Clinical trial NCT03599518
Conditions: Non Small Cell Lung Cancer
Sponsor: Daiichi Sankyo Co., Ltd.
Start date: 2018-09-21; Completion date: 2020-06-29
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study has two parts: dose escalation and dose expansion.

The primary objectives are:

* For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with gefitinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with gefitinib in the study population
* For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with gefitinib in the study population.

In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles.

The number of treatment cycles is not fixed in this study. Participants will continue study treatment for 36 months unless they decide not to (withdraw consent), their disease gets worse \[progressive disease (PD)\], or side effects become unacceptable (unacceptable toxicity).

Detailed description:

Arms: arm 1: Participants receive DS-1205c (at planned doses given orally twice daily: 200 mg, 400 mg, 800 mg, 1000 mg, 1200 mg) in combination with daily 250 mg oral dose of gefitinib
Interventions: intervention 1: DS-1205c intervention 2: Gefitinib
Intervention descriptions: intervention 1: DS-1205c 200 mg capsule for oral administration intervention 2: Gefitinib 250 mg tablet for oral administration

Protocol documents:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
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CLINICAL STUDY PROTOCOL 
 
A MULTICENTER, OPEN-LABEL PHASE 1 STUDY 
OF DS-1205c IN COMBINATION WITH GEFITINIB 
IN SUBJECTS WITH METASTATIC OR 
UNRESECTABLE EGFR-MUTANT NON-SMALL 
CELL LUNG CANCER 
 
DS1205-A-J102 
 
VERSION 5.0, 29 JULY 2019 
VERSION 4.0, 08 APRIL 2019 
VERSION 3.0, 29 OCTOBER 2018 
VERSION 2.0, 29 JUNE 2018 
VERSION 1.0, 29 MAY 2018 
 
DAIICHI SANKYO 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo.  The 
information is provided to you in confidence which is requested under an agreed upon 
and signed Confidentiality and Disclosure Agreement.  Do not give this document or any 
copy of it or reveal any proprietary information contained in it to any third party (other 
than those in your organization who are assisting you in this work and are bound by the 
Confidentiality and Disclosure Agreement) without the prior written permission of an 
authorized representative of Daiichi Sankyo.


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INVESTIGATOR AGREEMENT 
A MULTICENTER, OPEN-LABEL PHASE 1 STUDY OF DS-1205c IN 
COMBINATION WITH GEFITINIB IN SUBJECTS WITH METASTATIC OR 
UNRESECTABLE EGFR-MUTANT NON-SMALL CELL LUNG CANCER 
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by the Daiichi Sankyo 
Co., LTD representative listed below. 
 
Print Name 
Signature 
Clinical Study Lead/ Clinical Scientist 
Title 
Date (DD MMM YYYY) 
Investigator’s Signature: 
I have fully discussed the objectives of this study and the contents of this protocol 
with the Sponsor’s representative. 
I understand that information contained in or pertaining to this protocol is confidential 
and should not be disclosed, other than to those directly involved in the execution or 
the ethical review of the study, without written authorization from the Sponsor.  It is, 
however, permissible to provide information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its 
requirements, subject to ethical and safety considerations and guidelines, and to 
conduct the study in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, International Council for Harmonisation guidelines on Good 
Clinical Practice (ICH E6), and applicable regional regulatory requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant 
regulatory authorities, my subjects’ study records in order to verify the data that I 
have entered into the case report forms.  I am aware of my responsibilities as a 
Principal Investigator as provided by the Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the 
study at any time for whatever reason; such a decision will be communicated to me in 
writing.  Conversely, should I decide to withdraw from execution of the study, I will 
communicate my intention immediately in writing to the Sponsor. 
Print Name 
Signature 
Title 
Date (DD MMM YYYY) 
PPD




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 To evaluate the effect on corrected QT interval 
(QTc) when DS-1205c is administered alone or in 
combination with gefitinib 
 To identify biomarkers that correlate with 
efficacy or toxicity to DS-1205c in combination 
with gefitinib 
 To assess changes in the profile of EGFR 
mutations and/or other genes in cell-free DNA 
(cfDNA) during treatment with DS-1205c in 
combination with gefitinib 
 To conduct metabolite analysis of DS-1205c 
Study Design: 
This is a multi-center, open-label, Phase 1 study of 
DS-1205c in combination with gefitinib in metastatic or 
unresectable EGFR-mutant NSCLC subjects who are 
T790M mutation-negative, after disease progression during 
treatment with gefitinib, erlotinib, afatinib, dacomitinib, or 
osimertinib. This study has 2 parts: Dose Escalation and 
Dose Expansion. 
Dose Escalation 
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Dose Escalation consists of a DS-1205c monotherapy 
run-in period (Cycle 0) followed by combination 
treatment of DS-1205c and gefitinib (Cycle 1 and 
beyond). 
Subjects will report to the clinic the morning of Cycle 0, 
Day 1 to obtain a baseline series of electrocardiograms 
(ECGs).  Subjects must have taken their final dose of 
gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib 
1 day prior to breakfast in clinic on Cycle 0, Day 1.  
ECGs will be obtained at specified time points over a 8-
hour period.  During a 7-day run-in period (Cycle 0), 
subjects will be administered DS-1205c orally twice 
daily (BID).  Safety, PK, vital sign, and ECG 
assessments will be obtained over the 7-day period. 
Cycle 1, Day 1: Following the end of the 7-day run-in 
period, DS-1205c will be administered orally BID in 
combination with gefitinib 250 mg administered orally 
once daily (QD), in 21-day cycles.  See table below. 
 
Dose Escalation Provisional Cohorts and Provisional 
Dosages 
 
Cycle 0 
Monotherapy 
(7-day cycle) 
Cycle 1 and Beyond 
Combination Therapy 
(21-day cycles) 
Cohorta 
DS-1205c 
Dosageb 
DS-1205c 
Dosageb 
Gefitinib 
Dosagec 
1 
200 mg BID 
200 mg BID 
250 mg QD 
2 
400 mg BID 
400 mg BID 
250 mg QD 
3 
600 mg BID 
600 mg BID 
250 mg QD 
4 
800 mg BID 
800 mg BID 
250 mg QD 
BID = twice daily; mg = milligrams; QD = once daily 
a The second subject in each cohort should start dosing at least 24 
hours after the initial dosing of the first subject. The cohort 
numbers in this table do not denote actual order of dose transition 
on the trial. 
b Administer with a meal, with 240 mL of water.  On the morning 
of Endpoint ECG days, breakfast should be started 30 minutes 
prior to dosing and should be completed within approximately 20 
minutes.  For all other dosings, it is recommended that meals 
(breakfast or dinner) be completed within approximately 30 
minutes, and DS‑1205c should be taken immediately after meal 
completion.  Doses of DS-1205c should be taken approximately 
12 hours apart. 
c Co-administer with morning dose of DS-1205c. 


