate of P-gp, MRP4 or BCRP are recommended to
be avoided whenever feasible. Guidance on medicines to avoid, medications that require close
monitoring and on washout periods is to be provided in appendix G. Except inhibitor or inducer
of CYP3A4, appropriate regular concomitant medication should be maintained during the study
period. Patients may receive any medication listed in appendix G that is clinically indicated for
treatment of adverse events.
4.2.4. Discontinuation of Investigational Product and withdrawal from
Study
Patients may be discontinued from investigational product in the following situations:
 
Patient decision. The patient is at any time free to withdraw his/her participation in the study,
without prejudice
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 
Adverse events
 
Severe non-compliance to this protocol as judged by the investigator and/or Sponsor
 
Disease progression as per RECIST 1.1, in the opinion of the investigator, the patient is no
longer receiving clinical benefit.
 
Patients incorrectly initiated on investigational product (Section 4.2.4.2)
 
Pregnancy
 
Termination of the study by the Sponsor
4.2.4.1. Procedures for discontinuation of a patient from investigational
product
Once the study treatment is permanently discontinued, then it cannot be restarted.
The investigator should complete a discontinuation visit eCRF upon a patient’s discontinuation
of study treatment or withdrawal from the study, see Section 4.2.4.3.
Any AEs and SAEs occurring in any patient who discontinues study treatment for reasons other
than disease progression should be collected until 28 days of last dosing. Also, unless consent
is withdrawn, tumor assessment should be performed as scheduled in the protocol (see Table 8,
Table 9, Table 10 and Table 11) until disease progression or subsequent anti-cancer therapy.
Study procedure related SAEs and anti-cancer treatment must be captured until the patient no
longer has tumor assessments (disease progression or permanent withdrawal from the study).
After the primary database lock, there may be some patients remaining on study treatment. For
these patients who are continuing to receive YH25448, Sponsor will collect information during
the treatment period and for 28(+7) days after last dose on SAEs, deaths (including those due
to disease progression), discontinuation due to AEs/SAEs and drug accountability.
4.2.4.2. Procedures for handling patients incorrectly initiated on
investigational product
Patients who fail to meet the inclusion/exclusion criteria should not, under any circumstances,
be enrolled or receive study medication. There can be no exceptions to this rule. Where patients
that do not meet the inclusion criteria are enrolled in error or incorrectly started on treatment,
or where patients subsequently fail to meet the study criteria post initiation, the investigator
should inform the Sponsor Study Physician immediately. The decision on when to discontinue
the ineligible patient from the study is based on the medical/safety risk for the patient. The
Sponsor Study Physician is to ensure all such contacts are appropriately documented.
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4.2.4.3. Procedure for withdrawal from study
Patients are at any time free to withdraw from the study (investigational product and
assessments), without prejudice to further treatment (withdrawal of consent). Such patients will
always be asked about the reason(s) and the presence of any adverse events. If possible, they
will be seen by an investigator and undergo the assessments and procedures scheduled for the
post study assessment. For Parts A, B and C only: A separate consent form for study withdrawal
will be provided to obtain withdrawal consent from the patients, and then the procedure will be
followed as option chosen from the withdrawal consent form. (see Section  6.2.6). Adverse
events should be followed up (see Sections 7.3) and the patient should return study drug.
5. TREATMENTS
5.1. Study Treatment
Patients will receive relevant dose level of YH25448 as assigned group orally QD for 21 days
in 21-day Cycles until documented evidence of disease progression, unacceptable toxicity,
noncompliance, or withdrawal of consent, or the investigator decides to discontinue treatment,
whichever comes first. Doses should be taken approximately 24 hours apart at the same time
point each day  before eating meal under fasting. Alternative frequencies (e.g. bid) or
intermittent schedules may be investigated in response to emerging safety, tolerability or PK
data. If a patient misses taking a scheduled dose, within a window of 12 hours, it is acceptable
to take the dose. If it is more than 12 hours after the dose time, the missed dose should not be
taken, and patients should be instructed to take the next dose at the next scheduled time. If a
patient vomits after taking their YH25448, they should not make up for this dose, but should
take the next scheduled dose.On the days when blood samples will be collected for PK analysis,
the scheduled dose should be taken at the investigational center after the pre-dose PK sample
has been collected. Patients should fast from midnight on the day before the study visit. If the
Patient vomits the dose, it should not be replaced but the time of vomiting should be captured
in source document. PK blood sampling should be done as planned. Patients should be
instructed to record the time of study drug administration and the dose actually taken in the
patient diary. Following the primary database lock, patients will not be required to complete the
patient diary.
5.1.1. Investigational Product
In this protocol, the investigational product is YH25448.
5.1.2. Non-investigational Product
In this protocol, the non-investigational product is none.
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5.1.3. Identification
The Sponsor will supply YH25448 as tablets for oral dosing. Additional information about the
investigational product may be found in the Investigators’ Brochure.
Table 6. Investigational Products Description
Code 
Dosage form and strength 
Manufacturer
YH25448 
10, 20, 40, 80 mg tablet 
Yuhan Corporation
5.1.4. Packaging and Labeling
YH25448 tablets will be packed in aluminum bags or Alu-Alu PTP. Packed aluminium bags or
Alu-Alu PTP of YH25448 will be dispensed at each dispensing visit depending on the dose.
The packaging includes aluminium bags or Alu-Alu PTP, zipper bags or carton, and a label.
The labels of Investigational Products will be in the local language and comply with the legal
requirements of each country. The label will include the following information: the Name of
the Sponsor, Study Code, For Clinical trial use only and /or any other market specific
requirements.
All investigational products should be kept in a secure place under appropriate storage
conditions. The investigational product label on the pack specifies the appropriate storage.
5.1.5. Handling and Dispensing
It is the responsibility of the investigator to ensure that investigational product is only dispensed
to study patients. The investigational product must be stored in a secure area and dispensed only
from official study centers by authorized personnel in accordance with local regulations.
The investigator should ensure that the investigational product is stored in accordance with the
environmental conditions (temperature, light etc.) recommended by the Sponsor. The sealed
packages of YH25448 in the form of tablet should be stored at room temperature.
Investigators and site staff are reminded to check temperatures and ensure that thermometers
are working correctly, as required for proper storage of investigational products. Any
temperature excursions should be reported to immediately.
If concerns regarding the quality or appearance of the investigational product arise, do not use
it and contact the Sponsor immediately.
The investigator or designee must maintain an accurate record of the shipment and dispensing
of study drug per local institutional guidelines. The study drugs are for investigational use only
and are to be used only within the context of this study. Drug accountability will be noted by
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the field monitor during site visits and at the completion of the study. Patients will be asked to
return all unused study drug and packaging on a regular basis, at the next visit of study drug
dispense and at the end of the study or at the time of study drug discontinuation.
5.2. Method of Assigning Patients to a Treatment
The treatment assignment will be controlled centrally.
5.3. Safety Review Committee
After each dose level during the dose escalation phase of the study, the SRC will evaluate the
available safety, tolerability and PK of YH25448 to decide the next dose. The SRC may be
convened in case of necessity to review the data and discuss each following mentioned in
Section 5.3 to decide on the topic after the completion of the dose escalation phase.
The SRC will consist of:
 
Sponsor Study Physician, who will chair the committee, or delegate
 
Principal Investigator or delegate from each investigational site who participates in each
cohort
In addition, other physicians from the following may be invited:
 
Medical Monitor or delegate
Study PK Scientist, Study Statistician may also be invited as appropriate. Further internal or
external experts may be consulted by the SRC as necessary. The SRC Charter for this study will
define the exact membership and who should be present for decisions to be made.
Once there are at least 3 evaluable patients for dose escalation phase at a dose level the SRC
will review and assess all available safety data from the cohort together with available PK data
to make a decision on the dose for the next cohort of patients. Any dose interruptions and
reductions will be taken into account. It is planned to conduct the SRC meeting regularly, but
the frequency may be adjusted according to patient enrollment rate, emerging data, etc.
The decision may be to:
 
Proceed with dose escalation refer to Section 4.1.2.
 
Expand the cohort to a maximum of 6 evaluable patients (except at MTD or an effective dose
as agreed by SRC if additional patients are recruited,)
 
De-escalate the dose either to a previous lower dose level or to a lower intermediarydose level
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 
Stop the dose escalation phase of the study
 
Initiate dose expansion phase and dose extension phase
 
Evaluate alternative dosing frequencies/intermittent dose schedules
 
Add additional patients at MTD
 
Evaluate the benefit and risk by reviewing safety at the expansion phase and dose extension
phase
When there are other patients that are ongoing at the time of this review, the SRC may decide
to defer their decision until these further patients become evaluable.
Any patient started on treatment in error, as he/she failed to comply with all of the selection
criteria but meets the criteria of an evaluable patient, will be reviewed on a case by case basis
by the SRC to determine if the patients data should be included or excluded in the decision for
dose escalation.
The decisions and decision-making of the SRC on the next dose level will be documented and
provided to the investigators prior to dosing any new patients.
5.4. Dose Modification
5.4.1. Toxicity management and dose modifications to YH25448
If a patient experiences a CTCAE grade 3 and/or unacceptable toxicity including a DLT not
attributable to the disease or disease-related processes under investigation, dosing will be
interrupted and supportive therapy administered as required in accordance with local
practice/guidelines. Patients with QTc prolongation fulfilling the DLT criteria (i.e. confirmed
QTc prolongation to >500 msec absolute or a > 60 msec increase from baseline) should have
study treatment interrupted and regular ECGs performed until resolution to baseline. If the QTc
prolongation toxicity does not resolve to ≤ grade 1 within 21 days the patient will be
permanently withdrawn from study treatment.
5.4.1.1. Escalation and Expansion patients
If any other toxicity resolves or reverts to ≤ CTCAE grade 2 within 21 days of onset and the
patient is showing clinical benefit, treatment with YH25448 may be restarted at the same dose
or one dose level lower which has been declared safe and tolerable by the SRC. Dose
modification will follow the rules below described in Figure 2 and may be agreed between the
investigator and Sponsor Study Physician as needed.
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Figure 2. Dose modifications for toxicity ofYH25448
If any other toxicity does not resolve to ≤ CTCAE grade 2 after 21 days, then the patient should
be withdrawn from the study and observed until resolution of the toxicity.
On resolution of toxicity within 21 days:
 
If a further episode of the same AE subsequently requires dose interruption, YH25448 must
restart at one dose level lower which has been declared safe and tolerable, in case ofCohort
1, restart may be at 10 mg on resolution /improvement of the AE at the discretion of the
Investigator.
 
If a different AE subsequently requires dose interruption, YH25448 may restart at the same
or one dose level lower which has been declared safe and tolerable, in case ofCohort 1, restart
may be at 10 mg on improvement of the AE at the discretion of the Investigator.
For particular cases which don’t follow the dose modification rules as defined in Figure 2, an
agreement should be reached with the Sponsor Study Physician.
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5.4.1.2. Extension patients
If any other toxicity resolves or reverts to dose modification rules as defined, treatment with
YH25448 may be restarted at the same dose or a lower dose following discussion and
agreement with the Sponsor Study Physician or delegated study physician as needed. There
will be no individual modifications to dosing schedule in response to toxicity, only potential
dose reduction or dose interruption.
If the toxicity does not resolve to ≤CTCAE grade 2 after 21 days, then the patient should be
withdrawn from the study and observed until resolution of the toxicity.
On resolution of toxicity within 21 days:
 
If an AE subsequently requires dose interruption, YH25448 may restart at the same dose or
the reduced dose, on resolution/improvement of the AE at the discretion of the Investigator
5.4.1.3. Patients Outside Korea
5.4.1.3.1. YH25448 dose reduction levels in response to toxicity
 Subjects who start YH25448 at a dose of 240 mg (Level 1), may be dose reduced one dose
level to 160 mg (Level -1) in response to study drug toxicity.
 Subjects who start YH25448 at a dose of 320 mg (Level 2), may be dose reduced one dose
level to 240 mg (Level 1) or two dose levels to 160 mg (Level -1) in response to study drug
toxicity.
 All doses are given on a once daily schedule
5.4.1.3.2. YH25448 dose modification guidelines for toxicities
If a patient experiences a CTCAE version 4.03 Grade 3 toxicity while receiving YH25448, or
other unacceptable toxicity, dosing with YH25448 will be interrupted and supportive therapy
administered as required in accordance with local practice/guidelines. If the toxicity resolves
or reverts to <CTCAE Grade 2 within 21 days of onset and the patient is showing clinical
benefit, treatment with YH25448 may be restarted at the same dose level. Dose modification
will follow the rules below described in Figure 3 and may be agreed between the investigator
and medical monitor as needed.
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Figure 3. Dose modifications for toxicity ofYH25448 in Part D
If a patient restarts YH25448 upon resolution of toxicity within 21 days:
 If a further episode of the same AE subsequently requires dose interruption, YH25448 must
be restarted at one dose level lower.  In this case, if the patient is already at Dose Level -1
then the study drug must be permanently discontinued.
 If a different AE subsequently requires dose interruption, YH25448 may be restarted at the
same or lower dose.
Patients with QTc prolongation fulfilling DLT criteria (ie, confirmed QTc prolongation to
>500 msec absolute or a >60 msec increase from baseline) should have the study treatment
interrupted and regular ECGs performed until resolution to baseline. If the QTc prolongation
toxicity does not resolve to < Grade 1 within 21 days the patient will be permanently withdrawn
from study treatment.
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5.4.1.4. All Patients
Guidelines for management of EGFR inhibitor-induced corneal ulceration, interstitial lung
disease, cardiac dysfunction, rash-related toxicities and diarrhea are provided below in
Sections 5.4.1.4.1, 5.4.1.4.2, 5.4.1.4.3, 5.4.1.4.4, and 5.4.1.4.5, respectively.
5.4.1.4.1. Guidelines for the management of YH25448 induced corneal ulceration
Patients experiencing corneal ulceration or Interstitial Lung Disease (ILD) will not be
permitted to restart study treatment.
Ophthalmic assessment, including slit lamp examination, fundoscopic examination, eye
examination and other tests by investigator’s judgement will be performed at screening and
should be repeated if a patient experiences any visual symptoms (including blurring of vision),
with additional tests if clinically indicated. Depending on the severity of visual symptoms,
investigator should observe 5.4.1 for dose interruptions and reductions.
5.4.1.4.2. Guidelines for the management of YH25448 induced interstitial lung disease
Patients with a past medical history of interstitial lung disease, drug-induced interstitial lung
disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically
active interstitial lung disease will be excluded from participation in this study. Patients with
any grade of interstitial lung disease (ILD) will stop YH25448 and be treated as medically
indicated. If new or worsening pulmonary symptoms (e.g., dyspnoea) or radiological
abnormality suggestive of interstitial lung disease is observed, an interruption in study
treatment dosing is recommended, and the Sponsor study team should be informed.
Investigator will perform a full diagnostic workup (including high-resolution computed
tomography (HRCT), blood and sputum culture, haematological parameters, bronchoscopy
with biopsy as needed) to exclude alternative causes such as lymphangitic carcinomatosis,
infection, allergy, cardiogenic edema, or pulmonary hemorrhage. In the presence of
confirmatory HRCT scans where other causes of respiratory symptoms have been excluded, a
diagnosis of interstitial lung disease should be considered and study treatment permanently
discontinued. In the absence of a diagnosis of interstitial lung disease study treatment may be
restarted following consultation with the Sponsor Study Physician.
5.4.1.4.3. Guidelines for the management of YH25448 induced cardiac dysfunction
Patients with confirmed symptomatic cardiac dysfunction (Grade ≥ 3 left ventricular systolic
dysfunction as defined by CTCAE) will be discontinued from study treatment. Asymptomatic
declines in LVEF  or elevated TnI will be handled with the process described in detail in
appendix B. If the LVEF is reported as a range, the average should be taken. If an investigator
is concerned that an adverse event may be related to cardiac dysfunction, an additional LVEF
measurement may be performed. Until the primary database lock, LVEF will be monitored at
screening, every 12 weeks , and TnI will be monitored at screening, everyvisit and as clinically
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SRC will review all potential cases of left ventricular systolic dysfunction (See appendix B of
this Clinical Study Protocol).
5.4.1.4.4. Guidelines for the prevention, monitoring, and management of YH25448 induced
rash-related adverse events
Prophylactic treatment
Starting at the initiation of study drug dosing and continuing during dosing subjects are to be
instructed to:
 use a thick, alcohol-free emollient cream (eg, glycerin and cetomacrogol cream) to prevent dry
skin and pruritis
 avoid immersion in hot water / detergent / solvents
 avoid exposure to sunlight.
 use broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with a skin
protection factor (SPF) ≥15 if sunlight exposure cannot be avoided
Reactive management
The following interventions and the stepwise algorithm shown in Table 7 are to be used for
EGFR inhibitor-induced rash
o Topical corticosteroids (eg, hydrocortisone 2.5% cream)
o Topical antibiotic (eg. clindamycin 1% gel)
o Topical corticosteroids and systemic antibiotics (minocycline 100 mg bid or first
generation cephalosporine (avoid CYP3A4 inhibitors)).
o For pruritic lesions, the use of cool compresses and oral antihistamine agents may be
helpful. 
o For fissuring, the use of Monsel’s solution (ferric subsulfate solution), silver nitrate,
or zinc oxide cream is advised. 
o For desquamation, thick emollients and mild soap are recommended. 
o For paronychia, antiseptic soaks and local potent corticosteroids in addition to oral
antibiotics are recommended and, if no improvement is seen, a dermatology or surgery
consultation is recommended. 
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 CTCAE version 4.03 Grade 1: Loperamide (4 mg at first onset, then 2 mg every 2-4 hours
until symptom free for 12 hours). Fluid intake of at least 2 L as described above. Study
treatment: should be continued at the same dose.
 CTCAE version 4.03 Grade 2: Loperamide (4 mg at first onset, then 2 mg every 2-4 hours
until symptom free for 12 hours), or consider diphenoxylate and atropine formulations (e.g.,
Lomotil®). Fluid intake of at least 2 L as described above. Monitor patient closely and
consider intravenous hydration. Study treatment: If not improved to Grade ≤1 within 24 hours
despite use of loperamide, hold treatment until Grade ≤1. If diarrhea of Grade >1 recurs after
initial improvement, consider reduction by one dose level
 CTCAE version 4.03 Grade 3: Oral therapy with diphenoxylate and atropine formulations (eg,
Lomotil®), or tincture of opium. Fluid intake ofat least 2 L should be maintained as described
above, intravenously if necessary. Consider use of octreotide (Sandostatin®) 100-150
microgram (μg) subcutaneously twice daily with escalation to 500 μg three times daily.
Consider hospitalization if does not improve to Grade ≤2 within 24 hours, or in presence of
fever, abdominal pain, etc. Study Treatment: Hold therapy. Upon resolution to Grade ≤1,
resume therapy with consideration of reduction by one dose level.
 CTCAE version 4.03 Grade 4: Maximal inpatient fluid and nutritional support, antibiotics as
indicated in judgment of investigator for fever, leucocytosis, marked dehydration, etc. Study
Treatment: Hold until Grade ≤1. Mandatory dose reduction by one dose level.
5.4.2. Assessment timings if dosing is interrupted
All other assessments, including laboratory safety assessments, vital signs and RECIST 1.1
should continue to be performed as per study plan, relative to the baseline assessments.
5.5. Treatment compliance and accountability
The investigational product should only be used as directed in this protocol. Details of
treatment with investigational product for each patient will be recorded in the Case Record
Form.
Patients should return all unused medication and empty containers to the investigator.
The study personnel at the investigational site will account for all drugs dispensed and for
appropriate return. The certificates of delivery and return should be signed.
Patients will be asked to record study drug dosing information including date and time of each
medication intake in a patient diary provided by the Sponsor until the primary data base lock.
Patients will bring the diaries, and all unused study drug and empty containers, to each study
visit. Compliance will be assessed by the investigator and/or study personnel at each visit using
pill counts and information provided by the patient diary. Investigator must report as protocol
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deviation if the subject of the study misses to take YH25448 4 days or more during one cycle,
which is 21 days. This information regarding the study drug administration including all
dosages prescribed and dispensed to the patient and all dose changes during the study must be
captured in the source document and recorded on the Dosage Administration Record of eCRF
at each visit until the primary database lock.
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QLQ: Quality of Life Questionnaire.
1. A treatment cycle is defined as 21 days for the purposes of scheduling procedures and evaluations. There will be no scheduled break between cycles.
2. Study visits will occur on Day 1 of every cycle until Cycle 7 and every other cycle from Cycle 7 onwards for dose escalation and dose expansion. But study visits
for dose extension will occur on Day 1 of every other cycle from Cycle 3 onwards (C1D1, C2D1, C3D1, C5D1, C7D1…).
3. 28-day Follow-up visit will be scheduled 28 days (+7 days) after discontinuation visit.
4. Unscheduled visits can be arranged if necessary. Study procedures will be at the discretion of the investigator.
5. All patients will attend a discontinuation visit within 7 days of permanent discontinuation of study drug, where all procedures for the discontinuation visit will
be performed. The discontinuation visit should occur before the start of a new treatment and the reason should be documented on the eCRF. After the primary
database lock, only clinically indicated tests by the investigator’s judgement will be performed.
6. Signed informed consent must be obtained before the patient undergoes any study-specific procedures.
7. T790M mutation must be centrally confirmed within 28 days before starting administration of YH25448 and a tissue sample must be collected after the progression
disease on the therapy recently (the patients with locally confirmed T790M mutation positive also can be enrolled for Part C 2nd line treatment cohort). During the
screening, if there is a sample which is meet the conditions required above, an archived tissue sample is able to be used for T790M mutation confirmation (Only in
part A, dose escalation phase, if an archive sample is collected after progression disease on authorized EGFR TKIs therapy regardless of the recent treatment, the
sample is able to be used for T790M mutation confirmation.) The Screening period can be extended to 42 days, if required, for the T790M tumor mutation testing
only. For the dose extension phase, collected tissue samples must be submitted for central confirmation prior to the start of YH25448.
8. Vital signs (heart rate, blood pressure and body temperature) will be performed at each scheduled visit as per section 6.2.3. These will be obtained after the patient
has rested for 10 minutes. The date and time of the assessment should be recorded.
9. Height will be taken only at Screening.
10.12-lead ECGs (in triplicate, approximately 2 minutes apart), with central reading by a cardiologist, will be performed as planned schedule in section 6.2.4. ECG
for dose escalation phase will be performed at screening and on Day 1 Cycle 0: pre-dose, 1,2,4,6,8,10,12, 24 hrs(Day 2) and 48 hrs(Day3) post-dose. Day 1, 8 and
15 Cycle 1 for all phase: pre-dose. Day 1 Cycle 1 for dose expansion and extension phases: 2, 4 hrs post-dose. Day 1 Cycle 2 for dose escalation and expansion
phases: pre-dose, 1, 2, 4, 6, 8, 10, 12 and 24(Day 2) post dose. On Day 1 of each subsequent visits: one assessment at any time during day and discontinuation
visit. For ECGs recorded in parallel with blood sampling for PK analysis, the blood sample should be collected subsequently after the triplicate ECGs have been
performed. From Cycle 3 to the primary database lock, an ECG will be performed on Day 1 of each scheduled visit cycle for safety monitoring but it will not be
time-matched and can be performed regardless of dosing time.
11. LVEF will be assessed using an echocardiogram or MUGA at Screening and every 12±1 weeks until the primary database lock visit. Additional assessment may
be performed if clinically indicated. If the result of TnI is positive, it will be re-tested by central laboratory within 3 days before permanent discontinuation of
study treatment. For any patient who has at least one echocardiogram or MUGA that is considered abnormal by local assessment, the Sponsor collects all
echocardiograms or MUGAs (obtained at Screening and all subsequent assessments) for the purpose of a central read.
12. Clinical Laboratory tests are not required if acceptable Screening is performed within 7 days prior to administration of study drug, unless the patient’s clinical
condition has changed significantly. But if the results of lab.test within 7 days prior to administration of study drug is not available, clinical lab.test should be
performed at baseline visit before IP intake. If needed, any clinical laboratory tests may be performed for safety evaluation of patients additionally.
13. At Screening and Discontinuation visit, all females of childbearing potential should complete a urine/serum pregnancy test per the practice of the center. Repeat
as necessary during the treatment period if clinically indicated.
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14. PK blood samples will be taken as per scheduled time on table 13 at section 6.3.1. Hospitalization for Day 1, 2, and 3 Cycle 0 and Day 1, 2 Cycle 2 is required for
PK blood sampling. Patients will take the first dose at the center; if the patient vomits the dose it should not be replaced but the time of vomiting should be captured
in source document. PK blood sampling should be done as planned.
15. The patient must have at least one lesion, has not been previously irradiated that can be accurately measured. Radiological and clinical tumor assessments will be
performed at Screening, and every 2 cycles (± 7 days) until objective disease progression using the RECIST 1.1 or, for patient who stop taking the study drug
without disease progression until disease progression or before subsequent anticancer therapy begins.
Baseline tumor assessment during screening must be performed within 28 days of the start of study drug. If there is only one measurable lesion and it should be
chosen for biopsy, tumor assessment should be performed at least 14 days after the biopsy. If the local treatment was given for brain metastases, baseline brain CT/MRI
must be taken after the treatment has been completed.
If there is no brain lesion before screening period, in Part A, brain CT/MRI can be performed at screening if suspected brain metastasis. In Part B and C, brain CT.MRI
will be performed after confirmation of T790M + centrally (EGFR for 1st line treatment cohort only). Tumor assessment for the brain lesion will be performed every
two cycles (± 7days), if the subject has the brain lesion at the baseline.
After the primary database lock, radiological disease evaluations are not required and may be performed at the discretion of the investigator in accordance with local
standard of care. The independent central review will not be performed anymore.
16. EORTC QLQ-C30 and EORTC QLQ LC13, QLQ BN20 (BrM patients only) should be completed prior to any other visit-specific procedures.
17. Until the primary database lock, Blood samples for cfDNA analysis will be collected on the same day of scheduled and any unscheduled tumor assessment as
possible.
18. To be taken during the screening period prior to the first drug administered.
19. Collect every 2 cycles (± 7 days) up to and including progression (corresponding with the RECIST 1.1 assessments and continuing after treatment discontinuation
in absence of disease progression).
20. All screening procedures and laboratory results must be available and reviewed before the patient receives the first dose of study drug. YH25448 should be taken
orally QD at approximately the similar time under fasting before meal, with a glass of water. The time of study drug administration for specific days should be
recorded in the patient diary which is distributed with study drug excluding the C0D1 visit in part A.
21. All patients correspond to RP2D who are confirmed disease progression for selected extension dose cohorts of dose expansion phase and all dose extension phase
will be followed for survival and any post-study anticancer treatment via at least a telephone contact every 6 weeks relative to progression until death or withdrawal
of consent. After the primary database lock, the survival and any post-study anticancer treatment will be followed every 12 weeks.
22. Unless the patients withdraw consent, they must be followed for AEs from the date of informed consent until 28 days after the last dose of study treatment. In the
event of serious or study drug-related toxicities, the patient will be followed until resolution or stabilization.
23. All patients who discontinue study drug without progression will continue to be followed any anti-cancer therapy and perform tumor assessment every 2 cycles
(±7 days) until disease progression or before subsequent anticancer therapy begins. If patients continue to receive the study drug after intracranial lesion has
shown clinical benefit regardless ofprogression for extracranial lesion, tumor assessment will be continued every 2 cycles until progression for intracranial lesion.
After the primary database lock, radiological disease evaluations are not required and may be performed at the discretion of the investigator in accordance with
local standard of care.
24. After the primary database lock, only clinically indicated tests will be performed by the investigator’s judgement. Only the minimum data (ie, whether performed,
date, etc.) will be collected in the EDC.
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25. After the primary database lock, only concomitant medications related to SAEs will be collected.
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8. Height will be taken only at Screening.
9.12-lead ECGs (in triplicate, approximately 2 minutes apart), with central reading by a cardiologist, will be performed as planned schedule in Section 6.2.4 and Table
12. ECG for Part D will be performed at screening; pre-dose on Day 1 Cycle 0, Day 1 Cycle 1 and Day 1 Cycle 2; 2 hrs post-dose on Day 1 Cycle 0; 1, 2, 4 hrs
post-dose on Day 1 Cycle 2; at any time during the day of Day 1 of Cycle 3 and of each subsequent visit onwards. For ECGs recorded in parallel with blood
sampling for PK analysis, the blood sample should be collected subsequently after the triplicate ECGs have been performed. From Cycle 3 onward, an ECG will
be performed on Day 1 of each scheduled visit cycle for safety monitoring but it will not be time-matched and can be performed regardless of dosing time. No
central ECG reading will be required following the primary database lock.
10. LVEF will be assessed using an echocardiogram or MUGA at Screening and every 12±1 weeks until the primary database lock visit. Additional assessment may
be performed if clinically indicated. If TnI laboratory value exceeds the ULN, it will be re-tested by local laboratory within 3 days. If considered clinically
significant, study treatment will be permanently discontinued after consultation with the Sponsor medical monitor. In Part D, central laboratory confirmation of
TnI local laboratory value is not required. For any patient who has at least one echocardiogram or MUGA that is considered abnormal by local assessment, the
Sponsor will collect all echocardiograms or MUGAs (obtained at Screening and all subsequent assessments) for the purpose of a central read. No ECHO/MUGA
collection or central readings will be done following primary database lock.
11. Ophthalmologic assessment will be performed at Screening and should be repeated if a subject experiences any visual symptoms (including blurring of vision),
with additional tests if clinically indicated.
12. Clinical Laboratory tests are not required if acceptable Screening is performed within 7 days prior to administration of study drug, unless the patient’s clinical
condition has changed significantly. But if the results of lab test within 7 days prior to administration of study drug is not available, clinical lab test should be
performed at baseline visit before IP intake. If needed, any additional clinical laboratory tests may be performed for safety evaluation of patients.
13. At Screening and Discontinuation visit, all females of childbearing potential should complete a urine/serum pregnancy test per the practice of the center. Repeat
as necessary during the treatment period if clinically indicated
14. Radiological and clinical tumor assessments will be performed at Screening, and every 2 cycles (± 7 days) until objective disease progression using the RECIST
1.1 or, for patient who stop taking the study drug without disease progression until disease progression or before subsequent anticancer therapy begins. Baseline
tumor assessment during screening must be performed within 28 days of the start of study drug. Ifthere is only one measurable lesion and it should be chosen
for biopsy, tumor assessment should be performed at least 14 days after the biopsy. If local treatment was given for brain metastases, baseline brain MRI must
be taken after the treatment has been completed. A brain MRI will be performed at screening and every two cycles (± 7 days), if the patient has a brain lesion at
baseline. After the primary database lock, radiological disease evaluations are not required and may be performed at the discretion of the investigator in
accordance with local standard of care.
15. All screening procedures and laboratory results must be available and reviewed before the patient receives the first dose of study drug. YH25448 should be taken
orally QD at approximately the similar time under fasting before meal, with a glass of water The time of study drug administration for specific days should be
recorded in the patient diary which is distributed with study drug excluding the C0D1 visit in part D. No patient diaries are required following primary database
lock.
16. Unless the patients withdraw consent, they must be followed for AEs from the date of informed consent until 28 days after the last dose of study treatment. In the
event of serious or study drug-related toxicities, the patient will be followed until resolution or stabilization.
17. All patients who discontinue study drug without progression will continue to be followed any anti-cancer therapy and perform tumor assessment every 2 cycles
(±7 days) until disease progression or before subsequent anticancer therapy begins. After the primary database lock, radiological disease evaluations are not
required and may be performed at the discretion of the investigator in accordance with local standard of care. Follow-up visits will be performed every 12 weeks
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prior to Protocol Amendment 11. As of Protocol Amendment 11, follow-up visits will not be required for patients in Part D. Patients in Part D will not remain on
study for radiological disease evaluations.
18. Physical examination, ECOG assessment and vital signs may be performed the day before a day during which a 10 h PK is planned.
19. Following informed consent, pharmacogenetic blood sample for assessment of genetic variants that encode drug-metabolizing enzyme GSTM1 may be
collected at any time during the study although collection during screening is preferred. PK blood samples may also be utilized for this process. No GSTM1
samples will be collected after the primary database lock.
20. As of Protocol Amendment 11, follow-up visits will not be required for patients in Part D; overall survival and subsequent anticancer therapy data will not be
collected.
21. After the primary database lock, only concomitant medications related to SAEs will be collected.
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Table 12. Time and Events Schedule for Pharmacokinetic (PK), and ECG Assessments for
Part D
Phase 
Day  
Time 
Window  
PK  
ECG
Single Dose/Cycle 0
D1 
Pre-dose 
-15 min  
X 
X
1 h  
±10 min  
X
2 h  
±1 hours 
X 
X
4 h  
±1 hours 
X
10 h  
±1 hours 
X
D2 
24 h  
±2 hours 
X
D3 
48 h  
±2 hours 
X
Multiple Dose
/Cycle 1
D1 
Pre-dose 
-15 min  
X 
X
D8 
Pre-dose 
-15 min  
X
D15 
Pre-dose 
-15 min  
X
Multiple Dose /Cycle 2
D1 
Pre-dose 
-15 min  
X 
X
1 h  
±10 min  
X 
X
2 h  
±1 hours 
X 
X
4 h  
±1 hours 
X 
X
10 h  
±1 hours 
X
D2 
Pre-dose (24 h) 
-15 min  
X
Every other cycle
from Cycle 3
onwards until the 
primary database
lock
D1 
Pre-dose 
-15 min  
X 
X
Discontinuation  
X
6.2. Safety Procedures
Prior to discharge from each in-patient and clinic visit, the Investigator or their deputy will be
responsible for reviewing all available data including vital signs and ECG tracings.
For Parts A, B and C: After the primary database lock, only clinically indicated tests per
investigator’s judgement will be performed.
For Part D: After primary database lock, please refer to Schedule of Activities.
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6.2.1. Enrollment and screening
At enrollment, each potential patient will provide informed consent prior to starting any study
specific procedures (see appendix D of this Clinical Study Protocol for Ethics and Regulatory
Requirements).
The Screening period can be extended to 42 days, if required, for the T790M tumor mutation
testing only.
If a patient is a screen failure, but at some point in the future meets all of the eligibility criteria,
the patient may be rescreened after a new informed consent has been obtained. Patients who
are rescreened will be assigned a new screening number and will start a new screening phase.
If the patient already have test result of T790M positive at previous screening, the collection
of tumor tissue sample for T790M mutation is not required.
Recruitment into the study will be conducted in a controlled manner. If a patient withdraws
from the study, then the enrolment code cannot be reused.
Demographic data and other characteristics will be recorded and will include date of birth or
age, gender, race and/or ethnicity according to local regulations, smoking history.
A standard medical, medication and surgical history will be obtained with review of the
selection criteria with the patient.
Each patient will undergo screening (see Study Plan Table 8, Table 9, Table 10 and Table 11)
during the 28 days prior to admission to confirm eligibility (see Sections 4.2.1 and 4.2.2).
Tumor assessments and other clinical data obtained as standard of care prior to consent may be
used for the study provided the assessments fall within the protocol specified period prior to
the first dose of study treatment.
6.2.2. Physical examination
A physical examination will be performed and include an assessment of the following: general
appearance, skin, head and neck (including ears, eyes, nose and throat), respiratory,
cardiovascular, abdomen, lymph nodes, thyroid, muscular-skeletal (including spine and
extremities) and neurological systems (see Study Plan Table 8, Table 9, Table 10 and Table
11).
Performance status will be assessed at the visits as indicated in the Study Plan (see Table 8,
Table 9, Table 10 and Table 11) according to ECOG criteria as follows:
0  Fully active, able to carry out all pre-disease activities without restrictions
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1  Restricted in physically strenuous activity but ambulatory and able to carry out work of a
light or sedentary nature e.g., light housework, office work
2  Ambulatory and capable of self-care, but unable to carry out any work activities. Up and
about more than 50% of waking hours
3  Capable of only limited self-care, confined to bed or chair more than 50% of waking Hours
4  Completely disabled, cannot carry on self-care, totally confined to bed or chair
5  Death
6.2.3. Vital signs
Blood pressure and pulse rate
Blood pressure and pulse rate will be measured after about 10 minutes rest. Assessments will
be performed at the visits as shown in the Study Plan (See Table 8, Table 9, and Table 10).
For Part A, B, and C: Observation will be recorded at the following times:
 
Screening
 
First dosing day (Day 1 Cycle 0) for dose escalation phase: pre-dose, 1, 2, 4, 6, 8, 10, 12, 24
hours (Day 2) and 48 hours (Day 3) post-dose
 
Day 1, Day 8 and Day 15, Cycle 1 (Multiple Dosing for all phases) : pre-dose
 
First day of multiple dosing (Day 1, Cycle 1) for dose expansion and extension phases : 1, 2,
3 and 4 hours post-dose
 
Day 1, Cycle 2 (Multiple dosing for dose escalation and expansion phases) : pre-dose, 1, 2, 4,
6, 8, 10, 12 and 24 hours (Day 2) post-dose
 
On Day 1 of each subsequent scheduled cycle visit; one assessment at any time during day
 
On occurrence of any cardiac AE
 
Unscheduled Visit if needed
 
Discontinuation visit
For Part D only: Observation will be recorded at the following times:
 Screening
 Pre-dose at each study treatment visit
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 On occurrence of any cardiac AE
 Unscheduled Visit if needed
 Discontinuation visit
 28 day follow-up visit
The timing and number of vital signs assessment may be altered depending on the emerging
PK and safety profile.
A -2 h window at pre-dose (Day 1 in Cycle 0, Cycle 1 and Cycle 2) and a ±15 min window at
1-12 h; a ±1 h window at 24 h and 48 h; a -2 h window at pre-dose (Day 8 and Day 15 in Cycle
1). In Part D, the physical exam may be performed the day before a day during which a 10 h
PK is planned.
Weight
Weight will be performed at screening and then at Day 1 of each subsequent scheduled cycles
and at the discontinuation visit
Body temperature
Body temperature will be performed at screening and then at Day 1, Day 2 in Cycle 0, at Day
1, Day 8, Day 15 in Cycle 1, at Day 1 in Cycle 2 and at Day 1 of each subsequent scheduled
cycles and at the discontinuation visit.
Height
Height will be assessed at screening only.
Any changes in vital signs should be recorded as an AE if applicable.
6.2.4. ECG
Resting 12-lead ECG
12-lead ECG will be performed at the visit indicated in the Study Plan for Parts A, B and C
(see Table 8, Table 9 and Table 10).
 
12-lead ECGs will be recorded at the following times until the primary  database lock:
Screening
 
First dosing day (Day 1 Cycle 0) for dose escalation phase: pre-dose, 1, 2, 4, 6, 8, 10, 12, 24
hours (Day 2) and 48 hours (Day 3) post-dose
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 
Day 1, Day 8 and Day 15, Cycle 1 (Multiple Dosing for all phases) : pre-dose
 
First day of multiple dosing (Day 1 Cycle 1) for dose expansion and extension phases : 2 and
4 hours post-dose
 
Day 1, Cycle 2 (Multiple dosing for dose escalation and expansion phases) : pre-dose, 1, 2, 4,
6, 8, 10, 12 and 24 hours (Day 2) post-dose
 
On Day 1 of each subsequent scheduled cycle visit; one assessment at any time during day
 
On occurrence of any cardiac AE
 
Unscheduled Visit if needed
 
Discontinuation visit
The timing and number of ECGs may be altered depending on the emerging PK and safety
profile. For patients in Part D, see Table 12.
A -2 h window at pre-dose (Day 1 in Cycle 0, Cycle 1 and Cycle 2) and a ±15 min window at
1-12 h; a ±1 h window at 24 h; a -2 h window at pre-dose (Day 8 and Day 15 in Cycle 1).
12-lead ECGs will be obtained after the patient has been resting semi-supine for at least 10
minutes prior to times indicated. All ECGs should be recorded with the patient in the same
physical position. For each time point three ECG recordings should be taken at about 2 minute
intervals. A standardized ECG machine should be used and until the primary database lock.
The patient should be examined using the same machine throughout the study if possible.
After paper ECGs have been recorded, the investigator or designated physician will review
each ECG prior to discharge from the clinic and may refer to a local cardiologist if appropriate
for immediate management of the patient. A paper copy and centrallyconfirmed results should
be filed in the patient’s medical records. If an abnormal ECG finding at screening or baseline
is considered to be clinically significant by the investigator, it should be reported as a
concurrent condition. For all ECGs details of rhythm, ECG intervals and an overall evaluation
will be recorded.
All ECG data will also be collected digitally and will be transferred electronically for central
analysis as described in the study specific ECG manual. Heart rate, PR, R-R, QRS and QT
intervals will be determined and reviewed by an external cardiologist. (ECG result at screening
should be read via paper ECG instead of central analysis.) After the primary database lock, the
central analysis transmissionprocedure using the standard ECG machine will not be performed,
but if necessary, it can be performed by site upon the investigator’s judgement.
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For Part D: After the primary database lock, a single ECG will be performed locally at each
study visit.
6.2.5. Laboratory safety assessment
Blood and urine samples for determination of clinical chemistry, hematology and urinalysis
will be taken at the visits as indicated in the Study Plan (see Table 8, Table 9, Table 10 and
Table 11).
All the laboratory safety assessments will be conducted at local labs under fasted condition.
Laboratory tests do not need to be repeated at baseline if the baseline visit is within 7 days of
the screening sample.
Blood and urine samples for safety assessment will be collected at the following times:
 
Screening
 
First dosing day (Day 1 Cycle 0 for Parts A and D, Day 1 Cycle 1 for Parts B and C) : pre-
dose (baseline)
 