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Dose escalation will be guided by the modified 
Continuous Reassessment Method (mCRM) using a 
Bayesian logistic regression model (BLRM) following 
the escalation with overdose control (EWOC) principle.  
In this method, a decision to escalate to the next cohort 
is based on review of all subjects who have completed 
the dose-limiting toxicity (DLT)-evaluation period. 
The DLT-evaluation period is defined as the 7 days of 
Cycle 0 plus the 21 days of Cycle 1 (28 days total).  A 
DLT-evaluable subject is defined as a subject who has 
received DS-1205c and EITHER has completed 
minimum safety evaluation requirements over the 
DLT-evaluation period OR has experienced a DLT 
during the DLT-evaluation period. 
The RDE will be decided based on an overall 
assessment of available safety and tolerability data from 
Cycle 1 and beyond, and all available PK, biomarker, 
and tumor response data.  Dose Escalation will be 
stopped if any of the following occur: (a) at least 6 
evaluable subjects have been enrolled at the RDE with at 
least 18 evaluable subjects in total enrolled in Dose 
Escalation, or (b) at least 9 evaluable subjects have been 
enrolled at a particular dose level, the model 
recommends continuing at the same dose level, and the 
posterior probability of the DLT rate falling within the 
target DLT interval is ≥ 50%, or (c) the starting dose is 
too toxic. 
Study Duration: 
Dose Escalation 
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 Enrollment is planned to occur over approximately 
12 months. 
 Treatment and follow-up will be completed when all 
subjects have either discontinued study treatment or 
completed last study visit  
The number of treatment cycles is not fixed in this study.  
Subjects will continue study treatment until withdrawal of 
consent, progressive disease (PD), or unacceptable toxicity 
for all subjects in Dose Escalation and Dose Expansion. 
Study Sites and Locations: 
Approximately 20 clinical sites within Japan.  Additional 
sites and countries may be added as needed. 
Subject Eligibility Criteria: 
Key Inclusion Criteria: 
1. Has histologically or cytologically documented 
adenocarcinoma NSCLC. 
2. Has locally advanced or metastatic NSCLC, not 
amenable to curative surgery or radiation.  
3. Has acquired resistance to EGFR TKI according to 
the Jackman criteria (PMID: 19949011): 
a. Historical confirmation that the tumor harbors an 
EGFR mutation known to be associated with 
EGFR TKI sensitivity (including G719X, exon 
19 deletion, L858R, L861Q),  OR 
b. Has experienced clinical benefit from an EGFR 
TKI, followed by systemic progression 
(Response Evaluation Criteria in Solid Tumors 
[RECIST version 1.1] or World Health 
Organization [WHO]) while on continuous 
treatment with an EGFR TKI. 
4. Is currently receiving and able to interrupt gefitinib 
or discontinue erlotinib, afatinib, dacomitinib, or 
osimertinib. 
5. Has been receiving gefitinib, erlotinib, afatinib, 
dacomitinib, or osimertinib for at least 6 weeks with 
well-controlled related toxicities less than Grade 3 in 
severity at the time of screening period.  Subjects 
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who have been receiving gefitinib must be taking 
gefitinib at a dose of 250 mg/day. 
6. Has radiological documentation of disease 
progression while receiving continuous treatment 
with gefitinib, erlotinib, afatinib, dacomitinib, or 
osimertinib. 
7. Has at least one measurable lesion per RECIST 
version 1.1. 
8. Is willing to provide archival tumor tissue from a 
biopsy performed after progression during treatment 
with gefitinib, erlotinib, afatinib, dacomitinib, or 
osimertinib OR has at least one lesion, not 
previously irradiated, amenable to core biopsy and is 
willing to undergo screening tumor biopsy. 
9. Demonstrates absence of EGFR T790M mutation in 
tumor tissue since progression during gefitinib, 
erlotinib, afatinib, dacomitinib, or osimertinib 
treatment. 
10. Has Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) of 0 or 1, with no 
deterioration over the previous 2 weeks.  
Key Exclusion Criteria: 
1. Has any evidence of small cell histology, or 
combined small cell and non-small cell histology, in 
original tumor biopsy or in screening biopsy 
performed since progression. 
2. Has previously documented evidence of anaplastic 
lymphoma kinase (ALK) fusion, ROS proto-
oncogene 1 (ROS1) fusion, BRAF V600E mutation, 
rearranged during transfection (RET) rearrangement, 
human epidermal growth factor receptor 2 (HER2) 
mutation, or MET exon 14 skipping mutation.  No 
new testing for these genomic alterations is required 
for Screening. 
3. Has received treatment with any of the following: 
a. Any cytotoxic chemotherapy, immune 
checkpoint inhibitor therapy, investigational 
agent or other anticancer drug(s) from a previous 
cancer treatment regimen or clinical study (other 
than EGFR TKI), within 14 days of the first dose 
of study treatment. 
b. Immune checkpoint inhibitor therapy within 30 
days of first dose of study treatment. 