Day 3 Cycle 0 for Part A only : prior to discharge from hospital
 
First day of multiple dosing, Day 1 Cycle 1 for Parts A and D : pre-dose
 
Multiple dosing, Days 15 of Cycle 1 : pre-dose
 
On Day 1 of each subsequent scheduled cycle visit : pre-dose
 
Unscheduled Visit for some parameters if needed
 
Discontinuation visit
The date of each collection will be recorded in the appropriate eCRF.
Following review of data from a group of patients the timing of blood samples may be adjusted
for subsequent groups of patient. Additional sampling times may be added ifindicated by the
emerging PK and safety profile.
Laboratory values that meet the criteria for CTCAE Grade 3 or have changed significantlyfrom
baseline and are considered to be of clinical concern will be repeated/confirmed within 7 days
and followed up as appropriate.
The following laboratory variables will be measured:
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Clinical chemistry (Serum/Plasma) 
Albumin
ALT
AST
Alkaline phosphatase
Total Bilirubin
Calcium
Total Creatinine
Glucose
HbA1C (screening and every 12 weeks )
Magnesium
Potassium
Sodium
Urea nitrogen
Troponin I (screening and every visit)
Hematology(Blood) 
Hemoglobin
Leukocyte
Hematocrit
Red blood cell (RBC) count
Absolute leukocyte differential count:
Neutrophils
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count
Reticulocytes
Urinalysis 
Glucose
Protein
Blood (RBC and WBC)
HbA1C will be conducted at screening and every 12 weeks to first dose and discontinuation
visit. And troponin I (TnI) will be conducted at screening and at the same visits at which blood
laboratory tests are performed.
For Parts A, B and C: After the primary database lock, laboratory tests such as HbA1C, TnI,
urinary tests, chemistry and hematology tests will be performed as clinically indicated per
investigator discretion.
For Part D: After the primary database lock, please refer to the Schedule of Activities.
Parts A, B and C
If TnI is determined to be positive (TnI+) until the primary database lock, it will be re-tested
by central laboratory within 3 days before permanent discontinuation of study treatment. A
positive result from the TnI test means when the laboratory value exceeds the ULN as per each
site or central laboratory range.
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Part D
TnI is positive (TnI+) when the laboratory value exceeds the ULN as per local laboratory range
and is clinically significant for a cardiac event. If TnI laboratory value exceeds the ULN, it will
be re-tested by local laboratory within 3 days. If considered clinically significant, study treatment
will be permanently discontinued after consultation with the Sponsor medical monitor. In Part D,
central laboratory confirmation of TnI local laboratory value is not required.
Additionally a urine/serum sample will be collected from all females of child bearing potential
at screening and discontinuation for a pregnancy test.
Cases where a patient shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN need to be
reported to the Sponsor within 24 hours. Prompt reporting of cases meeting Hy’s law criteria
(via the SAE expedited reporting system) is required for compliance with regulatory guidelines.
The investigator is responsible for, without delay, determining whether a patient meets
potential Hy’s law criteria. The investigator needs to perform additional examinations for this
and confirm the results with the Sponsor’s Study Physician. Details of identification of
potential Hy’s Law cases and actions to take are detailed in Appendix A.
For blood volume see Section 6.6.1.
6.2.6. Other Safety Assessment
6.2.6.1. Ophthalmologic examination
Ophthalmic assessment, including slit lamp examination, fundoscopic examination, eye
examination and other tests by investigator’s judgement will be performed at screening and
should be repeated if a patient experiences any visual symptoms (including blurring of vision),
with additional tests if clinically indicated. Any clinically significant findings, including those
confirmed by the ophthalmologist must be reported as an AE. Photographs should be
performed to record any clinically significant findings. These photographs should be available
for review bythe Sponsor if necessary. Ophthalmologyexamination results should be collected
in eCRF.
6.2.6.2. Echocardiography (or MUGA Scan)
Until the primary database lock, Echocardiography (or MUGA scan) to assess LVEF will be
conducted at baseline (prior to first dose of YH25448), 12 weeks after the first dose of
YH25448 and 12-weekly thereafter (± 1 week). Additional assessments can be conducted at
the discretion of the investigator within every 12 weeks or during discontinuation visit. The
modality of the cardiac function  assessments must be consistent within a patient i.e. if
echocardiography is used for the screening assessment then echocardiography should also be
used for subsequent scans if required. The patients should also be examined using the same
machine and operator whenever possible. Until the primary database lock, For any patient who
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has at least one echocardiogram or MUGA that is considered abnormal by local assessment,
the Sponsor collects all echocardiograms or MUGAs (obtained at Screening and all subsequent
assessments) for the purpose of a central read.
6.2.6.3. Hepatitis screen, HIV screen
All patients will be screened for Hepatitis B surface antigen (HBsAg). Screening for Hepatitis
C will be based on HCV antibodies. Additional hepatitis examination could be conducted if
required.
Evaluation for HIV seropositivity will be performed, and, if positive, the further test can be
determined as per investigator’s decision if needed.
Appropriate counseling will be made available by the Investigator in the event of a positive
finding. Notification of regional and/or national authorities, if required by law, will be the
responsibility of the Investigator.
Results will be available as source data and will not be recorded within the eCRF.
6.2.6.4. Follow-up
A post study assessment will be performed at the time investigational product is permanently
discontinued (see Table 8, Table 9, Table 10 and Table 11).
28 day follow-up should be made with the patient 28+ 7 days following the discontinuation of
YH25448 to collect new AEs and follow up on any ongoing AEs and concomitant medications
(including any subsequent cancer therapy). Refer to Section 7.3 for full details on AE
recordings during follow-up.
Patients who discontinue YH25448 for reasons other than progression  in expansion and
extension phases will continue RECIST 1.1 assessments every 2 cycles (relative to first dose
of multiple dosing) before subsequent anticancer therapy begins.
Patients with intracranial disease who are confirmed progression only in extracranial lesion
will continue to perform RECIST 1.1 assessment every 2 cycles for intracranial lesion until
progression if patients continuously administrate study drugs (for Parts A, B and C). After the
primary database lock, radiological disease evaluations are not required and may be performed
at the discretion of the investigator in accordance with local standard of care.
AEs and SAEs should be collected until 28 days from the last day of dosing, and details of
concomitant medications (including any subsequent cancer therapy) should continue to be
collected as detailed in the study plan (see Table 8, Table 9, Table 10 and Table 11) up to the
28-day follow up visit. For those patients in expansion and extension phases an additional PRO
QoL questionnaire should be completed on progression or discontinuation visit (Table 9 and
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Table 10).
Only patient in dose extension, expansion phases and Part D (prior to Protocol Amendment 11)
who is receiving treatment for selected dose after completing the 28-day follow-up visit will
be followed for overall survival and subsequent anticancer therapy, via telephone contact,
every 12 weeks until death, lost to follow-up or withdraws consent. As of Protocol
Amendment 11, follow-up visits will not be required for patients in Part D; overall survival
and subsequent anticancer therapy data will not be collected.
6.3. Pharmacokinetics
6.3.1. Collection of pharmacokinetic samples
Venous blood samples (approximately 9 mL for Parts A, B and C; 6 mL for Part D) for
determination of concentrations of YH25448 and its potential metabolites, including M7, in
plasma will be taken at the times presented in Table 13. The date and time of collection of each
sample and the date and time of dose will be recorded. For patients in Part D, see also Table
12.
Table 13. PK blood sample schedule
Phase
Single dose 
Multiple dose
Day 1, Cycle 0 
Day 1, 8, 15, Cycle 1 
Day 1, Cycle 2
Part A  
Pre-dose (0 h), 0.5, 1, 2, 
4, 6, 8, 10, 12, 24, 48, 60 
hrs post-dose 
Each pre-dose (0 h) 
Pre-dose (0 h), 0.5, 1, 2,
4, 6, 8, 10, 12, 24 hrs
post-dose
Part B  
- 
Each pre-dose (0 h) 
Pre-dose (0 h), 0.5, 1, 2,
4, 6, 8, 10, 12, 24 hrs
post-dose
Part C  
- 
Each pre-dose (0 h) 
-
Part D* 
Pre-dose (0 h), 1, 2, 4, 10, 
24, 48 hrs post-dose 
Each pre-dose (0 h)
Pre-dose (0 h), 1, 2, 4, 10,
24 hrs post-dose
* Additional blood samples will be taken on Day 1 in every other cycle from Cycle 3 onwards
until the primary database lock.
For Parts A, B and C, a ±5 min window will be allowed for blood samples taken at 0.5, 1 h; a
±10 min window at 2-12 h; a ±1 h window at 24 h; a ±2 h window at 48, 60 h. A -2 h window
will be allowed for samples taken at pre-dose in Day 1, Cycle 0 and Cycle 1; a -15 min window
at pre-dose in Day 8 and Day 15, Cycle 1. The samples for pre-dose in each day should be
taken prior to the administration of IP.
The timing of the pharmacokinetic samples may be adjusted during the study, dependent on
emerging data, in order to ensure appropriate characterization of the plasma concentration-time
profiles. The total number of samples and the total volume of blood taken from each patient
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will not exceed that detailed in Section 6.6.1. Residual samples may be analyzed for
exploratory biomarkers.
No PK blood samples will be taken following primary database lock.
Details of blood sample collection, handling, shipment, storage and processing for PK analysis
of the plasma concentrations of YH25448 will be provided to the center in the laboratory
manual. 
6.3.2. Determination of drug concentration in pharmacokinetic samples
Concentrations of YH25448 and its potential metabolites, including M7, in plasma and CSF
will be analyzed, using an appropriate bioanalytical method. Full details of the analytical
method used will be described in a separate bioanalytical report.
All samples still within the known stability of the analyses of interest (i.e., YH25448 and its
metabolite M7) at the time of receipt by the bioanalytical laboratory will be analyzed.
In addition, the pharmacokinetic samples may be subjected to further analyses by the Sponsor
in order to investigate the presence and/or identity of additional drug metabolites. Any results
from such analyses will be reported separately from the Clinical Study Report. Any residual
plasma after PK analysis may be used for exploratory research into factors that may influence
development of NSCLC and/or response to YH25448.
Details on sample processing, handling, shipment and storage are provided in the laboratory
manual.
6.4. Exploratory Research
6.4.1. Exploratory biomarker research
If a patient agrees to participate in the exploratory biomarker research component of the study
biological samples (e.g., plasma, serum, archived and study-obtained tumor, etc.) will be
collected and may be analyzed for exploratory biomarkers to assess correlations with disease
activity, effects of study drug and clinical outcomes.
The results of this exploratory biomarker research will be reported separately and will not form
part of the Clinical Study Report.
The results of this exploratory biomarker research may be pooled with biomarker data from
other studies with the study drug to generate hypotheses to be tested in future studies.
No samples will be taken for exploratory research following primary database lock
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6.4.1.1. Collection of Tumor Samples
All patients will be asked to provide consent to supply a sample of their archival tumor blocks,
T790M mutation must be centrally confirmed within 28 days before starting administration of
YH25448 and a tissue sample must be collected after the progression disease on the therapy
recently (except for Part D). During the screening, if there is a sample which is meet the
conditions required above, an archived tissue sample is able to be used for T790M mutation
confirmation (Only in part A, dose escalation phase, if an archive sample is collected after
progression disease on authorized EGFR TKIs therapy regardless of the recent treatment, the
sample is able to be used for T790M mutation confirmation). Any archival biopsy samples
taken following previous lines of therapy will also be asked to provide consent to supply it, if
available. In each case the previous patient treatment must be clearly indicated for each sample
provided. For the 1st line treatment cohort of Part C dose extension phase, the tumor tissue
sample collected prior to initiation of the study treatment should be submitted for central
confirmation. The mutation test will be performed later. For the 2nd line treatment cohort of
Part C, if the T790M mutation is confirmed locally, then the collected tumor tissue sample
must be submitted for the central confirmation before the enrollment.
All patients (except for Part D) will be asked to consent to optional biopsies. These biopsy
samples will be used to support the development of the diagnostic assay and further exploratory
research.
The optional screening sample should be obtained at the same time and as part of the same
sample procedure as the mandatory biopsy for T790M status.
Tumor samples will preferably be in the form of a formalin fixed paraffin embedded block
(tissue derived from the diagnostic tumor or a metastatic site). If this is not possible, slides of
freshly prepared unstained 5 micron sections from the archival tumor block may be provided.
Further details on sample processing, handling and shipment are provided in the laboratory
manual.
6.4.1.2. Collection of exploratory Blood-born biomarker
Approximately 20 mL blood sample will be collected to provide plasma to evaluate genetic
mutations including but not limited to EGFR mutations, which may be predictive of the activity
of YH25448. But the volume of blood can be reduced by 10 mL considering patients’ condition.
For sampling schedule, see Study Plan (Table 8, Table 9 and Table 10).
Details of sample collection, processing, shipping and storage will be described in the
laboratory manual.
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6.4.1.3. Collection of plasma for exploratory analysis of cfDNA
All patients (except for Part D) will be requested to provide mandatory plasma samples for
analysis of circulating free tumor DNA (cfDNA) until the primary database lock at screening
and every 2 cycles until disease progression (as per RECIST 1.1). The sample may be used to
further investigate the relationship between PK and blood-born biomarkers.
Approximately 20 mL blood sample will be collected to provide plasma but the volume of
blood can be reduced by 10 mL considering patients’ condition.
Plasma samples will be taken at the following times:
 
Screening
 
Pre-dose Day 1
 
Every 2 cycles up to and including progression (corresponding with the RECIST  1.1
assessments)
 
Discontinuation of treatment
The samples will be analyzed for a range of oncology biomarkers which may correlate with
drug response.
Details on sample processing, handling, shipment and storage are provided in the laboratory
manual.
6.4.1.4. Collection of cerebrospinal fluid
If the patient agrees, a sample of CSF (minimum 2 mL up to 5 mL) will be obtained at one time
point taken at any time from Day 1 Cycle 2 onwards. Samples will be collected, labeled and
stored and shipped as detailed in the laboratory manual.
Any residual CSF after PK analysis may be used for exploratory research into factors that may
influence development of NSCLC and/or response to YH25448.
For Part D: No CSF samples will be collected
6.4.2. Collection of Pharmacogenetics samples
If a patient agrees to participate in the host pharmacogenetics research component of the study,
a blood sample will be collected. The results of this pharmacogenetic research will be reported
separately and will not form part of the Clinical Study Report.
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In Parts A, B or C, the 10mL of blood sample for genetic research will be obtained from the
patients immediately prior to the first administration of YH25448 in the study. In Part D the
10mL blood sample for assessment of genetic variants of GSTM1 may be collected at any time
during the study although collection during screening is preferred. PK blood samples may also
be utilized for this process. Although genotype is a stable parameter, early sample collection is
preferred to avoid introducing bias through excluding patients who may withdraw due to an
adverse event. Such patients would be important to include in any genetic analysis. If for any
reason the sample is not drawn prior to dosing, it may be taken at any visit until the last study
visit. Only one sample should be collected per patient for genetics during the study. Samples
will be collected, labeled, stored and shipped as detailed in the Laboratory Manual.
6.5. Patient Reported outcomes
The following PROs will be administered: EORTC QLQ C-30, QLQ-LC13 and QLQ-BN20
until the primary database lock.
EORTC QLQ-C30 and QIQ-LC 13 and QLQ-BN20
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group 1993. It consists
of 30 items and measures cancer patients’ functioning (HRQoL) and symptoms10. The EORTC
QLQ-BN20 (BrM patients only) was developed for use among brain cancer patients varying in
disease stage and treatment modality (i.e. surgery, chemotherapy, radiotherapy, etc.). It should
always be complemented by the QLQ-C3011. Relevant symptom questions from QLQ-BN20
will be used to explore CNS symptom improvement. The QLQ-LC13 is a complementary
module measuring lung cancer associated symptoms and side-effects from conventional
chemotherapy and radiotherapy.12
Administration of PROs
Questionnaires will be administered using paper questionnaires. The patient should complete
the questionnaires at the scheduled clinic visit at screening, every 2 cycles relative to the first
dose of multiple dosing and progression as specified in the study plan (Table 8, Table 9 and
Table 10).The patient should also complete a questionnaire progression. If any scheduled PRO
assessment is not completed, the reason for non-completion should be recorded.
PROs will be filled out prior to any other center activities when patient visit the center. The
patients will be instructed to complete the PRO independently. This center will have a
designated quiet space for patients to use when completing the assessments. Each center should
allocate responsibility for PRO assessment to a specified individual (e.g. a research nurse). It
is important that the value and relevance of HRQoL data are explained carefully to participating
patients so that they are motivated to comply with data collection. The research nurse or
appointed individual should also stress that the information is confidential. Therefore, if the
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patient has any medical problems he/she should discuss them with the doctor or research nurse
separately from their HRQoL assessment.
The instructions for completion of questionnaires are:
 
It must be completed before any investigations or discussions about the status of the patient’s
disease with the clinic staff.
 
The patient must complete it themselves without any intervention from family, friends, centre
staff etc.
 
The only exception to this is if the patient is blind or illiterate. In this case the questionnaire
may be read to the patient verbatim, however the reader must not aid in the interpretation of
questions or in the selection of answers.
 
Only one answer to every question should be checked.
 
Centre personnel should not review the responses to the questionnaire with the patient or with
any other centre staff.
Following completion, the research nurse or appointed individual may quickly scan the
questionnaire visually for completeness and should confirm verbally with the patient that the
questionnaire has been completed fully.
6.6. Biological sampling procedures
6.6.1. Volume of blood
The number of samples taken, as well as the volume required for each analysis, may be changed
during the study as new data on YH25448 become available. The estimated total volume of
blood that will be drawn from each patient in this study for mandatory and optional samples,
see Table 14.
Safety laboratory assessments will be performed locally at each center’s laboratory by means
of their established methods. The number of samples/blood volumes is therefore patient to site-
specific change.
Table 14. Blood Volume
Assessment
Visit 
Blood 
Biomarker & 
Pharmacogenetic 
Testing3 
cfDNA  
(except 
for Part 
D) 
Safety  
(hematology 
and
chemistry)
PK for Parts 
A, B and C2
PK for Part D4
Screening 
(20 mL1+10mL) 
20mL 
15mL 
-
Day 1, Cycle 0 
- 
20mL 
15mL 
81 mL (9 mL x 
30 mL (6 mL x
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every 2 
cycles
correspon  
ding to 
RECIST
1.1 tumor
assessmen
t1
9) 
5)
Day 2, Cycle 0 
- 
- 
9 mL 
6 mL 
Day 3, Cycle 0 
- 
15mL 
18 mL(9 mL x 
2)
6 mL
Day 1, Cycle 1 
- 
15mL 
9 mL 
6 mL 
Day 8, Cycle 1 
- 
- 
9 mL 
6 mL 
Day 15, Cycle 1 
- 
15mL 
9 mL 
6 mL 
Day 1~2, Cycle 2 
and every 2 
cycles 
- 
15mL 
Cycle 2, Day 1: 
81 mL (9 mL x 
9) 
Cycle 2, Day 2: 
9 mL 
Cycle 2, Day 1:
30 mL (6 mL x
5)
Cycle 2, Day 2:
6 mL
Every other
cycle from
Cycle 3
onwards, Day
1: 6mL
Unscheduled 
visit
- 
(15mL) 
-
Discontinuation 
- 
15mL 
-
1. The volume of blood for blood biomarker and cfDNA can be reduced by 10 mL considering patient’s condition
(for Parts A, B and C only).
2. Cycle 0 for Part A; Cycle 1 for Parts A, B and C; Cycle 2 for Parts A and B; About 9 ml blood sample will be
collected at a time.
3. It is optional samples
4. About 6 ml blood sample will be collected at a time for Part D.
6.6.2. Handling, storage and destruction of biological samples
The samples will be used up, or disposed of after analyses or retained for further use as
described below.
Any PK sample remaining after analysis for YH25448 and its potential metabolites, including
M7, may be used for exploratory biomarker analyses. These analyses are for Sponsor use only
and will not be included in the Clinical Study Report.
Biological samples for future research will be retained at the Sponsor or its designee for a
maximum of 15 years following the finalization of the Clinical Study Report. The results from
future analysis will not be reported in the Clinical Study Report but separately in a bioanalytical
method validation report.
6.6.3. Pharmacokinetic samples
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of
the test samples and reported in a separate bioanalytical report.
Key samples for metabolite identification and/or analysis will be retained at designated contract
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laboratory, on behalf ofthe Sponsor for a maximum of 5 years following the finalization of the
Clinical Study Report. The results from the investigation will not be reported in the Clinical
Study Report but separately report.
6.6.4. Samples for exploratory research
Details of sample collection, processing, shipping and storage will be described in the
laboratory manual.
Each sample for exploratory research will be identified with the study number and patient
enrolment number. In this way exploratory biomarker and genetic data may be correlated with
clinical data, samples destroyed in the case of withdrawal of consent and regulatory audit
enabled.
Where genetic analysis will be undertaken the processes adopted for the coding and storage of
samples will be more stringent in order to maintain patient confidentiality. As an added
precaution, irrespective of the type of sample, the DNA sample will be assigned a unique
number replacing the information on the sample tube. Thereafter, the DNA sample will be
identifiable by the unique DNA number only. The DNA number will be used to identify the
sample and corresponding data at the Sponsor, or at the designated contract laboratory. No
personal details identifying the individual will be available to any person (Sponsor employee
or contract laboratory staff) working with the DNA.
The samples and data for genetic analysis in this study will be single coded. The link between
the patient enrolment code and the DNA number will be maintained and stored in a secure
environment, with restricted access at the Sponsor, or at the designated contract laboratory.
The link will be used to identify the relevant DNA samples for analysis, facilitate correlation
of genotypic results with clinical data, allow regulatory audit and to trace samples for
destruction in the case of withdrawal of consent when the patient has requested
disposal/destruction of collected samples not yet analyzed.
6.6.5. Labeling and shipment of biohazard samples
The Principal Investigator ensures that samples are labeled and shipped in accordance with the
Laboratory Manual and the Biological Substance, Category B (materials containing or
suspected to contain infectious substances that do not meet Category A criteria), see
appendix C of this Clinical Study Protocol ‘IATA 6.2 Guidance Document’.
Any samples identified as infectious category A materials are not shipped and no further
samples taken from the patient unless agreed with  the Sponsor and appropriate labeling,
shipment and containment provisions are approved.
All archival tumor samples should be shipped at ambient temperature as per the laboratory
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manual to the Sponsor designated central Contract Research Organization.
6.6.6. Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each center keeps full traceability of collected biological samples
from the patients while in storage at the center until shipment or disposal (where appropriate)
and keeps documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
The sponsor keeps oversight of the entire life cycle through internal procedures, monitoring of
study centers and auditing of external laboratory providers.
Samples retained for further use are registered in the Sponsor or the designated contract
laboratory during the entire life cycle.
6.6.7. Withdrawal of informed consent for donated biological samples
If a patient withdraws consent to the use of voluntarily donated biological samples, then the
samples will be disposed of/destroyed, and the action documented. If samples are already
analyzed, the Sponsor is not obliged to destroy the results of this research. The patient may
continue in the study.
The Principal Investigator:
 
Ensures the Sponsor is notified immediately of the patient’s withdrawal ofinformed consent
to the use of donated biological samples
 
Ensures that biological samples from that patient, if stored at the study centre, are immediately
identified, disposed of/destroyed, and the action documented
 
Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn consent
immediately and that samples are disposed of/destroyed, the action documented and the signed
document returned to the study centre
6.7. Anti-tumor activity
6.7.1. Tumor assessments
RECIST 1.1 guidelines for measurable, non-measurable, target lesions (TLs) and non-target
lesions (NTLs) and the objective tumor response criteria are presented in appendix F of this
Clinical Study Protocol. Baseline CT or MRI assessments of chest and abdomen (including
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liver and adrenal glands) must be performed no more than 28 days before the start of study
treatment, and ideally should be performed as close as possible to the start of study treatment.
Additional imaging may be performed based on individual patient signs and symptoms MRI
(or CT if not applied to MRI) scan of the brain should be performed in all patients. In Part D
(patients outside Korea) a brain MRI will be performed at screening in all patients. The
methods of assessment used at baseline should be used at each subsequent follow-up
assessment. Follow-up assessments should be performed every 2 cycles (± 7 days) after the
start of multiple dosing until objective disease progression as defined by RECIST 1.1 even if
a patient discontinues treatment prior to progression. After the primary database lock,
radiological disease evaluations are not required and may be performed at the discretion of the
investigator in accordance with local standard of care. Responses and disease progression
status will be recorded in EDC.
Any other sites at which new disease is suspected should also be appropriately imaged. If an
unscheduled assessment is performed and the patient has not progressed, every attempt should
be made to perform subsequent assessments at the scheduled visits whilst the patient remains
on study treatment.
Categorization of objective tumor response assessment will be based on the RECIST 1.1
guidelines for response: CR (complete response), PR (partial response), SD (stable disease)
and PD (progression of disease). Target lesion progression will be calculated in comparison to
when the tumor burden was at a minimum (i.e. smallest sum of diameters previously recorded
on study). In the absence of progression, tumor response (CR, PR, SD) will be calculated in
comparison to the baseline tumor measurements obtained before starting treatment.
If the investigator is in doubt as to whether progression has occurred, particularly with response
to NTLs or the appearance of a new lesion, it is advisable to continue treatment and reassess
the patient’s status at the next scheduled assessment or sooner if clinically indicated. If repeated
scans confirm progression, then the date of the initial scan should be declared as the date of
progression.
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an
overall level of substantial worsening in non-target disease such that, even in presence of SD
or PR in target disease, the overall tumor burden has increased sufficiently to merit
discontinuation of therapy. A modest ‘increase’ in the size of one or more NTLs is usually not
sufficient to qualify for unequivocal disease progression status.
The RECIST 1.1 guidelines for measurable, non-measurable, target and non-target lesions and
the objective tumor response criteria (complete response, partial response, stable disease or
progression of disease) will be modified for the separate assessment of extracranial disease and
intracranial disease in brain metastatic patients according to Appendix F.
Intracranial disease will be assessed separately from extracranial disease using RECIST 1.1
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criteria and appendix F  and a separate assessment of CR (complete response), PR (partial
response), SD (stable disease) and PD (progression of disease). Target lesion (TL) progression
will be calculated in comparison to when the tumor burden was at a minimum (i.e. smallest
sum of diameters previously recorded on study). In the absence of progression, tumor response
(CR, PR, SD) will be calculated in comparison to the baseline tumor measurements obtained
before starting treatment.
If study treatment continues after the patient experiences disease progression extracranially but
with improved/stable intracranial disease, the patient should continue RECIST 1.1 assessments
based on appendix F every 2 cycles until disease progression intracranially (for Parts A, B and
C only) After the primary database lock, radiological disease evaluations are not required and
may be performed at the discretion of the investigator in accordance with local standard of care.
Responses and disease progression status will be recorded in EDC.
Table 15. Radiological assessment follow-up according to the response
Extracranial 
Response 
Intracranial
Response
Overall response 
Radiological Assessment Follow-up
Non-PD or NE 
Non-PD or NE 
Non-PD or NE
Continue radiological assessments
until disease progression
PD  
Non-PD or NE 
PD  
Continue radiological assessments
until disease progression
intracranially
Non-PD or NE 
PD  
PD  
Discontinue radiological assessment
PD  
PD  
PD  
Discontinue radiological assessment
Non-PD: complete response, partial response, stable disease
PD: progressive disease
NE: Not evaluable
It is important to follow the assessment schedule as closely as possible. Please refer to the study
plan in Section 6.1 and appendix F.
All RECIST 1.1 assessment images will be reviewed centrally (for Parts A, B and C only).
Duplicates may be collected and stored by the Sponsor appointed representative, and sent for
independent central review, if deemed appropriate.
The independent central review will be performed for all patients (for Parts A, B and C only).
Details of the independent central review will be documented in the Independent Review
Charter.
After the primary database lock, the independent central review will not be performed anymore.
7. ADVERSE EVENTS
The principal investigator is responsible for ensuring that all staff involved in the study is
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familiar with the content of this section.
7.1. Definitions of adverse events
An adverse event is the development of an undesirable medical condition or the deterioration
of a pre-existing medical condition following or during exposure to a pharmaceutical product,
whether or not considered causally related to the product. An undesirable medical condition
can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram). In clinical
studies, an AE can include an undesirable medical condition occurring at any time, including
run-in or washout periods, even if no study treatment has been administered.
Any deterioration of the disease under study and associated symptoms or findings should not
be regarded as an adverse event as far as the deterioration can be anticipated (see Section 7.3.7).
The term adverse event is used generally to include any AE whether serious or non-serious.
7.2. Definition of Serious Adverse Events
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., run-in,
treatment, washout and follow-up), that fulfils one or more of the following criteria:
 
Results in death
 
Is life-threatening (defined as an event in which the patient was at risk of death at the time of
the event; it does not refer to an event which hypothetically might have caused death if it were
more severe)
 
Requires in patient hospitalization or causes prolongation of existing hospitalization (see note
below for exceptions)
 
Results in persistent or significant disability/incapacity or substantial disruption of the ability
to conduct normal life functions
 
Is or results in a congenital abnormality or birth defect
 
Any important medical event such as the occurrence of drug dependence or abuse or blood
disorders. (defined as a medical event(s) that may not be immediately life-threatening or result
in death or hospitalization but, based upon appropriate medical and scientific judgment, may
jeopardize the patient or may require intervention [e.g., medical, surgical] to prevent one of
the other serious outcomes listed in the definition above.) Examples of such events include,
but are not limited to, intensive treatment in an emergency room or at home for allergic
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.)
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All pregnancies, regardless of outcome, must be reported to the Sponsor on a Pregnancy
Surveillance Form. Although cancer is not always serious by regulatory definition, these events
should be reported to the Sponsor in an expedited manner according as SAEs.
NOTE:
The following hospitalizations are not considered SAEs in Sponsor clinical studies:
 
a visit to the emergency room or other hospital department < 24 hours, that does not result in
admission (unless considered an "important medical event" or event life threatening)
 
elective surgery, planned prior to signing consent
 
admissions as per the protocol for a planned medical/surgical procedure
 
routine health assessment requiring admission for baseline/trending of health status (e.g.,
routine colonoscopy)
 
medical/surgical admission for purposes other than remedying ill health state and that are
planned prior to entry into the study. Appropriate documentation is required in these cases
 
admission due to another life circumstance that carries no bearing on health status and requires
no medical/surgical intervention (e.g., lack of housing, economic inadequacy, care-giver
respite, family circumstances, administrative)
7.3. Recording of adverse events
7.3.1. Time period for collection of adverse events
AEs will be collected throughout the study, from informed consent until the end of the follow-
up period. The follow-up period is defined as 28 days after study treatment is discontinued.
SAEs occurring in the 28 follow-up period should be reported to the Sponsor in the usual
manner (see Section 7.4).
Following discontinuation of YH25448, SAEs considered related to study procedures should
continue to be collected.
After the primary database lock, there may be some patients remaining on study treatment. For
these patients who are continuing to receive YH25448, the Sponsor will collect information
(during the treatment period and for 28 days after last dose) on SAEs, deaths (including those
due to disease progression), discontinuation due to AEs/SAEs and drug accountability only.
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7.3.2. Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the
investigator for as long as medically indicated, but without further recording in the CRF. The
Sponsor retains the right to request additional information for any patient with ongoing AE(s)
at the end of the study, if judged necessary.
If an investigator learns of any SAEs, including death, at any time after a patient has completed
the study and he/she considers there is a reasonable possibility that the event is related to
YH25448, the investigator should notify the Sponsor.
7.3.3. Variables
The following variables will be collected for each AE:
 
AE diagnosis/description
 
The date when the AE started and stopped
 
CTCAE grade
 
Whether the AE is serious or not
 
Investigator causality rating against the investigational product (yes or no)       (Certain,
Probable/Likely, Possible, Unassessable/Unclassifiable will be considered to ‘Yes’ and
Unlikely, Not related will be considered to ‘No’.)
 
Action taken with regard to investigational product
 
Outcome
For SAEs other variables will be collected including treatment given for the event.
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity,
an AE of severe intensity need not necessarily be considered serious. For example, nausea that
persists for several hours may be considered severe nausea, but not a SAE. On the other hand,
a stroke that results in only a limited degree of disability may be considered a mild stroke but
would be a SAE. Seriousness is defined by the criteria in Section 7.2.
The grading scales found in the  National Cancer Institute CTCAE 4.03 version  will be
utilized for all events with an assigned CTCAE grading. For those events without assigned
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and
severe events into CTCAE grades should be used. A copy of the CTCAE version can be
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downloaded 
from 
the 
Cancer 
Therapy 
Evaluation 
Programmed 
website
(https://ctep.cancer.gov/).
7.3.4. Causality collection
The investigator will assess causal relationship between investigational product and each
adverse 
event, 
and 
answer 
‘yes 
(Certain, 
Probable/Likely, 
Possible,
Unassessable/Unclassifiable)’ or ‘no (Unlikely, Not related)’ to the question: ‘Do you consider
that there is a reasonable possibility that the event may have been caused by the investigational
product?’
For SAEs causal relationship will also be assessed for other medication and study procedure.
Note that for SAEs that could be associated with any study procedure the causal relationship is
implied as ‘yes’.
7.3.5. Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or care provider or reported in response to the
open question from the study personnel: ‘Have you had any health problems since the previous
visit/you were last asked?’, or revealed by observation will be collected and recorded in the
eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to
recording a list of signs and symptoms. However, if a diagnosis is known and there are other
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or
symptom will be recorded separately.
7.3.6. Adverse events based on examinations and tests
The results from protocol mandated laboratory tests, vital signs, ECGs and other safety
assessments will be summarized in the Clinical Study Report. Deterioration as compared to
baseline in these parameters will therefore only be reported as AEs if they fulfill any of the
criteria for a SAE, a DLT or are the reason for discontinuation of treatment with the
investigational product unless clearly due to progression of disease under study (see Disease
progression as below).
If deterioration in a laboratory value, vital sign, ECG or other safety assessment is associated
with clinical signs and symptoms, the sign or symptom will be reported as an AE and the
associated laboratory result or other finding will be considered as additional information.
Wherever possible the reporting investigator uses the clinical, rather than the laboratory term
(e.g., anemia versus low hemoglobin value). In the absence of clinical signs and symptoms,
clinically relevant deteriorations in non-mandated parameters should be reported as AE(s).
Deterioration of a laboratory value that is unequivocally due to disease progression should not
be reported as an AE.
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Any new or aggravated clinically relevant abnormal medical finding at a physical examination
as compared with the baseline assessment will be reported as an AE.
7.3.7. Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to
the disease for which the investigational product is being studied. It may be an increase in the
severity of the disease under study and/or increases in the symptoms of the disease. The
development of new, or progression of existing metastasis to the primary cancer under study
should be considered as disease progression and not an AE. Events that are unequivocally due
to disease progression should not be reported as AEs during the study.
7.3.8. New cancers
New cancers are those that are not the primary reason for the administration of the study
treatment and have been identified after the patient’s inclusion in this study. They do not
include metastases of the original cancer. The development of a new cancer should be regarded
as an AE and should be reported according as the AE.
7.3.9. Handling of deaths
All deaths that occur during the study, or within the follow-up period after the administration
of the last dose of investigational product, should be reported as follows:
 
Death, which is unequivocally due to disease progression, should be communicated to the
study monitor at the next monitoring visit and should be documented in the CRF module, but
should not be reported as a SAE during the study
 
Where death is not clearly due to disease progression of the disease under study the AE
causing the death should be reported to the study monitor as an SAE within 24 hours. The
report should contain a comment regarding the co-involvement of progression of disease, if
appropriate, and should assign a single primary cause of death together with any contributory
causes
 
Deaths with an unknown cause should always be reported as a SAE but every effort should
be made to establish a cause of death. A post-mortem may be helpful in the assessment of the
cause of death, and if performed a copy of the post-mortem results (with translation of
important parts into English) should be reported in an expedited fashion to a Sponsor
representative within the usual timeframes
7.4. Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational
product or to the study procedure(s) and will be recorded in the eCRF.
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If any SAE occurs in the course of the study, then investigators or other centerpersonnel inform
appropriate Sponsor representatives immediately, or no later than 24 hours of when he or she
becomes aware of it.
The designated Sponsor representative works with the investigator to ensure that all the
necessary information is provided to pharmacovigilance department within one calendar day
of initial receipt for fatal and life threatening events and all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing,
active follow-up is undertaken immediately. Investigators or other center personnel inform the
Sponsor representatives of any follow-up information on a previously reported SAE
immediately, or no later than 24 hours of when he/ she becomes aware of it.
Once the investigators or other center personnel indicate an AE is serious, then the investigator
or other study center personnel reports a SAE to the appropriate Sponsor representative. The
Sponsor representative will advise the investigator/study center personnel how to proceed.
7.5. Contact Information for reporting SAE
SAE EMAIL TRANSMISSION: 
SAE CONTACT
COUNTRY  
Toll Free Fax-No 
Toll Free Phone-No
SOUTH KOREA  
 
OUTSIDE KOREA  
 
SAE Alternative CONTACT
SOUTH KOREA:
OUTSIDE KOREA:
7.6. Overdose
There are no data on overdosing is available since this is the first study in humans with
YH25448. There is no definition of what constitutes an overdose and no known antidote.
Except the case of the dose escalation, investigators will be advised that any patient who
receives a higher dose than that intendeddaily dose should be monitored closely, managed with
appropriate supportive care and followed up expectantly.
Such overdoses should be recorded as follows:
 
An overdose with associated AEs/SAEs is recorded as the AE diagnosis/symptoms on the
relevant AE/SAE modules in the eCRF and on the overdose eCRF module.
PPD
PPD
PPD
PPD
PPD
P
PPD
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 
An overdose with no associated symptoms is only reported on the overdose eCRF module.
If an overdose with associated AEs/SAEs occurs in the course of the study, then investigators
or site staff inform the Sponsor representatives immediately a completed Report within 24
hours of knowledge of the event.
The designated Sponsor representative works with the investigator to ensure that all relevant
information is provided to the eCRF.
For overdoses associated with a SAE, standard reporting timelines apply, see Section 7.4.
7.7. Pregnancy
All pregnancies and their subsequent outcome (spontaneous miscarriage, elective termination,
ectopic pregnancy, normal birth or congenital abnormality) should be reported to the Sponsor
using the appropriate forms during the course of the study and within 28 days of the last dose
of YH25448.
7.7.1. Maternal exposure
If a patient becomes pregnant during the course of the study investigational product should be
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the
investigational product under study may have interfered with the effectiveness of a
contraceptive medication. Congenital abnormalities/birth defects and spontaneous
miscarriages should be reported and handled as SAEs. Elective abortions without
complications should not be handled as AEs. The outcome of a pregnancy should be followed
up and documented even if the patient was withdrawn from the study but not more than 30
days after completion of the pregnancy.
If a pregnancy occurs during exposure to investigational product or in the 28 days after
discontinuing investigational product, then investigators or other center personnel inform the
Sponsor representatives immediately by faxing or emailing a completed Pregnancy Report
within 24 hours of knowledge of the event.
The same timelines apply when outcome information is available.
7.7.2. Paternal exposure
Pregnancy of a patient’s partner is not considered to be an adverse event.
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However, the outcome of all pregnancies (spontaneous miscarriage, elective termination,
ectopic pregnancy, normal birth or congenital abnormality) should if possible be followed up
and documented.
To capture information about a pregnancy from the partner of a male patient, the male patient’s
partner consent must be obtained to collect information related to the pregnancy and outcome.
A consent form specific to this situation must be used. The outcome of any conception
occurring from the date of the first dose until 3 months after dosing ends should be followed
up and documented.
7.7.3. Requirements for Pregnancy Testing
All WOCBP MUST have a negative pregnancy test result at screening prior to receiving the
investigational product and discontinuation visit (refer to inclusion criterion 2 in section 4.2.1).
If the pregnancy test result is positive, the patient must not receive the investigational product
and must not continue in the study.
Pregnancy testing must also be performed throughout the study as specified in Section 6.1 (see
flow chart/time and events schedule) and the results of all pregnancy tests (positive or negative)
recorded on eCRF.
In addition, all WOCBP should be instructed to contact the investigator immediately if they
suspect they might be pregnant (e.g., missed or late menstrual period) at any time during study
participation.
7.7.4. Reporting of Pregnancy
If, following administration of the investigational product, it is subsequently discovered that a
study patient is pregnant or may have been pregnant, the investigator must immediately notify
the Sponsor representative of this event, record the pregnancy on the Pregnancy Surveillance
Form (not an SAE form) within 24 hours. Initial information on a pregnancy must be reported
immediately to the Sponsor and the outcome information provided once the outcome is known.
Completed Pregnancy Surveillance Forms must be forwarded to the Sponsor in accordance
with SAE reporting procedures described in Section 7.4.
Protocol-required procedures for study discontinuation and follow-up must be performed with
the patient unless contraindicated by pregnancy (e.g., X-ray studies). Other appropriate
pregnancy follow-up procedures should be considered if indicated. Follow-up information
regarding the course of the pregnancy, including prenatal and neonatal outcome must be
reported on the Pregnancy Surveillance Form.
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Any pregnancy that occurs in a female partner of a male study participant should be reported
to the Sponsor study physician. Information on this pregnancy will be collected on the
Pregnancy Surveillance Form.
8. STATISTICAL CONSIDERATIONS
8.1. Sample Size Determination
Part A: Dose Escalation Phase
Approximately 30 patients with EGFRm+ NSCLC who had progressed following prior EGFR
TKIs therapy will be enrolled in dose escalation phase. The total number of patients will depend
upon the number of dose escalations necessary. At least 3 and up to 6 evaluable patients will
be required for each dose cohort.
Part B: Dose Expansion Phase
Approximately 20 evaluable patients with T790M+ mutation NSCLC, on the basis of central
confirmed T790M mutation result, regardless ofasymptomatic brain metastasis or without brain
metastasis (2nd line expansion with/without BrM) who had progressed following prior EGFR
TKIs therapy will be enrolled per dose cohort. There are no specific stopping criteria for this
phase of the study, however, emerging data from expansion phases will be monitored regularly
and decided to stop patients enrollment by the SRC.
Part C: Dose Extension Phase
2nd  line therapy cohort
A total of 60 evaluable patients is required for the 2nd line therapy cohort in Part C. This sample
size will provide 88% power to test a difference of 45% (not considered clinically compelling)
versus 65% (ORR of minimal clinically meaningful) using a one-sided 0.025 alpha level13.
An example of ORR and the corresponding 95% confidence interval is provided below:
 40% ORR (24/60 responses); 95% CI [27.6%, 52.4%]
 50% ORR (30/60 responses); 95% CI [37.3%, 62.7%]
 60% ORR (36/60 responses); 95% CI [47.6%, 72.4%]
 70% ORR (42/60 responses); 95% CI [58.4%, 81.6%]
 80% ORR (48/60 responses); 95% CI [69.9%, 90.1%]
1st line therapy cohort
A total of 40 evaluable patients is required for the 1st line therapy cohort in Part C. This sample
size will provide 93% power to test a difference of 55% (not considered clinically compelling)
versus 80% using a one-sided 0.025 alpha level14, 15.
An example of ORR and the corresponding 95% confidence intervals is provided below:
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 50% ORR (20/40 responses); 95% CI [34.5%, 65.5%]
 60% ORR (24/40 responses); 95% CI [44.8%, 75.2%]
 70% ORR (28/40 responses); 95% CI [55.8%, 84.2%]
 80% ORR (32/40 responses); 95% CI [67.6%, 92.4%]
 90% ORR (36/40 responses); 95% CI [80.7%, 99.3%]
Part D: Patients Outside Korea
Approximately 12-15 patients outside Korea will be enrolled at each 240 mg and 320 mg dose
level to provide a minimum of 6 Caucasian patients with evaluable PK. Although enrollment
will not be based on race, it is expected that approximately 80% of patients will be Caucasian.
All patients will have progressed following prior EGFR TKI therapy.
8.2. Populations for Analyses
The analyses of data will be based on different populations according to the purpose of the
analyses. Throughout the safety results sections, erroneously treated patients (e.g., those
assigned to receive dose A mg who actually received dose B mg, those who failed to meet the
selection criteria) will be accounted for in the actual dose group received. Analysis populations
are described below:
 
Screened population: all patients who have signed a written ICF and received a screening
number
 
Safety analysis population: All patients who received at least one dose of IP
 
Evaluable for response population: All patients in the safety analysis population who has a
baseline RECIST 1.1 assessment whose tumor EGFR mutation status was confirmed via a
central testing. Central testing results must match the cohort to which they were assigned. For
Part D, all patients in the safety analysis population who have a baseline RECIST 1.1
assessment (no central testing of EGFR mutation status is required).
 