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c. Major surgery (excluding placement of vascular 
access) within 4 weeks of the first dose of study 
treatment. 
d. Radiotherapy treatment to more than 30% of the 
bone marrow or with a wide field of radiation 
within 4 weeks, or palliative radiation therapy 
within 2 weeks of the first dose of study drug 
treatment. 
4. Has history of other active malignancy within 3 
years prior to enrollment, except: 
a. Adequately treated non-melanoma skin cancer 
OR 
b. Superficial bladder tumors (Tumor stage “a” 
[Ta], Tumor stage “is” [Tis], Tumor stage “1” 
[T1]) OR 
c. Curatively treated in situ disease OR 
d. Low-risk non-metastatic prostate cancer (with 
Gleason score < 7 on antiandrogen therapy)  
5. Has spinal cord compression or clinically active 
brain metastases, defined as untreated and 
symptomatic, or requiring therapy with 
corticosteroids or anticonvulsants to control 
associated symptoms.  Subjects with clinically 
inactive brain metastases may be included in the 
study.  Subjects with treated brain metastases that 
are no longer symptomatic and who require no 
treatment with corticosteroids or anticonvulsants 
may be included in the study if they have recovered 
from the acute toxic effect of radiotherapy.  A 
minimum of 2 weeks must have elapsed between the 
end of whole brain radiotherapy and study 
enrollment (1 week for stereotactic radiotherapy). 
6. Presence of retinal disease in the eye that is not due 
to neovascular age-related macular degeneration 
(nAMD; eg, significant diabetic retinopathy, 
glaucomatous retinal atrophy, retinal detachment). 
7. Has history of myocardial infarction within the past 
6 months. 
8. Has symptomatic congestive heart failure (New 
York Heart Association [NYHA] Classes II IV), 
unstable angina, or cardiac arrhythmia requiring 
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9. Has left ventricular ejection fraction (LVEF) < 45% 
by either echocardiogram (ECHO) or multigated 
acquisition (MUGA) scan. 
10. Has 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, or PR 
interval > 250 milliseconds (ms). 
11. Has a mean corrected QT interval using Fridericia’s 
correction (QTcF) prolongation >470 ms for females 
and >450 ms for males in three successive Screening 
measurements. 
12. Unable or unwilling to discontinue concomitant use 
of drugs that are known to prolong the QT interval.    
13. Has any factors that increase the risk of QTc 
prolongation or risk of arrhythmic events, such as 
congenital long QT. syndrome, family history of 
long QT syndrome or unexplained sudden death 
under 40 years of age in first-degree relatives. 
14. Has a history of (non-infectious) interstitial lung 
disease (ILD)/pneumonitis that required 
corticosteroid treatment, has current 
ILD/pneumonitis, or has suspected ILD/pneumonitis 
which cannot be ruled out by imaging at screening. 
15. Has history of pancreatitis within the past 6 months. 
Dosage Form and Route of 
Administration: 
DS-1205c is supplied as 200 mg capsules, white opaque 
with red lines, packaged in high-density polyethylene 
(HDPE) bottles of 32 capsules.  DS-1205c will be taken 
orally BID with doses taken approximately 12 hours apart.  
DS-1205c should be administered or taken with a meal, 
with 240 mL of water.  On the morning of Endpoint ECG 
days, breakfast should be started 30 minutes prior to dosing 
and should be completed within approximately 20 minutes.  
For all other dosings, it is recommended that meals 
(breakfast or dinner) be completed within approximately 30 
minutes; DS-1205c should be taken immediately after meal 
completion. 
Gefitinib is prescribed as 250 mg tablets.  Beginning with 
Day 1 of Cycle 1, gefitinib will be co-administered orally 
QD with the morning dose of DS-1205c. 
Study Endpoints:  
Dose Escalation 
Primary Endpoints (ie, Primary Outcome Measures): 


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 To determine the safety and tolerability of 
DS-1205c in combination with gefitinib, the 
endpoints will include DLTs, serious adverse 
events (SAEs), treatment-emergent adverse 
events (TEAEs), physical examination findings 
(including ECOG PS), vital sign measurements, 
ophthalmologic findings, standard clinical 
laboratory parameters, ECG parameters 
(including the change-from-baseline ECG 
parameters: heart rate [HR]; PR; QTcF; and QRS 
intervals [∆HR, ∆PR, ∆QTcF, and ∆QRS]), 
ECHO or MUGA findings, and radiographic 
findings.  Adverse events (AEs) and abnormal 
laboratory findings will be graded according to 
the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-
CTCAE) version 5.0.  
Secondary Endpoints (ie, Secondary Outcome 
Measures) 
 Cycle 0: To assess PK of DS-1205a, the 
endpoints will include plasma concentration of 
DS-1205a versus time, and maximum plasma 
concentration (Cmax), the actual sampling time to 
reach Cmax (Tmax), trough plasma concentration 
(Ctrough), area under the plasma concentration-
time curve during a dosing interval (AUCtau), 
and other PK parameters, as appropriate. 
 Cycle 1 and beyond: To assess the PK of 
DS-1205a, and gefitinib, the endpoints will 
include plasma concentration of DS-1205a, and 
gefitinib versus time, and maximum observed 
analyte concentration during a dosing interval 
(Tau) (Cmax), Tmax, Ctrough, AUCtau, and 
other PK parameters, as appropriate.  
 The efficacy endpoint is the objective response 
rate (ORR, the number of subjects with best 
objective response [complete response (CR) or 
partial response (PR), divided by the number of 
subjects in the analysis population]), as 
determined by Investigator assessment based on 
RECIST version 1.1.  Additional efficacy 
endpoints are duration of response (DOR, the 
time from documentation of tumor response 
[either CR or PR] to disease progression), disease 
control rate (DCR, the sum of CR rate, PR rate, 


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and stable disease (SD) rate), progression-free 
survival (PFS), time to response (TTR) and 
overall survival (OS).  
Exploratory Endpoints (ie, Exploratory Outcome 
Measures) 
 Biomarkers measured in tumor specimens (eg, 
AXL immunohistochemistry [IHC], AXL and 
AXL pathway genes measured by NanoString 
multiplex RNA and/or other methods, and/or 
protein analysis) that correlate with response or 
toxicity to DS-1205c in combination with 
gefitinib will be assessed. 
 Biomarkers measured in plasma (eg, cfDNA) that 
correlate with response or toxicity to DS-1205c in 
combination with gefitinib will be assessed. 
 EGFR mutation(s) or mutations in other genes in 
cfDNA during treatment with DS-1205c in 
combination with gefitinib will be assessed. 
 To assess change-from-baseline QTcF (∆QTcF) 
when DS-1205c is administered alone or in 
combination with gefitinib. 
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Planned Sample Size: 
Dose Escalation 
Approximately 18 subjects will be enrolled. 
 
 
Statistical Analyses: 
The final efficacy analysis will occur after all subjects have 
either discontinued the study or completed last study visit 
or contact. 
Safety Analyses:  
The safety profile will be based on SAEs, TEAEs, Aes, 
standard clinical laboratory measurements, vital sign 
measurements, ECG parameters, physical examination 
findings, ECHO/MUGA findings, and ophthalmologic 
findings.  Aes and abnormal laboratory values will be 
graded according to the NCI-CTCAE version 5.0.  
Safety analyses in general will be descriptive and will be 
presented in tabular format with the appropriate 
summary statistics.  In Dose Escalation, the number of 
DLTs identified among the DLT-evaluable subjects in 
the DLT-evaluable set will be listed and summarized. 
Clinical interpretation of ECGs will be summarized 
descriptively. 
Pharmacokinetic (PK) Analyses:  
PK parameters for each subject will be estimated using 
non-compartmental analysis (NCA).  Descriptive 
statistics will be provided for all plasma concentration 
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data by analyte/dose/study day/time and for each PK 
parameter by analyte/dose/study day, as appropriate.  
Efficacy Analyses:  
The efficacy analysis will be performed for the subjects 
who received at least one dose of study drug by dose 
level within each part and overall.  The analysis will be 
based on subjects dosed at the level of RDE at both the 
dose escalation part and the dose expansion part.  
Analyses will be performed for each dose level.  
Subjects with unknown or missing response will be 
treated as non-responders.  The estimate of ORR will be 
reported as a summary statistic.  The DCR will be 
reported as a summary statistic, and point estimates and 
2-sided 95% exact binomial confidence intervals (CIs) 
will be provided.  Time to event variables including 
DOR, TTR, PFS, and OS will be summarized with 
median event times with 2-sided 95% CI using the 
Kaplan-Meier method.  
Biomarker Analyses:  
Tissue biopsy obtained from a site of PD and prior to 
study treatment will be analyzed for AXL expression 
using IHC, and the mRNA of several hundred genes will 
be measured using NanoString or other method(s).  
Biomarkers will be summarized using descriptive and 
correlative analyses, as appropriate.  
Exploratory Analyses: 
The Concentration-QTc analysis plan will be presented 
in a separate document. 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT ......................................................................... 2 
PROTOCOL SYNOPSIS....................................................................................... 3 
TABLE OF CONTENTS ..................................................................................... 15 
LIST OF TABLES ............................................................................................... 23 
LIST OF FIGURES ............................................................................................. 24 
LIST OF ABBREVIATIONS .............................................................................. 25 
1. 
INTRODUCTION............................................................................... 31 
1.1. 
Data Summary ..................................................................................... 31 
1.1.1. 
Study Drug .......................................................................................... 31 
1.1.1.1. 
Name ................................................................................................... 31 
1.1.1.2. 
Description .......................................................................................... 31 
1.1.1.3. 
Intended Use Under Investigation ....................................................... 31 
1.1.2. 
Nonclinical Studies ............................................................................. 31 
1.1.2.1. 
Pharmacology ...................................................................................... 31 
1.1.2.2. 
Safety Pharmacology .......................................................................... 34 
1.1.2.3. 
Pharmacokinetics and Drug Metabolism ............................................ 35 
1.1.2.4. 
Toxicology .......................................................................................... 36 
1.1.3. 
Clinical Experience ............................................................................. 37 
1.2. 
Background ......................................................................................... 37 
1.2.1. 
Metastatic or Unresectable EGFR-Mutant NSCLC ............................ 37 
1.3. 
Study Rationale and Dose Selection ................................................... 40 
1.3.1. 
Study Rationale ................................................................................... 40 
1.3.2. 
Study Dose Setting .............................................................................. 40 
1.3.2.1. 
DS-1205c Starting Dose ...................................................................... 40 
1.3.2.2. 
Gefitinib Dosage ................................................................................. 41 
1.4. 
Risks and Benefits for Study Subjects ................................................ 41 
1.4.1. 
Potential Risks Associated With DS-1205c ........................................ 41 
1.4.2. 
Potential Risks Associated With Gefitinib .......................................... 41 
1.4.3. 
Pharmacokinetic Drug Interaction ...................................................... 41 
1.4.3.1. 
Evaluation of the Potential for PK Interaction Effect on Gefitinib by 
DS-1205c............................................................................................. 42 


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1.4.3.2. 
Evaluation of the Potential for PK Interaction Effect on DS-1205c by 
Gefitinib .............................................................................................. 42 
1.4.4. 
Potential Benefit Associated with DS-1205c ...................................... 42 
2. 
STUDY OBJECTIVES AND HYPOTHESIS .................................... 44 
2.1. 
Study Objectives ................................................................................. 44 
2.1.1. 
Dose Escalation ................................................................................... 44 
2.1.2. 
Dose Expansion ................................................................................... 44 
2.2. 
Study Hypothesis ................................................................................ 45 
2.2.1. 
Dose Escalation ................................................................................... 45 
2.2.2. 
Dose Expansion ................................................................................... 45 
2.3. 
Study Endpoints .................................................................................. 45 
2.3.1. 
Dose Escalation ................................................................................... 45 
2.3.2. 
Dose Expansion ................................................................................... 46 
3. 
STUDY DESIGN ................................................................................ 48 
3.1. 
Overall Design Summary .................................................................... 48 
3.2. 
Treatment Groups ................................................................................ 48 
3.2.1. 
Dose Escalation ................................................................................... 49 
3.2.1.1. 
Cycle 0 (Monotherapy, 7 Days) .......................................................... 49 
3.2.1.2. 
Cycle 1 and Beyond (Combination Therapy) ..................................... 50 
3.2.1.3. 
Dose-Limiting Toxicities (DLT) ......................................................... 51 
3.2.1.4. 
Safety Review Meetings ..................................................................... 55 
3.2.1.5. 
Stopping Rule for Recommended Dose for Expansion 
Determination ...................................................................................... 55 
3.2.1.6. 
Determination of Recommended Dose for Expansion ........................ 55 
3.2.2. 
Dose Expansion ................................................................................... 55 
3.2.2.1. 
Stopping Rule for Other Consideration(s) .......................................... 56 
3.3. 
Duration of Subject Participation ........................................................ 56 
3.4. 
Duration of Study ................................................................................ 56 
4. 
STUDY POPULATION ..................................................................... 57 
4.1. 
Inclusion Criteria ................................................................................. 57 
4.2. 
Exclusion Criteria ................................................................................ 59 
5. 
STUDY TREATMENT(S) ................................................................. 62 
5.1. 
Assigning Subjects to Treatments and Blinding ................................. 62 