Brain metastatic full analysis population: All patients in the evaluable for response population
who have a measurable and/or unmeasurable intracranial lesion at baseline.
 
Brain metastatic evaluable for response population: All patients in the brain metastatic full
analysis population who have at least one measurable intracranial lesion at baseline.
 
Pharmacokinetic analysis population: All patients who have at least one measurable
concentration collected post-dose.
 
Exploratory biomarkers analysis population: All patients that participate in the exploratory
biomarker research.
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8.3. Patient Disposition
The number of patients in the safety, evaluable for response, pharmacokinetic populations will
be summarized by dose level, overall, and by institute. The screened population will only be
summarized overall and by study center. Screening failures (i.e., patients who signed the ICF
but are not received at least one dose of IP) and the associated reasons for failure will be
tabulated overall.
All enrolled patients will be accounted for in the patient disposition table. The number of
patients and percentage of patients will be presented for discontinued patients, and for each
reason for discontinuation. Reasons for discontinuation of investigational product will be listed
including the study day of treatment discontinuation and will be summarized by dose group.
Important deviations from protocol will be summarized and listed for all patients.
8.4. Demographics and Other Baseline Characteristics
Demographic, baseline characteristics, extent of disease, ECOG performance status and
smoking status of the patients will be listed for each patient and summarized by dose group.
Baseline information (e.g. medical and surgical history), prior chemotherapy, prior
radiotherapy and concomitant medications (baseline and post first dose) will also be listed
individually for each patient and summarized by dose group.
No statistical tests will be performed.
8.5. Assessment of Treatment Compliance
Exposure to investigational product i.e., total amount of study drug received will be listed for
all patients.
Total exposure and total time on study (date of last dose minus date of first dose) will be
summarized by the following: mean, standard deviation, minimum, maximum, median and
number of observations. In addition, the number and percentage of patients with at least one
dose interruption/dose delay and at least one dose reduction will be presented separately for
the initial period defined as 21 days of multiple dosing (Cycle 1) and for any time following
this initial period of the study.
8.6. Endpoint Definition
Efficacy analyses will be performed based on the evaluable for response population. Sensitivity
analysis will be performed to assess the robustness of the conclusions of the efficacy analysis.
Safety analysis will be performed using the safety analysis population. PK analysis will be
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performed using the pharmacokinetic analysis population. Unless specified otherwise, baseline
for efficacy parameters is defined as the last non-missing efficacy measurement before the first
administration of IP.
8.6.1. Efficacy Endpoints
8.6.1.1. Primary Endpoints (Parts A, B, and C)
 
Safety and tolerability (primary for dose escalation and expansion phase)
 
Objective response rate (ORR) (primary for dose extension, secondary for dose escalation and
expansion phase)
8.6.1.2. Secondary Endpoints (Parts A, B, and C)
 
PK parameters of YH25448 and its metabolites following a single oral dose and multiple oral
doses.
 
Duration of Response (DoR), disease control rate (DCR), tumor shrinkage
 
Progression free survival (PFS) (secondary for dose expansion and extension phases)
 
Overall survival (OS) (secondary for the selected extension dose in extension phase and
extension phase)
 
For the BrM patients only (secondary for dose expansion and extension phases): objective
intracranial response rate (OIRR), duration of intracranial response (DoIR), intracranial
progression free survival (IPFS)
8.6.1.3. Primary and Secondary Efficacy Endpoints for Part D
Primary Endpoints
 
Safety, tolerability, and PK of YH25448
Secondary Endpoints
 PK profiles of potential YH25448 metabolites in plasma, including M7, following a single
oral dose and at steady state.
 Overall response rate (ORR)
 Duration of response (DoR)
 Disease control rate (DCR)
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 Tumor shrinkage
 Progression free survival (PFS)
 Overall survival (OS)
8.6.2. Safety Variables
AEs, physical examination, clinical laboratory information, vital signs, ECOG performance
status, ECG parameters, and concomitant medications/procedures will be tabulated and
summarized.
8.6.3. Pharmacokinetic Endpoints
For each patient, the following PK parameters will be calculated, whenever possible, based on
the plasma and CSF concentrations of YH25448 and its potential metabolites, including M6
and M7:
Following the single dose in Parts A and D:
Area under the plasma concentration-time curve from zero to the time of the last quantitative
concentration (AUCt), from zero to infinity (AUCinf) and from zero to 24 hours (AUC0 24),
maximum plasma concentration (Cmax), time to reach Cmax  (Tmax), apparent terminal
elimination half-life (t1/2), apparent terminal elimination rate constant (λz) of YH25448 and its
metabolites, and apparent plasma clearance (CL/F), apparent volume of distribution (Vd/F) of
YH25448, metabolic ratio (MR) of metabolites.
Following the multiple doses in Parts A, B and D:
Area under the plasma concentration-time curve from zero to the end of the dosing interval
(AUCss), maximum plasma concentration at steady state (Cmax,ss), time to reach Cmax,ss (Tmax,ss),
accumulation ratio (Rac) of YH25448 and its metabolites, and apparent plasma clearance at
steady state (CLss/F) of YH25448, metabolic ratio at steady state (MRss) of metabolites.
If sufficient data are available, population pharmacokinetic analysis of plasma concentration-
time data of YH25448 may be performed using nonlinear mixed-effects modeling and will be
reported in a separate report.
Following the multiple doses in Parts A, B and C:
CSF concentration (CCSF) of YH25448 and its metabolites.
Following the multiple doses in all four Parts:
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Trough plasma concentrations on Days 1, 8, 15 of Cycle 1 (CD1, CD8, CD15).
8.6.4. Exploratory Endpoints
Parts A, B, and C
 
Patient Reported Outcome: EORTC QLQ LC-13, QLQ C-30, QLQ BN-20 (Brain
metastasis patients only)
 
Metabolite identification
 
Biomarker data
 
Pharmacogenetics
 
Diagnostic tumor samples
Part D
 
Pharmacogenetic assessment of variants that encode GSTM1
8.7. Analyses
A detailed statistical analysis plan (SAP) will be completed prior to the final database lock. It
will include details on the methodology used in the statistical analyses as well as details
regarding reporting and data derivations.
With the exception of some safety and PK summaries that may be combined, data from the
dose escalation and the dose expansion cohorts will be presented separately. PK summaries of
Part D will be presented separately. All summaries will present data by dose group. Data from
the extension cohort will always be presented separately. Pooled analysis as deemed
appropriate will be defined in the SAP.
The data may be assessed to determine RD. At the completion of cycle 2 of the last patient in
Part B, cycle 4 of the last patient in Part C 1st line, and cycle 6 of the last patient in Part C 2nd
line, the database freeze will be performed for analysis. After appropriate follow-up to assess key
endpoints, the primary database lock will be performed and will be reported in a CSR
After, the final database is locked to assess overall survival and safety, the relevant information
may be provided separately from CSR.
The intent of all efficacy analyses from the expansion and extension phase is that it be focused
on the population whose tumor EGFR mutation status is identified via central testing. Patients
central test results must match the cohort to which they were assigned (i.e. T790M+ in the
expansion phase).
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8.7.1. Calculation or Derivation of Variables
8.7.1.1. Tumor Response Variables
For the investigator’s assessment, at each visit patients will be assigned a RECIST visit
response of CR, PR, SD or PD depending on the status of their disease compared to baseline
and previous assessments.
Progression of TLs will be calculated in comparison to when the tumor burden was at a
minimum (i.e., smallest sum of diameters previously recorded on study). In the absence of
progression, tumor response (CR, PR, SD) will be calculated in comparison to the baseline
tumor measurements obtained before starting treatment.
If a patient has had a tumor assessment, which cannot be evaluated, then the patient will be
assigned a visit response of not evaluable (NE) unless there is evidence of progression in which
case the response will be assigned as PD.
A visit response of CR will not be allowed if any of the TL data is missing.
For endpoints assessed by independent central review (ICR), review of all radiological imaging
data will be carried out using RECIST version 1.1 and appendix F.
For brain metastatic patients, at each visit all patients will be assigned a appendix F extracranial
visit response depending on the status of their disease compared with baseline and previous
visit assessments. In addition, patients with intracranial disease will be assigned an intracranial
visit response.
Overall visit response will be derived as from the extracranial time-point response and
intracranial time-point response (Appendix F).
Overall tumor response and intracranial response by appendix F  will be reported for BrM
patients.
The following tumor response variables will then be derived:
 
Overall tumor response in brain metastatic patients
- 
Best objective response/objective response rate/disease control rate
- 
Duration of response
- 
Progression free survival
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 
Intracranial disease in brain metastatic patients
- 
Intracranial best objective response/objective response rate/disease control rate
- 
Duration of intracranial response
- 
Week 6 and week 12 percentage change in tumor size
- 
Intracranial progression free survival
Best Overall Response (BOR)
The BOR categories (CR, PR, SD [including non-CR/non-PD], PD, NE, Unknown) will be
derived based upon time point tumor responses during the study as assessed by ICR as well as
the investigator. BOR of SD must occur at least 5 weeks (6weeks minus the 7-day visit window)
after the first dose of IP. If a patient has a BOR of non-CR/non-PD, the patient’s BOR will be
grouped with the SD category. Individual target, non-target and new lesion assessments, as
well as tumor response by visit, by ICR and investigator, will be listed.
8.7.1.2. Pharmacokinetic Variables
Cmax, Cmax,ss, Tmax, Tmax,ss, CD1, CD8, CD15 and CCSF  will be determined by visual inspections of
the concentration-time profiles. AUCt, AUC0 24 and AUCss will be calculated using the linear
trapezoidal rule. Where appropriate, AUCinf will be extrapolated to infinity using the formula
AUCinf AUCt+Ct/λz (where Ct is the last measurable concentration). Where possible λz will be
calculated by log-linear regression of the terminal phase of the concentration-time profiles
where there are sufficient data, and t1/2 will be calculated as ln2/λz. CL/F and CLss/F will be
determined from ratio of dose/AUCinf and dose/AUCss, respectively. Vd/F will be determined
from the formula dose/(λz x AUCinf). MR and MRss will be calculated as the ratio of the AUCinf
of metabolite/AUCinfof YH25448 and the ratio of the AUCss of metabolite/AUCss of YH25448,
respectively. Rac will be calculated as the ratio of the AUCss/AUC0 24.
The PK parameters will be calculated, if appropriate, using commercial software such as
WinNonlin (Pharsight Corporation, Version 6.4 or higher). The actual sampling times will be
used in the PK parameter calculations, and the PK parameters will be derived using
noncompartmental methods. Other data handling procedures will be detailed in the SAP.
8.7.2. Efficacy Analyses
8.7.2.1. Primary Analyses
Part A and Part B: Dose Escalation and Dose Expansion Phase and Part D
Safety and tolerability will be assessed in terms of AEs, physical examination, laboratory data,
vital signs and ECG assessments. All patients who receive at least one dose of YH25448 will
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be included in the assessment of the safety profile (safety analysis population). These safety
measures will be listed and summarized descriptively in the safety analysis population, as
appropriate.
Part C: Dose Extension Phase
Objective Response Rate (ORR)
Objective response rate (ORR) is defined as the percentage of patients who have at least one
confirmed partial or complete response (PR or CR) (according to RECIST 1.1 or appendix F)
prior to disease progression or recurrence.
A visit response of CR is defined when all target lesions (TLs) and non-target lesions (NTLs)
present at baseline have disappeared (with the exception of lymph nodes which must be <10mm
to be considered non-pathological) and no new lesions have developed since baseline. A visit
response of PR is defined when the sum of diameters of the TLs has decreased by 30% or more
compared to baseline (with no evidence of progression) and the NTLs are at least stable with
no evidence of new lesions. A confirmed response of PR or CR means that a response of PR
or CR is recorded at one visit and confirmed by repeat imaging at least 4 weeks later with no
evidence of progression between confirmation visits.
In the case of stable disease, measurements should have met the stable disease criteria for a
minimum interval of 5 weeks (6 weeks minus the 7-day visit window) following the start of
treatment.
The analysis population for objective tumor response rate will be the “evaluable for response”
population.
Patients who do not have a tumor response assessment for any reason will be considered non-
responders and will be included in the denominator when calculating the response rate. Data
obtained up until progression, or last evaluable assessment in the absence of progression, will
be included in the assessment of ORR. However, any complete response or partial response
which occurred after a further anticancer therapy was received will not be included in
numerator of the ORR calculation. ORR will be presented with two-sided 95% confidence
intervals using the normal approximation.
Analyses will be performed for assessments by ICR as well as by investigator, but the primary
analysis for ORR will be based on ICR.
8.7.2.2. Secondary Analyses
Duration of Response (DoR)
Duration of response (DoR) is defined as the time from the date of first documented responses
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(that is subsequently confirmed) until date of documented progression or death (same as PFS
event time) whichever comes first. The time of the initial response will be defined as the latest
of the dates contributing towards the first visit response of PR or CR. If a patient does not
progress following a response, then their duration of response will use the PFS censoring time.
DoR in responding patients will be summarized and the number of responding patients with a
duration of response (>3; >6; >9; >12 months) will be presented. A Kaplan-Meier plot and
median DoR with 95% CI (calculated from the Kaplan-Meier plot) will be presented by dose
level and total.
Progression Free Survival (PFS)
PFS is defined as the time from first dosing date until documented disease progression or death
from any cause whichever first based on ICR as well as investigator assessment using RECIST
1.1 or appendix F. Patients who have not progressed or died at the time of analysis will be
censored at the time of the latest date of assessment from their last evaluable RECIST 1.1
assessment. In general, the PFS censoring rules and definition of progression date follow the
Food and Drug Administration (FDA) “Guidance for Industry Clinical Trial Endpoints for the
Approval of Cancer Drugs and Biologics (2007)”.
If the patient progresses or dies after two or more missed visits, the patient will be censored at
the time of the latest evaluable RECIST 1.1 assessment. If the patient has no evaluable visits
or does not have baseline data they will be censored at day 0 unless they die within two visits
of baseline. Two missed tumor assessment visit is defined as no assessment within 14 weeks
(98 days) of start of treatment or the previous evaluable RECIST 1.1 measurement.
If a patient discontinues treatment prior to progression and/or receives a subsequent therapy
prior to progression then these patients will continue to be followed until evidence of objective
disease progression as defined by RECIST 1.1.
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Table 16. The definition of outcome
Situation 
Data of Progression or Censoring 
Outcome
No baseline tumor assessments 
First administrated date 
Censored
Progression documented  
between scheduled visits 
Earliest of 
- Date of radiological assessment
showing new lesion (if progression
is based on new lesion);
Or
- Date of last radiological
assessment of measured lesions (if
progression is based on increase in
sum of measured lesions)
Progressed
No progression  
Date of last radiological assessment 
of measured lesions
Censored
Treatment discontinuation for 
undocumented progression
Treatment discontinuation for
toxicity or other reason
New anticancer treatment started
Death before first PD assessment 
Date of death  
Progressed
Death between adequate
assessment visit
Death or progression after two or 
more missed assessments 
Date of last radiological assessment 
of measured lesions
Censored
Note: PFS includes documented progression only
The analysis population for progression free survival will be the safety analysis population for
the expansion and extension phases. PFS will be summarized for the expansion and extension
phases. PFS will be displayed using Kaplan-Meier plot. The number of events, median
(calculated from the Kaplan-Meier plot), and proportion of patients without an event at 6, 12,
and 18 months will be summarized.
Disease Control Rate (DCR)
DCR is defined as the proportion of patients with a best overall, extracranial and intracranial
response of CR, PR or SD.
In the case of stable disease, assessments should have met the stable disease criteria for at least
5 weeks after the study start.
Two-sided 95% confidence intervals DCR will be calculated using asymptotic normal
approximation by dose level and total.
Tumor Shrinkage (Change in Tumor Size)
Tumor size is defined as the sum of the lengths of the longest diameters of the RECIST 1.1 or
appendix F target lesions. Percentage change in tumor size will be determined for patients with
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measurable disease at baseline and is derived at each visit by the percentage change in the sum
of the diameters of TLs compared to baseline.
The best change in tumor size (defined as the maximum reduction from baseline or the
minimum increase from baseline, in the absence of a reduction) will include all assessments
prior to progression or start of subsequent anti-cancer therapy. Missing target lesion data at
visits may be imputed using appropriate imputation rules.
For brain metastatic patients, change in tumor size will be reported separately for extracranial
disease and intracranial.
The analysis population for change in tumor size will be the evaluable for response population.
Summaries and waterfall plots (bar charts) indicating percentage change from baseline in the
sum of the diameters of target lesions at week 6 and week 12 may be produced, if appropriate,
depending on how much data is obtained in patients with measurable disease at baseline. If
there is only limited data then percentage change in tumor size will be listed only.
Objective Intracranial Response Rate (OIRR)
OIRR is defined as the percentage of patients who have at least one confirmed partial or
complete response (PR or CR) in intracranial lesion, according to appendix F prior to disease
progression or recurrence in brain metastatic patients.
The OIRR will be analyzed by the brain metastatic full analysis population and brain metastatic
evaluable for response population.
OIRR will be presented with two-sided 95% confidence intervals (Clopper-Pearson interval)
by dose level and total.
Duration of Intracranial Response (DoIR)
DoIR is defined as the time from the date of first documented responses (that is subsequently
confirmed) in intracranial disease until date of documented progression or death (same as
intracranial PFS event time according to appendix F) whichever comes first in brain metastatic
patients. The time of the initial intracranial response will be defined as the latest of the dates
contributing towards the first visit response of PR or CR. If a patient does not progress
following a response, then their duration of response will use the PFS censoring time.
DoIR will be analyzed by brain metastatic evaluable for response population. DoIR in
intracranial responding patients will be summarized and the number of responding patients
with a duration of response (>3; >6; >9; >12 months) will be presented in brain metastatic
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patients. A Kaplan-Meier plot and median DoIR with 95% CI (calculated from the Kaplan-
Meier plot) will be presented by dose level and total.
Intracranial Progression Free Survival (IPFS)
IPFS is defined as the time from first dosing date until documented disease progression or death
from any cause whichever first based on ICR as well as investigator assessment using RECIST
1.1 or appendix F in brain metastatic patients. Patients who have not progressed or died at the
time of analysis will be censored at the time of the latest date of assessment from their last
evaluable RECIST 1.1 assessment.
IPFS will be summarized based on the brain metastatic full analysis population.
IPFS will be presented in the Kaplan-Meier plot. The number of events, median (calculated
from the Kaplan-Meier plot), and proportion of patients without an event at 6, 12, and 18
months will be summarized.
Overall Survival (OS)
OS will be assessed based on the date of first dose and vital status at the time of data cut off
date.
OS is defined as the interval between the date of first dose and the date of patient death due to
any cause. Patients who are lost to follow-up and patients who are alive at the date of data cut-
off will be censored at the date the patient was last known alive.
The analysis population for OS will be the safety analysis population. OS will be summarized
for the selected extension dose in expansion phase and extension phase. OS will be displayed
using Kaplan Meier plots. The number of events, median (calculated from the Kaplan Meier
plot), and proportion of patients without an event at 6, 12 and 18 months will be summarized.
As appropriate, summaries of the number and percentage of patients who have died, are still in
survival follow-up, are lost to follow-up and have withdrawn consent will be presented.
8.7.3. Safety Analyses
All patients who receive at least one dose of YH25448 will be included in the assessment of
the safety profile (safety analysis population). At the end of the study, appropriate summaries
of all safety data will be produced, as defined below.
The safety parameters are AEs, clinical laboratory parameters, vital signs, and physical
examination and ECG parameters. For each safety parameter, the last non-missing safety
assessment made before the date of the first administration of IP will be used as the baseline
for all analyses of that safety parameter. Continuous variables will be summarized by number
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of patients, mean, SD, median, minimum, and maximum values. Categorical variables will be
summarized by frequency distribution (number and percentage of patients).
8.7.3.1. Adverse Events
Data from all cycles of initial treatment will be combined in the presentation of safety data.
AEs will be listed individually by patient and dose group. For patients who have a dose
modification, all AEs (due to drug or otherwise) will be assigned to the initial dose group.
Any AE occurring before the first dose of investigational product (i.e., before study Day 1) will
be included in the data listings but will not be included in the summary tables of adverse events.
Any AE occurring within the defined 28 day follow-up period after discontinuation of
investigational product will be included in the AE summaries. Any adverse events in this period
that occur after a patient has received further therapy for cancer (following discontinuation of
investigational product) will be flagged in the data listings. AEs occurring after the 28 day
follow-up period after discontinuation of investigational product will be listed separately, but
not included in the summaries.
All adverse events will be coded using latest version Medical Dictionary for Regulatory
Activities (MedDRA). The Common Terminology Criteria for Adverse Events (CTCAE) grade
will be assigned by the investigator. Severity of all AEs will be graded according to the CTCAE,
Version 4.0.
The number and percentage of patients reporting AEs in each dose group will be tabulated by
system organ class and preferred term; by system organ class, preferred term and severity; and
by system organ class, preferred term and relationship to the IP. If more than one AE is coded
to the same preferred term for the same patient, the patient will be counted only once for that
preferred term using the most severe and most related occurrence for the summarization by
severity and by relationship to the IP.
The distribution of AEs by severity and relationship to the IP will be summarized by dose
group.
Listings will be presented for patients with SAEs and patients with AEs leading to
discontinuation, and patients who die (if any).
8.7.3.2. Clinical Laboratory Parameters
Descriptive statistics for clinical laboratory values (in SI units) and changes from the baseline
values at each assessment time point will be presented by dose group for each clinical
laboratory parameter.
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For all laboratory variables, which are included in the current version of CTCAE, the CTCAE
grade will be calculated. Summary statistics of mean, median, standard deviation, minimum,
maximum and number of observations will be used.
Any qualitative assessments will be summarized for all patients using the number of patients
with results of negative, trace or positive.
The number and percentage of patients with clinical significance will be tabulated by dose
group. A supportive listing of patients with clinical significant changes in post-baseline values
will be provided, including the patient number, study center and baseline and post-baseline
values. A listing of all AEs related to clinical significant changes in laboratory values will also
be provided.
8.7.3.3. Vital Signs
Descriptive statistics for vital signs (pulse rate, systolic and diastolic blood pressure, height,
body weight and body temperature) and changes from baseline values (except for height) at
each visit and at the end of the observational period will be presented by dose group.
8.7.3.4. 12-lead Electrocardiogram
The number and percentage of patients with clinically significant changes in post-baseline 12-
lead ECG findings will be tabulated by dose group.
A supportive listing of patients with clinically significant changes in post-baseline 12-lead
ECG findings will be provided, including the patient number, study center and baseline and
post-baseline findings. A listing of all AEs occurring in patients who have clinically significant
changes in post baseline findings will also be provided.
8.7.3.5. Physical Examination
The number and percentage of patients with clinically significant changes in post-baseline
physical examination findings will be tabulated by dose group. A supportive listing of patients
with clinically significant changes in post-baseline physical examination findings will be
provided, including the patient number, study center and baseline and post-baseline findings.
A listing of physical examination findings at screening will be provided as part of the medical
history listing. Any new abnormal physical examination findings at each visit or early
termination or change (worsening) since the previous physical examination will be provided in
the AE listing.
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8.7.4. Pharmacokinetic Analyses
Plasma concentrations of YH25448 and its metabolites will be summarized by nominal
sampling time. Plasma concentrations, CSF concentrations and PK parameters will be
summarized according to dose by the following summary statistics: number of patients,
arithmetic mean, standard deviation, arithmetic coefficient of variation, median, minimum,
maximum, geometric mean, and geometric coefficient of variation. Parameters following
single and multiple dosing will be summarized separately.
The dose proportionality  of YH25448 will be assessed using a power model with ln-
transformed AUCt, Cmax, AUCss, Cmax,ss values as dependent variables and the ln-transformed
dose as an independent variable.
Comparison of PK profiles and parameters for patients outside Korea and Korean patients after
administration of single dose and multiple dose of 240 and 320 mg will be conducted. Log-
transformed primary parameters, Cmax, and AUClast, Cmax,ss and AUCss, will be analyzed by
analysis of variance, and point estimates and 90% confidence intervals of the geometric mean
ratio (patients outside Korea /Korean patients) will be calculated.
8.7.5. Exploratory Analyses
The following variables will be summarized descriptively and may be further analyzed if
deemed appropriate and details of the statistical method will be specified in accordance with
the statistical analysis plan.
 