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5.1.1. 
Treatment Group(s)/Sequence(s) ........................................................ 62 
5.1.2. 
Enrollment ........................................................................................... 62 
5.2. 
Study Drug(s) ...................................................................................... 63 
5.2.1. 
Description .......................................................................................... 63 
5.2.2. 
Labeling and Packaging ...................................................................... 63 
5.2.3. 
Preparation .......................................................................................... 63 
5.2.4. 
Administration..................................................................................... 63 
5.2.5. 
Storage ................................................................................................. 64 
5.2.6. 
Drug Accountability ............................................................................ 64 
5.3. 
Treatment Compliance ........................................................................ 65 
5.4. 
Dose Interruptions and Reductions ..................................................... 65 
5.4.1. 
Dose Interruptions ............................................................................... 66 
5.4.2. 
Dose Reductions.................................................................................. 77 
5.5. 
Prior and Concomitant Medications, Treatments, and Procedures ..... 77 
5.5.1. 
Prior Medication(s), Treatment(s), and Procedure(s) ......................... 77 
5.5.2. 
Concomitant Medication(s) ................................................................. 78 
5.5.3. 
Prohibited Medications ....................................................................... 78 
5.6. 
Subject Withdrawal/Discontinuation .................................................. 79 
5.6.1. 
Reasons for Withdrawal/Discontinuation ........................................... 79 
5.6.2. 
Withdrawal Procedures ....................................................................... 80 
5.6.3. 
Subject Re-Screening Procedures ....................................................... 80 
6. 
STUDY PROCEDURES .................................................................... 82 
6.1. 
Dose Escalation ................................................................................... 82 
6.1.1. 
Screening (Dose Escalation) ............................................................... 82 
6.1.1.1. 
Tissue Requirement (Dose Escalation) ............................................... 82 
6.1.1.2. 
Screening (Dose Escalation) ............................................................... 83 
6.1.2. 
Cycle 0 (Dose Escalation) ................................................................... 85 
6.1.2.1. 
Cycle 0, Day 1 (Dose Escalation) ..................................................... 85 
6.1.2.2. 
Cycle 0, Day 1 (Dose Escalation) ....................................................... 86 
6.1.2.3. 
Cycle 0, Day 2 (Dose Escalation) ....................................................... 87 
6.1.2.4. 
Cycle 0, Day 4 (Dose Escalation) ....................................................... 88 
6.1.2.5. 
Cycle 0, Day 6 (Dose Escalation) ....................................................... 89 


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6.1.2.6. 
Cycle 0, Day 7 (Dose Escalation) ....................................................... 90 
6.1.3. 
Cycle 1 and Beyond (Dose Escalation) ............................................... 92 
6.1.3.1. 
Cycle 1, Day 1 (Dose Escalation) ....................................................... 92 
6.1.3.2. 
Cycle 1, Day 4, Day 8, and Day 15 (Dose Escalation) ....................... 93 
6.1.3.3. 
Cycle 2, Day 1 (Dose Escalation) ....................................................... 94 
6.1.3.4. 
Cycle 2, Day 2 and Day 8 (Dose Escalation) ...................................... 96 
6.1.3.5. 
Tumor Assessments (Dose Escalation) ............................................... 97 
6.1.3.6. 
Chest Radiograph for Safety Evaluation (Dose Escalation) ............... 98 
6.1.3.7. 
Cycle 3 and Subsequent Cycles, Day 1 (Dose Escalation) ................. 98 
6.1.3.8. 
End-of-Treatment (EOT) Visit (Dose Escalation) .............................. 99 
6.1.3.9. 
Follow-Up Call (Dose Escalation) .................................................... 101 
6.1.3.10. New Cancer Treatment and Survival Follow-up (Dose Escalation) . 101 
6.2. 
Dose Expansion ................................................................................. 101 
6.2.1. 
Screening (Dose Expansion) ............................................................. 101 
6.2.1.1. 
Tissue Screening (Dose Expansion).................................................. 101 
6.2.1.2. 
Screening (Dose Expansion) ............................................................. 102 
6.2.2. 
Treatment (Dose Expansion) ............................................................. 103 
6.2.2.1. 
Cycle 1, Day 9 (Dose Expansion) ................................................... 104 
6.2.2.2. 
Cycle 1, Day 1 (Dose Expansion) ..................................................... 104 
6.2.2.3. 
Cycle 1, Day 8 and Day 15 (Dose Expansion) .................................. 105 
6.2.2.4. 
Cycle 2, Day 1 (Dose Expansion) ..................................................... 106 
6.2.2.5. 
Cycle 2, Day 2 and Day 8 (Dose Expansion) .................................... 108 
6.2.2.6. 
Tumor Assessments (Dose Expansion) ............................................. 108 
6.2.2.7. 
Chest Radiograph for Safety Evaluation (Dose Expansion) ............. 109 
6.2.2.8. 
Cycle 3 and Subsequent Cycles (Dose Expansion)........................... 109 
6.2.2.9. 
End-of-Treatment (EOT) Visit (Dose Expansion) ............................ 111 
6.2.2.10. Follow-Up Call (Dose Expansion) .................................................... 112 
6.2.2.11. New Cancer Treatment and Survival Follow-up (Dose Expansion) . 112 
6.3. 
Schedule of Events ............................................................................ 112 
7. 
EFFICACY ASSESSMENTS ........................................................... 129 
7.1. 
Assessments for Efficacy Endpoint(s) .............................................. 129 
7.1.1. 
Efficacy Endpoint(s) ......................................................................... 129 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS ............................................................................... 130 
8.1. 
Pharmacokinetic (PK) Assessment(s) ............................................... 130 
8.2. 
Biomarkers ........................................................................................ 130 
8.2.1. 
Pharmacodynamic Biomarker Assessments in Blood Samples ........ 130 
8.2.2. 
Biomarker Assessments in Tumor Tissue Samples .......................... 131 
8.2.2.1. 
Tumor Biopsy Sample Collection ..................................................... 131 
8.2.2.2. 
Tumor Tissue Biomarker Analysis ................................................... 132 
8.2.3. 
Additional Biomarker Assessments .................................................. 132 
8.2.4. 
Disclosure of the Results of Biomarker Assessment ........................ 133 
8.3. 
Pharmacogenomic Analysis .............................................................. 133 
8.3.1. 
Study Subjects for Pharmacogenomic Analysis ............................... 133 
8.3.2. 
Collection of Specimens for Pharmacogenomic Analysis ................ 133 
8.3.2.1. 
Pharmacogenomic Endpoints ............................................................ 133 
8.3.2.2. 
Disclosure of the Results of Pharmacogenomic Analysis................. 134 
8.3.2.3. 
Storage and Disposal of Specimens for Pharmacogenomic Analysis134 
9. 
SAFETY EVALUATION AND REPORTING................................ 135 
9.1. 
Adverse Events .................................................................................. 135 
9.2. 
Safety Endpoints ............................................................................... 136 
9.3. 
Adverse Events of Special Interest (AESI) ....................................... 136 
9.3.1. 
Elevations of Aminotransferase(s) and Bilirubin .............................. 136 
9.3.2. 
Prolonged QTc Interval（≥ Grade 2） ............................................. 136 
9.3.3. 
Interstitial Lung Disease ................................................................... 136 
9.4. 
Definitions ......................................................................................... 137 
9.4.1. 
Adverse Event ................................................................................... 137 
9.4.2. 
Serious Adverse Event ...................................................................... 137 
9.4.3. 
Adverse Event Severity ..................................................................... 138 
9.4.4. 
Causality Assessment ........................................................................ 138 
9.4.5. 
Action Taken Regarding Study Drug(s) ........................................... 139 
9.4.6. 
Other Action Taken for Event ........................................................... 139 
9.4.7. 
Adverse Event Outcome ................................................................... 139 
9.5. 
Serious Adverse Events Reporting Procedure For Investigators ...... 139 


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9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Institutional Ethics Committee.................................. 140 
9.7. 
Exposure In Utero During Clinical Studies ...................................... 141 
9.8. 
Clinical Laboratory Evaluations ....................................................... 141 
9.9. 
Vital Signs ......................................................................................... 142 
9.10. 
Electrocardiograms ........................................................................... 142 
9.10.1. 
Safety ECGs ...................................................................................... 142 
9.11. 
Physical Examinations ...................................................................... 143 
9.12. 
Other Examinations ........................................................................... 143 
10. 
OTHER ASSESSMENTS ................................................................. 145 
11. 
STATISTICAL METHODS ............................................................. 146 
11.1. 
General Statistical Considerations .................................................... 146 
11.2. 
Analysis Sets ..................................................................................... 146 
11.3. 
Study Population Data....................................................................... 147 
11.4. 
Efficacy Analyses .............................................................................. 147 
11.5. 
Pharmacokinetic Analyses ................................................................ 148 
11.6. 
Safety Analyses ................................................................................. 148 
11.6.1. 
Adverse Event Analyses ................................................................... 148 
11.6.2. 
Electrocardiogram Analyses ............................................................. 149 
11.6.3. 
Clinical Laboratory Evaluation Analyses ......................................... 149 
11.6.4. 
Vital Sign Analyses ........................................................................... 149 
11.6.5. 
Physical Examination Analyses ........................................................ 149 
11.6.6. 
Interstitial Lung Disease Analysis and Adjudication ........................ 149 
11.7. 
Interim Analyses ............................................................................... 150 
11.8. 
Data Monitoring Committee ............................................................. 150 
11.9. 
Sample Size Determination ............................................................... 150 
11.10. 
Statistical Analysis Process ............................................................... 150 
11.11. 
Specification of Modified Continuous Reassessment Method with 
Escalation With Overdose Control .................................................... 151 
11.11.1. Bayesian Logistic Regression Model for Modified Continuous 
Reassessment Method ....................................................................... 151 
11.11.2. Prior Specification for Bayesian Logistic Regression Model 
Parameters ......................................................................................... 151 


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11.11.3. Escalation With Overdose Control Principle .................................... 152 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE .................... 153 
12.1. 
Monitoring and Inspections............................................................... 153 
12.2. 
Data Collection .................................................................................. 153 
12.3. 
Data Management ............................................................................. 154 
12.4. 
Study Documentation and Storage .................................................... 154 
12.5. 
Record Keeping ................................................................................. 155 
13. 
FINANCING AND INSURANCE ................................................... 156 
13.1. 
Finances ............................................................................................. 156 
13.2. 
Reimbursement, Indemnity, and Insurance ....................................... 156 
14. 
PUBLICATION POLICY ................................................................. 157 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION..... 158 
15.1. 
Compliance Statement, Ethics and Regulatory Compliance ............. 158 
15.2. 
Subject Confidentiality ...................................................................... 158 
15.3. 
Informed Consent .............................................................................. 158 
15.4. 
Regulatory Compliance ..................................................................... 159 
15.5. 
Protocol Deviations ........................................................................... 160 
15.6. 
Supply of New Information Affecting the Conduct of the Study ..... 160 
15.7. 
Protocol Amendments ....................................................................... 161 
15.8. 
Study Termination ............................................................................. 161 
15.9. 
Data and Safety Monitoring Board ................................................... 161 
15.10. 
Address List ...................................................................................... 161 
15.10.1. Sponsor .............................................................................................. 161 
16. 
REFERENCES .................................................................................. 162 
17. 
APPENDICES................................................................................... 166 
17.1. 
Cockcroft-Gault Equation ................................................................. 166 
17.2. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 ............ 167 
17.2.1. 
Measurability of Tumor at Baseline .................................................. 167 
17.2.1.1. Definitions ......................................................................................... 167 
17.2.1.2. Specifications by Methods of Measurements ................................... 168 
17.2.2. 
Tumor Response Evaluation ............................................................. 168 
17.2.2.1. Assessment of Overall Tumor Burden and Measurable Disease ...... 168 


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17.2.2.2. Baseline Documentation of “Target” and “Non-target” Lesions ...... 168 
17.2.2.3. Response Criteria .............................................................................. 169 
17.2.2.4. Evaluation of Best Overall Response ................................................ 172 
17.3. 
New York Heart Association Functional Capacity and Objective 
Assessment ........................................................................................ 175 
17.4. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
(PS) .................................................................................................... 176 
17.5. 
National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0 ........................................................................... 177 
17.6. 
QT-Prolonging Medications and CYP3A4 Inhibitors/Inducers ........ 178 
 