Patient Reports Outcomes
Results from the exploratory analyses may be reported separately from the Clinical Study
Report for the main study
 
Metabolite identification
 
Biomarker data
 
Pharmacogenetics
 
Diagnostic tumor samples
8.8. Other Analyses
8.8.1. Subgroup Analyses
Subgroup analyses may be performed as appropriate based on the selected demographic and
other baseline characteristics for the primary endpoint as well as for the other endpoints as
appropriate. These will be further detailed in the SAP.
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8.8.2. Analyses to Characterize the Exposure-Response Relationship
A population PK/PD approach will be used to investigate the relationship PK and selected
efficacy, PD and/or safety endpoints, where deemed appropriate. The results of any such
analyses may be reported separately from the Clinical Study Report for the main study.
8.9. Interim Analyses
Not applicable
8.10. Sensitivity Analyses
The same methods of analysis will be applied to analyze ORR, DoR, DCR, tumor shrinkage
and PFS based on the RECIST 1.1 data assessed by the investigator. In Part C, the same
methods of analysis will be applied to analyze YH25448 anticancer effects (ORR, DoR, DCR
and tumor shrinkage) for all patients with a positive EGFR mutation status in the central and/or
local testing.
9. ADMINISTRATIVE SECTION
9.1. Compliance
9.1.1. Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the
protocol must be discussed with, or be prepared by the Sponsor. The investigator should not
implement any deviation or changes to the protocol without prior review and documented
approval from the IRB of an amendment, except where necessary to eliminate an immediate
hazard(s) to study patients. Any significant deviation must be documented.
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior
to obtaining IRB approval, as soon as possible the deviation or change is to be submitted as
soon as possible to:
 
Relevant IRB(s) for review and approval
 
Yuhan Corporation (Parts A, B and C)
 
Janssen Research & Development, LLC (Part D)
 
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s) must be sent
to the Sponsor.
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If an amendment substantially alters the study design or increases potential risk to a patient: (1)
the consent form must be revised and submitted to the IRB(s) for review and approval; (2) the
revised form must be used to obtain consent from patients currently enrolled in the study if
they are affected by the amendment; and (3) the new form must be used to obtain consent from
new patients prior to enrollment.
9.1.2. Monitoring
Representatives ofthe Sponsor must be allowed to visit all study center locations periodically
to assess the data quality and study integrity. On center they will review study records and
directly compare them with source documents, discuss the conduct of the study with the
investigator, and verify that the facilities remain acceptable.
In addition, the study may be evaluated by Sponsor auditors and government inspectors who
must be allowed access to CRFs, source documents, other study files, and study facilities. 
Sponsor audit reports will be kept confidential.
The investigator must notify the Sponsor promptly of any inspections scheduled by regulatory
authorities, and promptly forward copies of inspection reports to the Sponsor.
9.1.3. Investigational Site Training
Sponsorwill provide appropriate investigational staff training prior to study initiation. Training
topics will include but are not limited to: ICH-GCP, AE reporting, study details and procedure,
study documentation, informed consent, and enrollment method.
For centers using the Sponsor electronic data capture tool, each individual making entries
and/or corrections on electronic CRFs must meet Sponsor training requirements and must only
access the Sponsor electronic data capture tool using the unique user account provided by the
Sponsor. User accounts are not to be shared or reassigned to other individuals.
For electronic CRFs, corrections are made through the Sponsor electronic data capture tool that
generates an automated audit trail including date and timestamp, full name of the person
making the correction and original entry. The system also prompts the user to document the
reason for the change which is also recorded in the audit trail.
Each individual electronically signing electronic CRFs must meet Sponsor training
requirements and must only access the Sponsor electronic data capture tool using the unique
user account provided by the Sponsor. User accounts are not to be shared or reassigned to other
individuals.
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9.2. Records Retention
The investigator must retain investigational product disposition records, copies of CRFs (or
electronic files), and source documents for the maximum period required by applicable
regulations and guidelines, or institution procedures, or for the period specified bythe Sponsor,
whichever is longer. The investigator must contact the Sponsor prior to destroying any records
associated with the study. The Sponsor will notify the investigator when the study records are
no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such
transfer is to be given in writing to the Sponsor.
9.2.1. Case Report Forms
Each investigator is required to prepare and maintain adequate and accurate case histories
designed to record all observations and other data pertinent to the investigation for each
individual treated in the investigation. Data reported on the CRFs that are derived from source
documents must be consistent with the source documents or the discrepancies must be
explained.
For centers using the Sponsor’s electronic data capture tool, electronic CRFs will be prepared
for all data collection fields except for fields specific to SAEs and pregnancy, which will be
reported on the Pregnancy Surveillance Form. Patients are to be identified by birth date and
patient number, where applicable. All requested information must be entered on the CRF in the
spaces provided. If the entry for an item is not available or is not applicable, it must be
documented as such (N/A); do not leave any space blank. Spaces may be left blank only in
those circumstances permitted by study-specific CRF completion guidelines provided by the
Sponsor. Electronic data transfer is acceptable.
The confidentiality of records that may be used to identify patients must be protected,
respecting privacy and confidentiality rules in accordance with the applicable regulatory
requirement(s).
The investigator will maintain a signature sheet to document the signatures and initials of all
persons authorized to make entries and/or corrections on the CRFs. The completed CRF,
including any paper SAE report or Pregnancy Surveillance Forms, must be promptly reviewed,
signed, and dated by an investigator or sub-investigator, who is a qualified physician. For
electronic CRFs, the review and approval/signature are completed electronically through the
Sponsorelectronic data capture tool. The investigator must retain a copy of the CRFs, including
records of the changes and corrections.
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9.2.2. Investigational Product Records
It is the responsibility of the principal investigator to ensure that a current record of
investigational product disposition is maintained at each study center where investigational
product is inventoried and dispensed. Records or logs must comply with applicable regulations
and guidelines and should include:
 
quantity received and placed in storage area
 
quantity currently in storage area
 
label ID number or batch number and use by date or re-test date
 
dates and initials of person responsible for each investigational product inventory
entry/movement
 
quantity dispensed to and returned by each patient, including unique patient identifiers
 
quantity transferred to another areas/centers for dispensing or storage
 
any details of non-study use (eg, lost, wasted, broken)
 
quantity returned to the Sponsor
The Sponsor will provide forms to facilitate inventory control if the staff at the investigational
center does not have an established system that meets these requirements.
9.3. Return and Destruction of Investigational Product
9.3.1. Return of Investigational Product
Upon completion or termination of the study, all unused and/or partially used investigational
product must be returned to the Sponsor.
It can be destroyed locally as permitted by local or site regulations, if needed. (Part D)
All investigational product returned to the Sponsor must be accompanied by the appropriate
documentation and clearly identified by protocol number on the outermost shipping container.
Returned supplies including empty vials should be in the original containers (eg, vials that have
clinical labels attached). The return of unused investigational product(s) should be arranged by
the responsible Study Monitor.
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9.3.2. Destruction of Investigational Product
At study close-out, the Sponsor will destroy all used and unused study drug as per SOP and
relative regulatory. Investigational sites will return to the Sponsor all used and unused study
drug, packaging and drug labels appropriately. A copy of completed drug accountability will be
provided to the Sponsor.
9.4. Publications
The data collected during this study are confidential and proprietary to the Sponsor. Any
publications or abstracts arising from this study require prior written approval from and must
adhere to the Sponsor’s publication requirements as set forth in the approved clinical trial
agreement (CTA). All draft publications, including abstracts or detailed summaries of any
proposed presentations, must be submitted to the Sponsor at the earliest practicable time for
review, but in any event not less than 30 days before submission or presentation unless
otherwise set forth in the CTA. The Sponsor retains the right to delete any confidential or
proprietary information contained in any proposed presentation or abstract and may delay
publication for purposes of filing a patent application.
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10. GLOSSARY OF TERMS
Term  
Definition
Adverse Event 
Any new untoward medical occurrence or worsening of a
pre-existing medical condition in a patient for clinical
investigation patient administered an investigational
(medicinal) product and that does not necessarily have a
causal relationship with this treatment. An adverse event
can therefore be any unfavorable and unintended sign
(including abnormal laboratory findings, for example),
symptom, or disease temporally associated with the use of
investigational product, whether or not considered related
to the investigational product.
Adverse Drug Reaction  
In the pre-approval clinical experience with a new
medicinal product or its new usages, particularly as the
therapeutic dose(s) may not be established: all noxious
and unintended responses to a medicinal product related
to any dose should be considered adverse drug reactions.
The phrase responses to a medicinal product means that a
causal relationship between a medicinal product and an
adverse event is at least a reasonable possibility, i.e. the
relationship cannot be ruled out.
Expedited Safety Report (ESR) 
Important findings which may be reported by the Sponsor:
SUSAR, increased frequency of a clinically significant
expected SAE, an SAE considered associated with study
procedures that could modify the conduct of the study,
lack of efficacy that poses significant hazard to study
patients, clinically significant safety findings from a
nonclinical (e.g., animal) study, important safety
recommendations from a study data monitoring
committee, or Sponsor decision to end or temporarily halt
a clinical study for safety reason
SUSAR  
Suspected (certainly, probably, or possibly related to the
investigational product), Unexpected Serious Adverse
Reactions
Unexpected 
Adverse 
Drug 
Reaction  
An adverse reaction, the nature or severity of which is not
consistent with the applicable product information (e.g.,
Investigator's Brochure for an unapproved investigational
product or package insert/summary of product
characteristics for an approved product)
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LIST OF ABBREVIATIONS
Term  
Definition
AE 
Adverse event
ALT  
Alanine aminotransferase
AST  
Aspartate aminotransferase
AUC0 24 
Area under the plasma concentration-time curve from zero to
24 hours
AUCinf 
Area under the plasma concentration-time curve from zero to
infinity
AUCss 
Area under the plasma concentration-time curve from zero to
the end of the dosing interval
AUCt 
Area under the plasma concentration-time curve from zero to
the time of the last quantitative concentration
BAD  
Biologically Active Dose
BBB 
Blood Brain Barrier
BrM  
Brain Metastasis
CCSF
CSF concentration
CDX  
Trough concentration on Day X
cfDNA
Circulating tumor deoxyribonucleic acid
CL/F  
Apparent plasma clearance
CLss/F
Apparent plasma clearance at steady state
Cmax
Maximum plasma concentration
Cmax,ss 
Maximum plasma concentration at steady state
CNS  
Central Nervous System
CR  
Complete response
CRF  
Case report form (electronic/paper)
CSF  
Cerebrospinal fluid
CT  
Computerised tomography
CTCAE 
Common Terminology Criteria for Adverse Events
DCR  
Disease Control Rate
DLT  
Dose-limiting toxicity
DNA  
Deoxyribonucleic acid
DoR  
Duration of Response
ECG  
Electrocardiogram
ECOG  
Eastern Co-operative Oncology group
EGFR  
Epidermal growth factor receptor
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EGFR m+
Epidermal growth factor receptor single activating mutation
positive
EORTC
European Organisation for Research and Treatment of
Cancer
FDA  
Food and Drug Administration
GCP  
Good Clinical Practice
HED  
Human equivalent dose
HNSTD  
Highest non-seriously toxic dose
HRQoL 
Health Related Qulaity of Life
IATA  
International Air Transport Association
IB  
Investigators brochure
IP  
Investigational Product
ICH  
International Committee on Harmonisation
MAD  
Maximum Absorbable Dose
MFDS  
Ministry of Food and Drug Safety
MR  
Metabolic ratio
MRss 
Metabolic ratio at steady state
MRI 
Magnetic resonance imaging
MRSD  
Maximum Recommended Starting Dose
MTD  
Maximum tolerated dose
NE 
Not evaluable
NOEL 
No observed effect level
NSCLC 
Non Small Cell Lung Cancer
NTL 
Non-target lesion
ORR  
Objective Response Rate
OS  
Overall Survival
PD  
Progression of disease
pEGFR  
phosphorylated EGFR
PFS 
Progression free survival
PK  
Pharmacokinetics
PR  
Partial response
PRO
Patient Reported Outcomes
QCP  
Quantitative Clinical Pharmacology
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QD  
Once Dialy
QT
ECG interval measured from the onset of the QRS complex
to the end of the T wave
QTc 
QT interval corrected for heart rate
Rac 
Accumulation ratio
RECIST  
Response Evaluation Criteria in Solid Tumors
SAE 
Serious adverse event
SD 
Stable disease
SRC  
Safety review committee
STD10 
Severely toxic dose in 10% of rodents
t1/2 
Apparent terminal elimination half-life
TKI 
Tyrosine kinase inhibitor
Tmax  
Time to reach Cmax
Tmax,ss 
Time to reach Cmax,ss
ULN  
Upper limit of normal
Vd/F  
Apparent volume of distribution
λz 
Apparent terminal elimination rate constant
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a modular supplement to the EORTC Core Quality ofLife Questionnaire (QLQ-C30) for
use in lung cancer clinical trials. EORTC Study Group on Qualiy of Life. Eur J Cancer,
1994;30A:635-642.
13. Clinical Pharmacology and Biopharmaceutics Review(s)
Center for Drug Evaluation and Research; Clinical Pharmacology and Biopharmaceutics
Review(s), Application Number: 208065Orig1s000
14. James W et al 2013
James W. Welsh, Ritsuko Komaki, Arya Amini, Mark F. Munsell, Wyatt Unger, Pamela
K. Allen, Joe Y. Chang, Jeffrey S. Wefel, Susan L, ea al. Phase II Trial of Erlotinib Plus
Concurrent Whole-Brain Radiation Therapy for Patients With Brain Metastases From
Non Small-Cell Lung Cancer. J Clin Oncol, 2013;31:895-902.
15. Martin S et al 2015
Schuler M, Wu YL, Hirsh V, O’Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV,
Massey D, Zazulina V, Yang JC. First-Line Afatinib versus Chemotherapy in Patients
with Non Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor
Gene Mutations and Brain Metastases. J Thorac Oncol, 2016;11:380-390.
16. Hoffknecht P et al 2015
Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schütz M, Serke M,
Stöhlmacher-Williams J, Märten A, Maria Huber R, Dickgreber NJ. Efficacy of the
Irreversible ErbB Family blocker Afatinib in Epidermal Growth Factor Receptor (EGFR)
Tyrosine Kinase Inhibitor (TKI)-Pretreated Non-Small-Cell Lung Cancer Patients with
Brain Metastases or Leptomeningeal Disease. J Thorac Oncol, 2015;10:156-163.
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17. FDA Guidance for Industry (issued July 2009)
‘Drug-induced 
liver 
injury: 
Premarketing 
clinical 
evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/UCM174090.pdf
18. Eisenhauer EA et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R.  New response
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer,
2009;45:228-247.
19. Tony S Mok et al 2017
Mok, T. S., Wu, Y.L., Ahn, M. J., Garassino, M. C., Kim, H. R., Ramalingam, S. S., Lee,
C. K. et al. Osimertinib or platinum pemetrexed in EGFR T790M positive lung cancer.
New England Journal of Medicine, 2017; 376(7), 629-640.
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Appendix A. Algorithm for Continuation, Dose Modification or Discontinuation of
YH25448 Based on Increases of Liver Biochemistry (Hy’s Law17)
A. Increases in ALT and Total bilirubin
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B. Increases in AST and Total bilirubin
AST = Aspartate Aminotransferase; ALT = Alanine Aminotransferase; ULN = Upper Limit of Normal;
ALP = Alkaline Phosphatase
a The Investigator must complete the specific CRF form and inform the Monitoring Team within 24 hours
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical
evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM174090.pdf
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Appendix B. Algorithm for Continuation and Discontinuation of YH25448 Based on LVEF
and TnI Assessments in Patients
CHF  congestive heart failure; LVEF  left ventricular ejection fraction; TnI  Troponin I
a LVEF < 40% can be repeated within 21 days, and YH25448 should be discontinued if LVEF
< 40% is confirmed. YH25448 should be held while the repeat LVEF is obtained.
b Class ≥ 3 as defined by New York Heart Association (NYHA) classification (2014)
Class I 
No limitations. Ordinary physical activity does not cause undue fatigue,
dyspnoea or palpitations (asymptomatic LV dysfunction).
Class II 
Slight limitation of physical activity. Ordinary physical activity results
in fatigue, palpitation, dyspnoea or angina pectoris (mild CHF)
Class III 
Marked limitation of physical activity. Less than ordinary physical
activity leads to symptoms (moderate CHF).
Class IV  
Unable to carry on any physical activity without discomfort. Symptoms
of CHF present at rest (severe CHF)
c Parts A, B, and C
If TnI is determined to be positive (TnI+), it will be re-tested by central laboratory within 3
days before permanent discontinuation of study treatment. A positive result from the TnI test
means when the laboratory value exceeds the ULN as per each site or central laboratory range.
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Part D
TnI is positive (TnI+) when the laboratory value exceeds the ULN as per local laboratory range
and is clinically significant for a cardiac event. If TnI laboratory value exceeds the ULN, it will
be re-tested by local laboratory within 3 days. If considered clinically significant, study treatment
will be permanently discontinued after consultation with the Sponsor medical monitor. In Part
D, central laboratory confirmation of TnI local laboratory value is not required.
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Appendix C. International Airline Transportation Association (IATA) Guidance
Document
Labeling and Shipment of Biohazard Samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3
categories.  For transport purposes the classification of infectious substances according to risk
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition (2005). 
Infectious substances are now classified either as Category A, Category B or Exempt.  There
is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to it
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise
healthy humans or animals.  Category A pathogens are eg. Ebola, Lassa fever virus
 
are to be packed and shipped in accordance with IATA Instruction 602
Category B Infectious Substances are infectious Substances that do not meet the criteria for
inclusion in Category A.  Category B pathogens are eg. Hepatitis A, B, C, D, and E viruses,
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN
number and proper shipping name:
 
UN 3373 Biological Substance, Category B
 
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
 
Clinical trial samples will fall into Category B or exempt under IATA regulations.
 
Clinical trial samples will routinely be packed and transported at ambient temperature in
IATA 650 compliant packaging.
 
Biological samples transported in dry ice require additional dangerous goods specification
for the dry-ice content.
 
IATA compliant courier and packaging materials should be used for packing and
transportation and packing should be done by an IATA certified person, as applicable.
 