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LIST OF TABLES 
Table 3.1: Dose Escalation Provisional Cohorts and Provisional Dosages ....... 49 
Table 5.1: Dose Interruption and Dose Resumption Criteria ............................ 67 
Table 6.1: Schedule of Events, Dose Escalation (Cycle 0) .............................. 113 
Table 6.2: Schedule of Events, Dose Escalation (Cycle 1 and Beyond) ......... 118 
Table 6.3: Schedule of Events, Dose Expansion ............................................. 123 
Table 9.1: Clinical Laboratory Tests ............................................................... 142 
Table 17.1: Overall Response: Subjects with Target (±Non-target) Disease .... 172 
Table 17.2: Best Overall Response When Confirmation of CR and PR Is 
Required .......................................................................................... 173 
Table 17.3: New York Heart Association Functional Capacity and Objective 
Assessment ..................................................................................... 175 
Table 17.4: Eastern Cooperative Oncology Group Performance Status Scale .. 176 
 


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LIST OF FIGURES 
Figure 1.1: Effects of Gefitinib and DS-1205b on Estimated Tumor Volume in 
HCC827-Bearing Nude Mice ........................................................... 32 
Figure 1.2: Effects of Erlotinib and DS-1205b on Estimated Tumor Volume in 
HCC827-Bearing Nude Mice ........................................................... 33 
Figure 1.3: Effects of Erlotinib and DS-1205b Using Acquired Erlotinib-
Resistance Subcutaneous Tumor Model of HCC827 ....................... 34 
Figure 3.1: Study Schema: Dose Escalation ....................................................... 48 
Figure 3.2: Study Schema: Dose Expansion ....................................................... 48 
Figure 5.1: Subject Enrollment Process .............................................................. 62 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
Δ 
change from baseline 
μM 
micromolar 
AC 
Adjudication Committee 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event(s) of special interest 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
anti-HBc antibody 
anti-hepatitis B core antibody 
anti-HBs antibody 
anti-hepatitis B surface antibody 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
AUC 
area under the plasma concentration-time curve 
AUC0-24h 
area under the plasma concentration-time curve from time 0 to 24 
hours 
AUCtau 
area under the plasma concentration-time curve during a dosing 
interval 
AXL 
receptor tyrosine kinase 
BID 
twice daily 
BLRM 
Bayesian logistic regression model 
BUN 
blood urea nitrogen 
CAP 
College of American Pathologists 
cDNA 
complementary DNA 
cfDNA 
cell-free DNA 
CHL 
Chinese hamster lung 
CI 
confidence interval 
CK 
creatine kinase 
Cmax 
maximum plasma concentration 
Ctrough 
trough plasma concentration 
CR 
complete response 
CRO 
Contract Research Organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria For Adverse Events 
CYP 
cytochrome P450 


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ABBREVIATION 
DEFINITION 
DCR 
disease control rate 
dL 
deciliter(s) 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DS-1205a 
N-[4-(2-Amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-
methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4'-oxo-1'-
(tetrahydro-2H-pyran-4-ylmethyl)-1',4'-dihydro-2,3'-bipyridine-5'-
carboxamide, free form of DS-1205c 
DS-1205b 
1 4/5 sulfate trihydrate of DS-1205a 
eCRF 
electronic Case Report Form 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EOT 
end of treatment 
ETV 
estimated tumor volume 
EWOC 
escalation with overdose control 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
g 
gram(s) 
G719X 
glycine 719 to alanine, cysteine, aspartate, or serine (mutation in 
EGFR) 
GAS6 
growth arrest-specific gene 6 
GCP 
Good Clinical Practice 
GLDH 
glutamate dehydrogenase 
GLP 
Good Laboratory Practic 
h 
hour 
Hb 
hemoglobin 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HED 
human equivalent dose 
HER2 
human epidermal growth factor receptor 2 


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ABBREVIATION 
DEFINITION 
hERG 
human ether-à-go-go related gene 
hGAS6 
human growth arrest-specific gene 6 
HGFs 
hematopoietic growth factors 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
HR 
heart rate 
HRCT 
high resolution computed tomography 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICMJE 
International Council of Medical Journal Editors  
IEC 
Institutional Ethics Committee 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
ILD AC 
Interstitial Lung Disease Adjudication Committee 
IND 
Investigational New Drug 
INN 
international non-proprietary name 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
kg 
kilogram(s) 
L858R 
leucine 858 to arginine (mutation in EGFR) 
L861Q 
leucine 861 to glutamine (mutation in EGFR) 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
MC 
methylcellulose 
mCRM 
modified Continuous Reassessment Method 
MedDRA 
Medical Dictionary for Regulatory Activities 
MET 
hepatocyte growth factor receptor 
µg 
microgram 
min 
minute 
mL 
milliliter 


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ABBREVIATION 
DEFINITION 
MRI 
magnetic resonance imaging 
mRNA 
messenger RNA 
ms 
millisecond(s) 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition (scan) 
nAMD 
neovascular age-related macular degeneration 
NCI 
National Cancer Institute 
NE 
not evaluable 
NGS 
next-generation DNA sequencing 
NIH3T3-AXL 
AXL cDNA-transfected NIH3T3 
nM 
nanomolar 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
OTC 
over-the-counter 
PD 
progressive disease  
P-gp 
P-glycoprotein 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PMID 
PubMed Unique Identifier 
PR 
partial response 
PR interval 
time from the beginning of the P wave (onset of atrial 
depolarization) to the beginning of the QRS complex (onset of 
ventricular depolarization) in the ECG 
PS 
Performance Status 
PT 
Preferred Term 
PT-INR 
prothrombin time-International Normalized Ratio 
aPTT 
activated partial thromboplastin time 
QA interval 
time between the onset of the Q wave in the ECG and the 
beginning of the rise in the following arterial blood pressure pulse 
QD 
once daily 
QRS interval 
duration of the QRS complex of the ECG 
QT interval 
time from the beginning of the Q wave to the end of the T wave in 
the ECG 
QTc  
corrected QT interval 