Samples routinely transported by road or rail are patient to local regulations which require
that they are also packed and transported in a safe and appropriate way to contain any risk
of infection or contamination by using approved couriers and packaging / containment
materials at all times.  The IATA 650 biological sample containment standards are
encouraged wherever possible when road or rail transport is used.
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Appendix D. Ethical and regulatory requirements
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the
Declaration of Helsinki and are consistent with the International Conference on Harmonisation
(ICH)/Good Clinical Practice (GCP) guidelines, applicable regulatory requirements and the
Sponsor policy on Bioethics and Human Biological Samples.
Ethics and regulatory review
An Ethics Committee should approve the final Clinical Study Protocol, including the final
version of the Informed Consent Form and any other written information and/or materials to be
provided to the patients.  This will include approval of the exploratory biomarker and
pharmacogenetic research and associated consent(s) forms.  The investigator/The Head of the
study center will ensure the distribution of these documents to the applicable Ethics Committee,
and to the study site staff.  In Japan, the head of the study center will ensure the distribution of
these documents to the applicable IRB, and the Principal Investigator to the Investigator and
study site staff.
The opinion of the Ethics Committee should be given in writing.  The investigator should
submit the written approval to the Sponsor before enrolment of any patient into the study. If
applicable this approval should clearly state that the exploratory biomarker and pharmacogenetic
research is approved.
The Ethics Committee should approve all advertising used to recruit patients for the study.
The Sponsor should approve any modifications to the Informed Consent Form that are needed
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the Ethics Committee
annually.
The Sponsor will handle the distribution of any of these documents to the national regulatory
authorities.
TheSponsor will provide Regulatory Authorities, Ethics Committees and Principal Investigators
(in Japan, also the Head of the study center) with safety updates/reports according to local
requirements, including SUSARs (Suspected Unexpected Serious Adverse Reactions), where
relevant.
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Each Principal Investigator is responsible for providing the Ethics Committees/Institutional
Review Board (IRB) with reports of any serious and unexpected adverse drug reactions from
any other study conducted with the investigational product.
Informed consent
Any incentives for patients who participate in the study as well as any provisions for patients
harmed as a consequence of study participation should be described in the informed consent
form that is approved by an Ethics Committee.
The Principal Investigator at each centre will:
 
Ensure that each patient is given full and adequate oral and written information about the
nature, purpose, possible risk and benefit of the study and the optional exploratory
biomarker and genetic research component(s)
 
Ensure that each patient is notified that they are free to withdraw from the study or the
research components at any time
 
Ensure that each patient is given the opportunity to ask questions and allowed time to
consider the information provided
 
Ensure each patient provides signed and dated informed consent before conducting any
procedure specifically for the study
 
Ensure each original, signed Informed Consent Form is stored in the Investigator’s Study
File/medical records
 
Ensure a copy of each signed Informed Consent Form is given to the patient
The exploratory biomarker and genetic research component(s) of this study are voluntary and
the patient may participate in the main study without participating in the exploratory biomarker
and/or genetic research part(s) of the study.  To participate in the exploratory biomarker and/or
genetic component of the study the patient should sign and date the consent form for the main
study and as applicable separate consent forms for the exploratory biomarker and/or the genetic
components of the study.
Changes to the protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Principal Investigator
and the Sponsor.
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If there are any substantial changes to the Clinical Study Protocol, then these changes will be
documented in a Clinical Study Protocol Amendment and where required in a new version of
the protocol (Revised Protocol).
The amendment should be approved by each Ethics Committee and if applicable, also the
national regulatory authority, before implementation.  Local requirements should be followed
for Revised Protocols.
The Sponsor will distribute any subsequent amendments and new versions of the protocol to
each Principal Investigator.
If a protocol amendment requires a change to a centre’s Informed Consent Form, the Sponsor
and the centre’s Ethics Committee should approve the revised Informed Consent Form before
the revised form is used.
If local regulations require, any administrative change will be communicated to or approved by
each Ethics Committee.
Audits and inspections
Authorized representatives ofthe Sponsor, a regulatory authority, or an Ethics Committee may
perform audits or inspections at the centre, including source data verification.  The purpose of
an audit or inspection is to systematically and independently examine all study-related activities
and documents, to determine whether these activities were conducted, and data were recorded,
analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP),
guidelines of the International Conference on Harmonisation (ICH), and any applicable
regulatory requirements.  The investigator will contact the Sponsor immediately if contacted
by a regulatory agency about an inspection at the centre.
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Appendix E. Data and study management
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a separate
document incorporating) wording that complies with relevant data protection and privacy
legislation.
Due to the exploratory nature of the biomarker and genetic research, there will be no routine
communication of these results to patients. The Sponsor will not provide individual results to
patients, any insurance company, any employer, their family members, general physician or any
other third party, unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to
the identity of the patient.  In exceptional circumstances, however, certain individuals might
see both the genetic data and the personal identifiers of a patient.  For example, in the case of
a medical emergency, an Sponsor Study Physician or an investigator might know a patient’s
identity and also have access to his or her genetic data.  Also regulatory authorities may require
access to the relevant files, though the patient’s medical information and the genetic files would
remain physically separate.
Pre-study activities
Before the first patient is entered into the study, it is necessary for a representative ofthe Sponsor
to visit the investigational study center to:
 
Determine the adequacy of the facilities
 
Determine availability of appropriate patients for the study
 
Discuss with the investigator(s) (and other personnel involved with the study) their
responsibilities with regard to protocol adherence, and the responsibilities of the Sponsor or
its representatives.  This will be documented in a Clinical Study Agreement between the
Sponsor and the investigator
Training of study site personnel
Before the first patient is entered into the study, a Sponsor representative will visit the study
center to review and discuss the requirements of the Clinical Study Protocol and related
documents with the investigational staff and also to train them in any study specific procedures
including collection of samples and the WBDC system utilised.  The additional requirements
for the collection of the patients’ samples for the exploratory biomarker and genetic research
will also be clarified.
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The Principal Investigator will ensure that appropriate training relevant to the study is given to
all of the staff, and that any new information relevant to the performance of this study is
forwarded to the staff involved.
The Principal Investigator will maintain a record of all staff members involved in the study
(medical, nursing and other staff).
Source data
Refer to the Clinical Study Agreement for location of source data.
Monitoring of the study
During the study, a Sponsor representative will have regular contacts with the study centers,
including visits to:
 
Provide information and support to the investigator(s)
 
Confirm that facilities remain acceptable
 
Confirm that the investigational team is adhering to the protocol including the specific
requirements of the biomarker and genetic research, that data are being accurately and
timely recorded in the CRFs, and that investigational product accountability checks are
being performed
 
Perform source data verification (a comparison of the data in the CRFs with the patient’s
medical records at the hospital or practice, and other records relevant to the study) including
verification of the Informed Consent Form(s)of participating patients.  This will require
direct access to all original records for each patient (eg, clinic charts)
 
If applicable, ensure withdrawal of informed consent to the use of the patient’s biological
samples is reported and biological samples are identified and disposed of/destroyed
accordingly, and the action is documented, and reported to the patient
The Sponsor representative will be available between visits if the investigator(s) or other staff
at the centre needs information and advice about the study conduct.
Data management by Sponsor/delegate
Data management will be performed by the Cognizant Data Management Centre.
Data entered in the WBDC system or data captured electronically will be immediately saved to
the applicable database and changes tracked to provide an audit trail. 
The data collected through third party sources will be obtained and reconciled against study data.
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Adverse events and medical/surgical history will be classified according to the terminology of
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications
will be classified according to the Sponsor Drug Dictionary.  All coding will be performed by
the Medical Coding Team at the Sponsor Data Management Centre/other party.
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the study
database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control procedures
will be applied to each stage of data handling to ensure that all data are reliable and have been
processed correctly.
When all data have been coded, validated, signed and locked, clean file will be declared.  Any
treatment-revealing data may thereafter be added and the final database will be locked.
Genotype data generated in this study will be stored in the Sponsor applicable database, or other
appropriate secure system, separate from the database used for the main study.
Some or all of the clinical datasets from the main study may be merged with the genetic data in
a suitable secure environment separate from the clinical database. The results from this genetic
research will be reported separately from the Clinical Study Report for the main study.
Study agreements
The Principal Investigator at each centre should comply with all the terms, conditions, and
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the
Clinical Study Protocol shall prevail with respect to the conduct of the study and the treatment
of patients and in all other respects, the terms of the Clinical study Agreement shall prevail.
Specific reference to requirements relating to this optional biomarker and genetic research will
be included in the study agreement(s).
Agreements between the Sponsor and the Principal Investigator should be in place before any
study-related procedures can take place, or patients be enrolled.
Archiving of study documents
The investigator follows the principles outlined in the Clinical Study Agreement.
End of study
The end of the study is defined as the last visit of the last patient undergoing the study.
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The study may be terminated at individual centres if the study procedures are not being
performed according to Good Clinical Practice (GCP), or if recruitment is slow. The Sponsor
may also terminate the entire study prematurely if concerns for safety arise within this study or
in any other study with YH25448.
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Appendix F. Guidelines for Evaluation of Objective Tumor Response Using RECIST 1.1
(Response Evaluation Criteria in Solid Tumors) FOR ASSESSMENT OF
INTRACRANIAL AND EXTRACRANIAL DISEASE18
Introduction
This appendix details the implementation of RECIST 1.1 Guidelines with regards to Investigator
assessment of tumor burden including protocol-specific requirements for this study. The criteria
has been modified to allow the separate assessment of CNS and extracranial disease in patients
with measurable brain metastases.
Definition of measurable, non-measurable, target and non-target lesions
Patients will be entered to different phases on this study according to the following inclusion
criteria
Patients without measurable BrM (except patients with measurable brain metastases), at least
one measurable extracranial lesion not previously irradiated or biopsied within the screening
period, (passed over 14 days at least in case of biopsied) that can be accurately measured at
baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥
15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is
suitable for accurate repeated measurements.
BrM patients: (patients with measurable brain metastases), at least one measurable intracranial
lesion has progressed or not responded to prior radiotherapy that can be accurately measured at
baseline as ≥ 10 mm in the longest diameter by magnetic resonance imaging (MRI) and which
is suitable for accurate repeated measurements.
Progression will be assessed as the visit response if there is progression extracranial disease
and/or intracranial disease. An overall visit response will be derived by combining the
intracranial and extracranial disease time point responses.
Measurable:
Extracranial Lesion: An extracranial lesions not previously irradiated or biopsied within the
screening period, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter
(except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or
magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
Patients with measurable brain metastases are not required to have measurable extracranial
disease
Brain metastasis: An intracranial brain lesion has progressed or not responded to prior
radiotherapy that can be accurately measured at baseline as ≥ 10 mm in the longest diameter by
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magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
Patients with measurable brain metastases are not required to have measurable extracranial
disease.
Non-measurable:
 
All other extracranial lesions, including small lesions (longest diameter <10 mm or
pathological lymph nodes with ≥10 to <15mm short axis at baseline*).
 
All other intracranial lesions, including small lesions (longest diameter < 10 mm)
 
Truly non-measurable lesions include the following: bone lesions, ascites, pleural /
pericardial effusion, and inflammatory breast disease, lymphangitic involvement of skin or
lung, abdominal masses /abdominal organomegaly identified by physical examination that
is not measurable by CT or MRI.
 
Previously irradiated extracranial lesions**
 
Previously irradiated intracranial lesions which have not progressed or responded to prior
radiotherapy**
 
Skin lesions assessed by clinical examination
* Nodes with <10mm short axis are considered non-pathological and should not be recorded or
followed as NTL.
**Localized post-radiation changes which affect lesion sizes may occur
Special Cases:
 
Lytic bone lesions or mixed lytic blastic lesions, with identifiable soft tissue components,
can be considered measurable if the soft tissue component meets the definition of
measurability. Blastic lesions are considered non-measurable.
 
Cystic metastases can be considered measurable lesions if they meet the criteria for
measurability from a radiological point of view, but if non-cystic lesions are present in the
same patient. These should be selected as target lesions.
Target lesions:
Extracranial lesions: A maximum of 5 measurable lesions (with a maximum of 2 lesions per
organ), representative of all lesions involved suitable for accurate repeated measurement, should
be identified as target lesions (TL) at baseline. Intracranial disease will be assessed separately.
Intracranial lesions: A maximum of 5 measurable lesions.
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Non-Target lesions:
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline.
Extracranial and intracranial disease (brain metastases) will be assessed separately. 
Methods of ASSESSMENT
The same method of assessment and the same technique should be used to characterize each
identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods to be used for RECIST 1.1 assessment is provided below and those
excluded from tumor assessments for this study are highlighted, with the rationale provided.
Table 1. Extracranial disease: Summary of Methods of Assessment
Target Lesions 
Non-Target Lesions 
New Lesions
CT (preferred) 
MRI 
CT (preferred) 
MRI 
Clinical examination 
X-ray, Chest x-ray  
CT (preferred)
MRI
Clinical examination
X-ray, Chest x-ray
Ultrasound
Bone Scan
FDG-PET
Table 2. Intracranial disease: Summary of Methods of Assessment
Target Lesions 
Non-Target Lesions 
New Lesions
MRI 
MRI 
MRI
CT and MRI (extracranial and intracranial disease)
CT and MRI are generally considered to be the best currently available and reproducible
methods to measure TL selected for response assessment and to assess NTL and identification
of any new lesions for extracranial disease
In this study it is recommended that CT examinations of the chest and abdomen (including liver
and adrenal glands). CT examination with intravenous (i.v.) contrast media administration is the
preferred method. 
MRI is generally considered to be the best currently available and reproducible method for
assessment of intracranial disease and for this study to measure TL selected for response
assessment and to assess NTL and identification of any new lesions.
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Clinical examination (extracranial disease only)
Clinical examination will not be used for assessment of TL.  Clinically detected lesions can be
selected as target lesions if they are assessed by CT or MRI scans.  Clinical examination can
be used to assess NTL and to identify the presence of new lesions.
X-ray (extracranial disease only)
Chest X-ray
Chest x-ray assessment will not be used for assessment of TLs as they will be assessed by CT
examination or MRI examination. Chest X-ray can, however, be used to assess NTL and to
identify the presence of new lesions.
Plain X-ray
Plain x-ray may be used as a method of assessment for bone NTL and to identify the presence
of new bone lesions.
Ultrasound (extracranial disease only)
Ultrasound examination will not be used for assessment of TL and NTLs as it is not a
reproducible method, does not provide an accurate assessment of tumor size and it is subjective
and operator dependent.  Ultrasound examination can, however, be used to identify the
presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed then
new lesions should be confirmed by CT or MRI examination.
Endoscopy and laparoscopy (extracranial and intracranial disease)
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated in
the context of tumor assessment.
Tumor markers (extracranial and intracranial disease)
Tumor markers will not be used for tumor response assessments as per RECIST 1.1.
Cytology and histology (extracranial and intracranial disease)
Histology will not be used as part of the tumor response assessment as per RECIST 1.1.
CSF cytology assessments will be performed and reported separately for the assessment of
clinical response for patients with leptomeningeal disease.
Cytological confirmation of the neoplastic origin of any effusion that appears or worsens during
treatment is required when the measurable tumor has met criteria for response or stable
disease. In such circumstances, the cytology is necessary to differentiate between response /
stable disease (an effusion may be a side effect of the treatment) and progressive disease (if the
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neoplastic origin of the fluid is confirmed). Where cytology findings are not available, any
effusion that significantly worsens (from trace to large) or appearance of clinically significant
effusion (requiring change in drug therapy) during the study treatment will be considered to be
progression of NTL, or disease progression due to new lesions.
Isotopic bone scan (extracranial disease only)
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or X-
ray at baseline should be recorded as NTL and followed by the same method as per baseline
assessment. 
Isotopic bone scans may be used as a method of assessment to identify the presence of new bone
lesions at follow-up visits. New lesions will be recorded where a positive hot-spot that was not
present on the baseline bone scan assessment is identified on a bone scan performed at any time
during the study.  The Investigator should consider the positive hot-spot to be a significant new
site of malignant disease and represent true disease progression in order to record the new lesion.
Confirmation by CT, MRI and x-ray is recommended where bone scan findings are equivocal.
FDG-PET scan (extracranial disease only)
FDG-PET scans may be used as a method for identifying new lesions, according with the
following algorithm:  New lesions will be recorded where there is positive FDG uptake* not
present on baseline FDG-PET scan or in a location corresponding to a new lesion on CT/MRI
at the same follow-up visit.  If there is no baseline FDG-PET scan available, and no evidence
of new lesions on CT/MRI scans then follow-up CT/MRI assessments should be continued,
scheduled as per protocol or clinical indicated, in order to confirm new lesions.
* A positive FDG-PET scan lesion should be reported only when an uptake greater than twice
that of the surrounding tissue is observed.
Tumor response evaluation
Schedule of evaluation
Imaging assessments will be performed using CT scan of the chest and abdomen (including liver
and adrenal glands) at base-line within 28 days of treatments start and then every 6 weeks ±
1week until objective disease progression or withdrawal from study. In addition all patients will
have a brain MRI scan at baseline and at follow-up in patients with confirmed brain metastases
on the baseline brain scan. In addition additional areas should be investigated based on the signs
and symptoms of the patient. Any other sites at which new disease is suspected should also be
appropriately imaged. If an unscheduled assessment was performed and the patient has not
progressed, every attempt should be made to perform the subsequent assessments at their
scheduled visits.
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Target lesions (TL)
Documentation of target lesions (extracranial lesions)
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including lymph
nodes), representative of all lesions involved should be identified as TL at baseline. Target
lesions should be selected on the basis of their size (longest diameter for non-nodal lesions or
short axis for nodal lesions), but in addition should be those that lend themselves to reproducible
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend
itself to reproducible measurement in which circumstance the next largest lesion, which can be
measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for non-
nodal lesions (or short axis for lymph nodes) on the extracranial lesions RECIST eCRF. All
measurements should be recorded in millimeters. At baseline the sum of the diameters for all TL
will be calculated and reported as the baseline sum of diameters. At follow-up visits the sum of
diameters for all TL will be calculated and reported as the follow-up sum of diameters.
Documentation of target lesions (intracranial lesions)
A maximum of 5 measurable lesions should be selected on the basis of their size (longest
diameter for non-nodal lesions or short axis for nodal lesions), but in addition should be those
that lend themselves to reproducible repeated measurements. It may be the case that, on occasion,
the largest lesion does not lend itself to reproducible measurement in which circumstance the
next largest lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for non-
nodal lesions (or short axis for lymph nodes) on the intracranial lesions RECIST eCRF. All
measurements should be recorded in millimeters. At baseline the sum of the diameters for all TL
will be calculated and reported as the baseline sum of diameters. At follow-up visits the sum of
diameters for all TL will be calculated and reported as the follow-up sum of diameters.
Special cases:
 
For TL measurable in 2 or 3 dimensions, always report the longest diameter. For
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis.
 
If the CT/MRI slice thickness used is > 5mm, the minimum size of measurable disease at
baseline should be twice the slice thickness of the baseline scan.
 
If a lesion has completely disappeared, the longest diameter should be recorded as 0 mm.
 
If a TL splits into two or more parts, then record the sum of the diameters of those parts.
 
If two or more TLs merge then the sum of the diameters of the combined lesion should be
recorded for one of the lesions and 0 mm recorded for the other lesion(s). 
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 
If a TL is believed to be present and is faintly seen but too small to measure, a default value
of 5mm should be assigned for extracranial and intracranial lesion, respectively. If an
accurate measure can be given, this should be recorded, even if it is below 5mm.
 
If a TL cannot be measured accurately due to it being too large, provide an estimate of the
size of the lesion.
 
When a TL has had any intervention e.g. radiotherapy, embolization, surgery etc., during
the study, the size of the TL should still be provided where possible.
Evaluation of target lesions (extracranial and intracranial lesions)
This section provides the definitions of the criteria used to determine objective tumor visit
response for TL.
Table 3. Evaluation of target lesions
Complete Response (CR) 
Disappearance of all target lesions since baseline.  Any
pathological lymph nodes selected as target lesions must have
a reduction in short axis to < 10 mm.
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of TL,
taking as reference the baseline sum of diameters
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target
lesions, taking as reference the smallest sum on study (this
includes the baseline sum if that is the smallest on study).  In
addition to the relative increase of 20%, the sum must also
demonstrate an absolute increase of at least 5mm  for
extracranial and intracranial lesion, respectively.
Not Evaluable (NE) 
Only relevant if any of the target lesions were not assessed or
not evaluable or had a lesion intervention at this visit. Note:
If the sum of diameters meets the progressive disease criteria,
progressive disease overrides not evaluable as a target lesion
response
Non-Target lesions (NTL)
Evaluation of non-target lesions (extracranial lesions)
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline. 
Measurements are not required for these lesions, but their status should be followed at
subsequent visits. At each visit an overall assessment of the NTL response should be recorded
by the Investigator. This section provides the definitions of the criteria used to determine and
record overall response for NTL at the investigational site at each visit.
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Evaluation of non-target lesions (intracranial lesions)
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline.
Measurements are not required for these lesions, but their status should be followed at
subsequent visits. At each visit an overall assessment of the NTL response should be recorded
by the Investigator. This section provides the definitions of the criteria used to determine and
record overall response for NTL at the investigational site at each visit.
In addition the investigator will be asked to record an assessment for leptomeningeal disease of
complete response, responding, stable or progressing in addition to assessment as part of the
non-target lesions for intracranial response assessment.
Table 4. Evaluation of Non-Target Lesions (extracranial and intracranial lesions)
Complete Response (CR) 
Disappearance of all non-target lesions since baseline. All
lymph nodes must be non-pathological in size (< 10 mm short
axis).
Non CR/Non PD  
Persistence of one or more NTL
Progression (PD) 
Unequivocal progression of existing non-target lesions.
Unequivocal progression may be due to an important
progression in one lesion only or in several lesions.  In all
cases the progression MUST be clinically significant for the
physician to consider changing (or stopping) therapy.
Not Evaluable (NE) 
Only relevant when one or some of the non-target lesions were
not assessed and, in the Investigator's opinion, they are not
able to provide an evaluable overall non-target lesion
assessment at this visit.
Note:  For patients without target lesions at baseline, this is
relevant if any of the non-target lesions were not assessed at
this visit and the progression criteria have not been met.
To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be an overall
level of substantial worsening in non-target disease such that, even in presence of SD or PR in
target lesions, the overall tumor burden has increased sufficiently to merit discontinuation of
therapy. A modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient
to qualify for unequivocal progression status.
New Lesions (extracranial and intracranial disease)
Details of any new lesions will also be recorded with the date of assessment. The presence of
one or more new lesions is assessed as progression.
A lesion identified at a follow up assessment in an anatomical location that was not scanned at
baseline is considered a new lesion and will indicate disease progression.
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The finding of a new lesion should be unequivocal: i.e. not attributable to differences in scanning
technique, change in imaging modality or findings thought to represent something other than
tumor.
If a new lesion is equivocal, for example because of its small size, the treatment and tumor
assessments should be continued until the new lesion has been confirmed. If repeat scans
confirm there is a new lesion, then the progression date should be declared using the date of the
initial scan.
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response: it is a reason for stopping
study therapy.
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without
objective evidence of disease progression at that time should continue to undergo tumor
assessments where possible until objective disease progression is observed.
Evaluation of Visit Response
The visit response will be derived separately for extracranial and intracranial disease separately
using the algorithm shown in table 5.
Table 5. Visit Response (extracranial and intracranial disease)
Target lesions 
Non-Target lesions New Lesions 
Overall response
CR  
CR  
No 
CR
CR  
NA  
No 
CR
NA  
CR  
No 
CR
CR  
Non CR/Non PD 
No 
PR
CR  
NE 
No 
PR
PR  
Non PD or NE 
No 
PR
SD 
Non PD or NE 
No 
SD
NA  
Non CR/Non PD  
No 
SD (Non CR/Non PD)
NE 
Non PD or NE 
No 
NE
NA  
NE 
No 
NE
PD  
Any  
Yes or No 
PD
Any  
PD  
Yes or No 
PD
Any  
Any  
Yes 
PD
CR  complete response, PR  partial response, SD  stable disease, PD  progressive disease,
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NE  not evaluable, NA  not applicable (only relevant if there were no TL/NTLs at baseline).
Overall visit response
The overall visit response will be using the algorithm shown in table 6 which is analogous to the
RECIST 1.1 approach where brain lesions are assessed as non-target lesions.
Table 6. Overall Visit Response (extracranial and intracranial disease)
Extracranial lesion 
visit response 
intracranial lesion visit 
response
Overall response
CR  
CR  
CR
CR  
NA  
CR
NA  
CR  
CR
CR  
PR or SD 
PR
CR  
NE 
PR
PR  
CR/PR/SD or NE 
PR
SD 
CR/PR/SD or NE 
SD
NA  
PR/SD  
SD
NE 
Non PD or NE 
NE
NA  
NE 
NE
PD  
Any  
PD
Any  
PD  
PD
CR  complete response, PR  partial response, SD  stable disease, PD  progressive disease,
NE  not evaluable, NA  not applicable
Confirmation of response
Imaging for confirmation of response (CR or PR) for intracranial or extra cranial disease should
be performed at the next scheduled visit (certainly no less than 4 weeks) following the date the
criteria for response were first met.
Central Review
The Contract Research Organization (CRO) appointed by Yuhan to perform the independent
central review for this study will provide specification for radiological imaging protocols in
standard acquisition guidelines documentation.
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Appendix G. GUIDANCE REGARDING POTENTIAL INTERACTIONS WITH
CONCOMITANT MEDICATIONS
The use of any natural/herbal products or other “folk remedies” (e.g. Ginseng and other
Traditional Chinese Medicine) should be discouraged, but use of these products, as well as use
of all vitamins, nutritional supplements, and all other concomitant medications must be recorded
in the eCRF.
YH25448 is an investigational drug for which no data on in vivo interactions are currently
available.  Based on in vitro data and predicted clinical exposure data, YH25448 is considered
unlikely to cause clinically significant drug interactions through inhibition or induction of
cytochrome P450 enzyme activity. 
In vitro data have shown that the principal CYP enzymes responsible for the Phase I metabolism
of YH25448 is CYP3A4/5. Therefore, drugs inhibiting CYP3A4/5 metabolism are
recommended not to combine with YH25448. Drugs inducing CYP3A4/5 metabolism should
also be avoided to combine with YH25448 if possible.
YH25448 is an inhibitor of P-gp, MRP4, and BCRP, which increases the bioavailability of
concomitant medication affecting p-gp, MRP4, and BCRP substrates by restricting intestinal P-
gp and BCRP. Therefore, the plasma concentration of digoxin and P-gp substrates should be
monitored closely and their dosage can be adjusted properly.
It is recommended that the starting and maintenance dose of statins should be as low as possible
and should be guided by the statin label. Monitoring of low- density lipoprotein (LDL)
cholesterol levels is advised. If the patient experiences any potentially relevant adverse events
suggestive of muscle toxicity including unexplained muscle pain, tenderness, or weakness,
particularly if accompanied by malaise or fever, the statin should be stopped, creatine kinase
(CK) levels should be checked, and any appropriate further management should be taken.
Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR.
Drugs inhibiting CYP3A4/5 metabolism that The Sponsor recommend are not combined
with YH25448
The contribution of Phase I metabolism to the total clearance of YH25448 is currently unknown
but, to ensure patient safety, the following inhibitors of CYP3A4/5 must not be used during this
study for any patient receiving YH25448 and the inhibitors are not only limited to the table
below.
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Table 1. Drug inhibiting CYP3A4/5
Contraindicated drugs 
Withdrawal period prior to YH25448
start
ketoconazole, 
itraconazole, 
indinavir, 
saquinovir, nelfinavir, atazanavir, amprenavir,
fosamprenavir, 
troleandomycin,
telithromycin, 
fluconazole, 
nefazodone,
cimetidine, 
aprepitant, 
miconazole,
fluvoxamine
amiodarone
erythromycin, clarithromycin, verapamil,
ritonavir, diltiazem  
1 week
27 weeks
2 weeks
This list is not intended to be exhaustive, and a similar restriction will apply to other agents that
are known to strongly modulate CYP3A4/5 activity.  Appropriate medical judgment is required. 
Please contact the Sponsor with any queries you have on this issue.
Drugs inducing CYP3A4 metabolism that the Sponsor recommend are not combined with
YH25448
To avoid potential reductions in exposure due to drug interactions, the following CYP3A4/5
inducers should be avoided if possible.
Table 2. Drug inducing CYP3A4/5
Contraindicated drugs 
Withdrawal period prior to YH25448
start
phenytoin, rifampicin, St. John's Wort, 
carbamazepine, 
primidone, 
griseofulvin,
barbiturates, 
troglitazone, 
pioglitazone,
oxcarbazepine, nevirapine, efavirenz, rifabutin
3 weeks
Phenobarbitone 
5 weeks
This list is not intended to be exhaustive, and a similar restriction will apply to other agents that
are known to strongly modulate CYP3A4/5 activity. Appropriate medical judgment is required. 
Please contact the Sponsor with any queries you have on this issue.
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Anti-convulsive drugs can be given to treat seizures at the discretion of the investigator when
necessary.
Dexamethasone, a commonly used steroid to relieve brain edema, is a weak CYP3A4/5 inducer
which may increase YH25448 clearance. Steroid is allowed to use in this study but must be
recorded in the eCRF.
Drugs that may prolong QT interval
The drugs listed in this section are taken from information provided by The Arizona Center for
Education and Research on Therapeutics and The Critical Path Institute, Tucson, Arizona and
Rockville, Maryland. Ref:  http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm.
Drugs known to prolong QT interval
The following drugs are known to prolong QT interval or induce Torsades de Pointes and should
not be combined with YH25448.  Recommended withdrawal periods following cessation of
treatment with these agents are provided in the table.
Table 3. Drugs prolonging QT interval
Contraindicated drug 
Withdrawal period prior to YH25448
start
Clarithromycin, 
droperidol, 
erythromycin, 
procainamide
2 days
Cisapride, 
disopyramide, 
dofetilide, 
domperidone, ibutilide, quinidine, sotalol,
sparfloxacin, thioridazine
7 days
Bepridil, 
chlorpromazine, 
halofantrine, 
haloperidol, mesoridazine
14 days
Levomethadyl, methadone, pimozide 
4 weeks
Arsenic trioxide 
6 weeks*
Pentamidine 
8 weeks
Amiodarone, chloroquine 
1 year
* 
Estimated value as pharmacokinetics of arsenic trioxide has not been studied
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Drugs that may possibly prolong QT interval
The use of the following drugs is permitted (notwithstanding other exclusions and restrictions)
provided the patient has been stable on therapy for the periods indicated.
Table 4. Drugs that may possibly prolong QT interval
Drug 
Minimum treatment period on
medication prior to YH25448 start
Alfuzosin, chloral hydrate, ciprofloxacin, 
dolasetron, 
foscarnet, 
galantamine,
gemifloxacin, 
isridipine, 
ketoconazole,
levofloxacin, 
mexiletine, 
nicardipine,
octreotide, ofloxacin, ondansetron, quetiapine,
ranolazine, 
telithromycin, 
tizanidine,
vardenafil, venlafaxine, ziprasidone
2 days
Amantadine, 
amitriptyline, 
amoxapine, 
clozapine, doxepin, felbamate, flecainide,
fluconazole, 
fosphenytoin, 
gatifloxacin,
granisetron, imipramine, indapamide, lithium,
moexipril/HCTZ, moxifloxacin, risperidone,
roxithromycin, sertraline, trimethoprin-sulfa,
trimipramine, voriconazole
7 days
Azithromycin, 
citalopram, 
clomipramine, 
itraconazole, 
nortriptyline, 
paroxetine,
solifenacin, tacrolimus
14 days
Fluoxetine 
5 weeks
Protriptyline 
6 weeks
Tamoxifen  
8weeks
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Appendix H. PATIENT REPORTED OUTCOMES (QLQ C-30)
EORTC QLQ-C30 (version3)
We are interested in some things about you and your health. Please answer all of the questions
yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. 
The information that you provide will remain strictly confidential.
Please fill in your initials:
Your birthdate (Day, Month, Year):
Today's date (Day, Month, Year):
___________________________________________________________________________
Not at A 
  Quite   Very
All 
Little   a Bit   Much
1. 
Do you have any trouble doing strenuous activities,
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4
3. 
Do you have any trouble taking a short walk outside of the house?
1 
2 
3 
4
4. 
Do you need to stay in bed or a chair during the day?
                                        1 
2 
3 
4
5. 
Do you need help with eating, dressing, washing
yourself or using the toilet?                       1 
2 
3 
4
During the past week:
Not at A 
  Quite   Very
All 
Little   a Bit   Much
6. 
Were you limited in doing either your work or other daily activities?
1 
2 
3 
4
7. 
Were you limited in pursuing your hobbies or other
leisure time activities? 
1 
2 
3 
4
8. 
Were you short of breath? 
1 
2 
3 
4
9. 
Have you had pain? 
1 
2 
3 
4
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10. 
Did you need to rest? 
1 
2 
3 
4
11. 
Have you had trouble sleeping? 
1 
2 
3 
4
12. 
Have you felt weak? 
1 
2 
3 
4
13. 
Have you lacked appetite? 
1 
2 
3 
4
14. 
Have you felt nauseated? 
1 
2 
3 
4
15. 
Have you vomited? 
1 
2 
3 
4
16. 
Have you  been constipated? 
1 
2 
3 
4
17. 
Have you had diarrhea? 
1 
2 
3 
4
18. 
Were you tired? 
1 
2 
3 
4
19. 
Did pain interfere with your daily activities? 
1 
2 
3 
4
20. 
Have you had difficulty in concentrating on things,
like reading a newspaper or watching television? 
1 
2 
3 
4
21. 
Did you feel tense? 
1 
2 
3 
4
22. 
Did you worry? 
1 
2 
3 
4
23. 
Did you feel irritable? 
1 
2 
3 
4
24. 
Did you feel depressed? 
1 
2 
3 
4
25. 
Have you had difficulty remembering things? 
1 
2 
3 
4
26. 
Has your physical condition or medical treatment
interfered with your family life? 
1 
2 
3 
4
27. 
Has your physical condition or medical treatment
interfered with your social activities? 
1 
2 
3 
4
28. 
Has your physical condition or medical treatment
caused you financial difficulties? 
1 
2 
3 
4
For the following questions please circle the number between 1 and 7 that best applies
to you
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29. 
How would you rate your overall health during the past week?
1 
2 
3 
4 
5 
6 
7
Very poor 
Excellent
30. 
How would you rate your overall quality of life during the past week?
1 
2 
3 
4 
5 
6 
7
Very poor 
Excellent
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Appendix I. PATIENT REPORTED OUTCOMES (QLQ LC-13)
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Appendix J. PATIENT REPORTED OUTCOMES (QLQ BN-20)
EORTC QLQ – BN-20
Patients sometimes report that they have the following symptoms. Please indicate the extent to
which you have experienced these symptoms or problems during the past week.
Please fill in your initials:
Your birthdate (Day, Month, Year):
Today's date (Day, Month, Year):
___________________________________________________________________________
During the past week:
Not at A 
  Quite   Very
All 
Little   a Bit   Much
1. 
Did you feel uncertain about the future? 
1 
2 
3 
4
2. 
Did you feel you had setbacks in your condition? 
1 
2 
3 
4
3. 
Were you concerned about disruption of family life? 
1 
2 
3 
4
4. 
Did you have headaches? 
1 
2 
3 
4
5. 
Did your outlook on the future worsen? 
1 
2 
3 
4
6. 
Did you have double vision? 
1 
2 
3 
4
7. 
Was your vision blurred? 
1 
2 
3 
4
8. 
Did you have difficulty reading because of your vision? 1 
2 
3 
4
9. 
Did you have seizures? 
1 
2 
3 
4
10. 
Did you have weakness on one side of your body? 
1 
2 
3 
4
11. 
Did you have trouble finding the right words to express yourself?
1 2 
3
12. 
Did you have difficulty speaking? 
1 
2 
3 
4
13. 
Did you have trouble communicating your thoughts? 
1 
2 
3 
4
14. 
Did you feel drowsy during the daytime? 
1 
2 
3 
4
15. 
Did you have trouble with your coordination? 
1 
2 
3 
4
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16. 
Did hair loss bother you? 
1 
2 
3 
4
17. 
Did itching of your skin bother you? 
1 
2 
3 
4
18. 
Did you have weakness of both legs? 
1 
2 
3 
4
19. 
Did you feel unsteady on your feet? 
1 
2 
3 
4
20. 
Did you have trouble controlling your bladder?        1 
2 
3 
4
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Appendix K. Information for Sponsor and Principal Investigators
[Principal Investigators]
(Dated on 09Dec2020)
PPD
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[Sponsor]
Sponsor Name 
Address
Yuhan Corporation
74, Noryangjin-ro, Dongjak-gu, Seoul,
06927, Korea
Janssen Research & Development, 
LLC  
920 U.S. Route 202, Raritan, NJ,
08869, United States of America
PPD
NCT04075396

Signature
User 
Date 
Reason
 
19-Nov-2021 
20:14:32
(GMT)
Document Approval
PPD
NCT04075396

CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 28 Apr 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
A Phase I/II, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Anti-Tumor Activity of YH25448 in Patients with EGFR Mutation 
Positive Advanced Non-Small Cell Lung Cancer (NSCLC) Part D
Protocol 73841937NSC2001; Phase 1/2, Part D
(also known as YH25448-201, Part D)
JNJ-73841937 (YH25448)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics,
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact
Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Status:
Approved
Date:
28 Apr 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-RIM-49311, 1.0
THIS APPENDIX APPLIES TO ALL CURRENTLY APPROVED VERSIONS OF 
PROTOCOL 73841937NSC2001
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04075396

COVID-19 Appendix
JNJ-73841937 (YH25448)
Clinical Protocol 73841937NSC2001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 28 Apr 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; and 
changes in hospital or clinic procedures required to address the COVID-19 challenge, including 
study site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for study 
related management in the event of disruption to the conduct of the study. This guidance does not 
supersede any local or government requirements or the clinical judgement of the investigator to 
protect the health and well-being of participants and site staff. If, at any time, a participant’s safety 
is considered to be at risk, study intervention will be discontinued, and study follow-up will be 
conducted as outlined in the protocol.
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up. However, if scheduled visits cannot be conducted in person at 
the study site it is suggested that they be performed to the extent possible remotely/virtually or 
delayed until such time that on-site visits can be resumed in order to continue participant 
monitoring in accordance with the protocol where possible. At each contact, participants will be 
interviewed to collect safety data. Key efficacy endpoint assessments should be performed if 
required and as feasible. Participants will also be questioned regarding general health status to 
fulfill any physical examination requirement. 
Modifications to protocol-required assessments may be permitted in alignment with this 
COVID-19 Appendix only after consultation with the participant, investigator, and the sponsor.
Missed assessments, study visits required by the protocol will still be considered protocol 
deviations and captured as “COVID-19 related” in the clinical trial management system. Study 
drug interruptions or discontinuations of study interventions and withdrawal from the study should 
be documented with the prefix “COVID-19-related” in the case report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a participant has tested positive for SARS-CoV-2 (COVID-19), the investigator should contact 
the Sponsor’s Medical Monitor to discuss plans for study intervention and follow-up. 
Modifications made to the study conduct as a result of the COVID-19 pandemic will be 
summarized in the clinical study report.
NCT04075396

COVID-19 Appendix
JNJ-73841937 (YH25448)
Clinical Protocol 73841937NSC2001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 28 Apr 2020
The guidance here-in is applicable until the clinical site returns to pre-pandemic operational 
capacity and practices:

Due to the COVID-19 pandemic, screening and enrollment into the 73841937NSC2001 
Part D study has been temporarily stopped at all study sites

The safety of the participants currently on study is a priority. Please continue with all 
scheduled visits, safety assessments, and radiographic assessments as far as possible.

If safety assessments such as echocardiography/MUGA, ophthalmologic exam and laboratory 
tests cannot be performed at the active clinical study site, patients will be permitted to use 
other facilities (at hospitals that have certified testing facilities). All results must be shared 
with the clinical study site and laboratory results must be available for the investigator to 
review prior to dosing. Copies of the results should be included in the participant’s study chart 
as a source document.

In the event the participant cannot visit the active clinical study site, telemedicine is allowed 
for the following activities: 

Review of body systems and collection of general health status (to be followed 
up with in-person examination if indicated) 

Review of new, and follow-up of existing, adverse events and concomitant 
medications between regularly scheduled on site visits. 

Please continue to collect PK samples as far as possible

If study imaging procedures cannot be performed at the active clinical study site, participants 
will be permitted to use other local imaging facilities (eg, at hospitals that are not the active 
study site). In these cases, digital copies should be made available to the investigator. Copies 
of the results should be included in the participant’s study chart as a source document. The 
sponsor’s Medical Monitor must be informed if radiographic assessments are delayed. 

If site visits are not feasible, participants may be eligible for home shipments of lazertinib 
where permitted and deemed feasible. If there is a need to consider shipment of lazertinib to 
a participant’s home, then the site must contact its Site Manager to discuss this option, so that 
the necessary approvals and arrangements can be put in place, subject to local regulatory 
guidelines. If required and permissible, shipment of study medication to a participant’s home 
would be the responsibility of the site (due to privacy issues), with support from the sponsor 
and requires 100% traceability (ie, courier tracking with a signed receipt). Participants 
continuing oral therapy at home should be monitored remotely on a schedule consistent with 
the protocol and instructed to hold study treatment in the event of worsening respiratory 
symptoms and contact their study sites/physicians immediately.

As SARS-CoV-2 represents a new infectious agent and COVID-19 a new clinical syndrome, 
it is unclear how infection with this virus, which can cause severe pneumonia, will impact the 
benefit/risk assessment with regards to lazertinib treatment. In addition, study treatment 
should be held in all participants with suspected (symptomatic) or documented SARS-CoV-2 
positive disease, until recovery from all infection related symptoms, and documented to be 
negative for SARS-CoV-2. Given the unmet medical need of this study population, and the 
unknown impact of prior COVID-19 infection on the risk of study treatment, re-initiation of 
study treatments should be evaluated with the sponsor’s Medical Monitor on a case-by-case 
basis, taking into account the severity of the COVID-19 related symptoms, and the observed 
NCT04075396

COVID-19 Appendix
JNJ-73841937 (YH25448)
Clinical Protocol 73841937NSC2001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 28 Apr 2020
clinical benefit from study treatment. Please report the event to the sponsor, following usual 
Adverse Event reporting requirements.

The sponsor’s Medical Monitor must be informed of any interruption in lazertinib treatment
due to COVID-19

Any deviations from Protocol 73841937NSC2001 Part D must be well documented and where 
applicable attributed to COVID-19. In accordance with Health Authority guidance the final 
Clinical Study Report must include these deviations. Case report forms should capture specific 
information, including the relationship to the COVID-19 pandemic. 

Monitoring Visits: When on-site monitoring by the sponsor is not feasible due to changes in 
hospital visitation policies, the sponsor’s site monitor will contact the study site to schedule 
remote visits. In such cases, on-site monitoring visits will resume when feasible, with 
increased frequency to address the source data verification backlog.
Even with staffing limitations during this COVID-19 pandemic, all routine operations related to 
clinical trials should be well-documented and archived as part of standard process. When 
conditions permit, all parties involved in this clinical trial should communicate relevant 
information so that all relevant parties remain sufficiently informed to take any necessary measures 
in a timely manner.
NCT04075396

NCT04075396