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ABBREVIATION 
DEFINITION 
QTcF 
corrected QT interval using Fridericia’s correction 
radio-HPLC 
radio-high-performance liquid chromatography 
RDE 
recommended dose for expansion 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RET 
rearranged during transfection 
ROS1 
ROS proto-oncogene 1 
RR interval 
time from the peak of one QRS complex to the peak of the next in 
the ECG 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAVER 
Serious Adverse Event Report 
SD 
stable disease 
SD 
standard deviation 
SID 
subject identification (number) 
SOC 
System Organ Class 
STD10 
severely toxic dose in 10% of animals 
SUSAR 
suspected unexpected serious adverse reaction 
T1 
Tumor stage “1” 
t1/2 
terminal elimination half-life 
T3 
triiodothyronine 
T4 
thyroxine 
T790M 
threonine 790 to methionine (mutation in EGFR) 
Ta 
Tumor stage “a” 
TAM 
TYRO-3, AXL, and MER 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TGIn 
tumor growth inhibition by net 
Tis 
Tumor stage “is” 
TK 
toxicokinetics 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to reach Cmax 
TSH 
thyroid stimulating hormone 
TTR 
time to response 
UGT 
UDP-glucuronosyltransferase 
ULN 
upper limit of normal 


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ABBREVIATION 
DEFINITION 
US 
United States 
WHODRUG 
World Health Organization Drug Dictionary 






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Figure 1.2: 
Effects of Erlotinib and DS-1205b on Estimated Tumor Volume in 
HCC827-Bearing Nude Mice 
 
Data points indicate mean ± SD (N = 8). 
No significant difference from the erlotinib 25 mg/kg, QD group was found in the erlotinib 25 mg/kg, QD + 
DS-1205b 25 mg/kg, BID and erlotinib 25 mg/kg, QD + DS 1205b 12.5 mg/kg, BID groups (Dunnett’s 
test). 
A significantly low value from the erlotinib 25 mg/kg, QD group was found in the erlotinib 25 mg/kg, QD 
+ DS-1205b 50 mg/kg, BID group on Days 59 to 80, 98 and 100 (P = 0.0257 to 0.0469; Dunnett’s test). 
A significantly low value from the vehicle control, BID group was found in the erlotinib 25 mg/kg, QD 
group on Days 3 to 24 (P = 0.0021 on Day 3, P = 0.0000 on Days 7 to 24; Student’s t test). 
No significant difference from the vehicle control, BID group was found in the DS-1205b groups 
(Dunnett’s test). 
A significantly low value from the vehicle control, BID group was found in the erlotinib 25 mg/kg, QD + 
DS-1205b 50 mg/kg, BID group on Days 3 to 24 (P = 0.0003 on Day 3, P = 0.0000 on Days 7 to 24; 
Dunnett’s test). 
A significantly low value from the vehicle control, BID group was found in the erlotinib 25 mg/kg, QD + 
DS-1205b 25 mg/kg, BID group on Days 3 to 24 (P = 0.0005 on Day 3, P = 0.0000 on Days 7 to 24; 
Dunnett’s test). 
A significantly low value from the vehicle control, BID group was found in the erlotinib 25 mg/kg, QD + 
DS-1205b 12.5 mg/kg, BID group on Days 3 to 24 (P = 0.0003 on Day 3, P = 0.0000 on Days 7 to 24; 
Dunnett’s test). 
DS-1205b effect on the acquired resistance of erlotinib in an in vivo study in nude mice 
subcutaneously inoculated with the human EGFR-mutant NSCLC cell line HCC827 was 
also examined.  Erlotinib resistant tumors were generated in female CanN.Cg-
Foxn1nu/CrlCrlj [Foxn1nu/Foxn1nu] mice by subcutaneous inguinal inoculation of 
HCC827 human NSCLC cells, followed by repeated erlotinib daily administration 
(25 mg/kg) for approximately 9 weeks on a 5 days on/2 days off schedule.  After 
generation of mice bearing erlotinib-resistant tumors, DS-1205b was given twice daily at 
doses of 25 or 50 mg/kg for approximately 7 weeks, on the days of erlotinib 
administration.  The measurements were further continued until the mean ETV of 


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vehicle-treated group reached a size not exceeding 1000 mm3.  The effects of DS-1205b 
on tumor growth are demonstrated in Figure 1.3.  The additional treatment of DS-1205b 
recovered the antitumor effect of erlotinib, when DS-1205b was given with twice daily 
administration for approximately 7 weeks with erlotinib.  At doses of DS-1205b 50 
mg/kg and 25 mg/kg, the tumor growth inhibition by net (TGIn) was 97% and 47% 
respectively at the end of administration, and a significant antitumor effect was seen at 
50 mg/kg (P  0.0100).  DS-1205b recovered antitumor activity of erlotinib in a dose-
dependent manner, which was confirmed by hypothesis testing of Spearman’s rank 
correlation coefficient (P  0.0002).  There were no mice with severe body weight loss, 
and no death or abnormal signs were observed in this study. 
Figure 1.3: 
Effects of Erlotinib and DS-1205b Using Acquired Erlotinib-
Resistance Subcutaneous Tumor Model of HCC827 
 
The HCC827 cells were inoculated subcutaneously into the inguinal region of female nude mice at 4 × 106 
cells/mouse.  From 53 days to 160 days after inoculation, erlotinib at the doses of 25 mg/kg was orally 
administered once daily (black solid line).  Additionally, DS-1205b or vehicle was orally administrated 
twice daily from Day 116 to Day 160.  The mean ETV of each group with the SE (N = 6) was plotted onto 
the graph. 
** : P < 0.01, * : P < 0.05, vs. Erlotinib + vehicle-treated control by parametric Dunnett’s test. 
1.1.2.2. 
Safety Pharmacology 
Safety pharmacology was assessed in a core battery of regulatory studies (International 
Council for Harmonisation [ICH] S7A and ICH S7B).  In the in vitro human ether-à-go-
go related gene (hERG) assay, DS-1205c inhibited hERG tail current, showing an 


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estimated IC50 value of 0.13 μM (equivalent to 0.09565 μg/mL of DS-1205a).  However, 
in a study using telemetered male cynomolgus monkeys, there were no DS-1205c-related 
changes noted in systolic blood pressure, diastolic blood, mean blood pressure, heart rate 
[HR], electrocardiogram (ECG) parameters (PR, QRS, QT, corrected QT [QTc] 
intervals), and QA interval at doses of up to 1000 mg/kg.  Furthermore, there were no 
effects in the ECG assessments at the same dose levels in the 4-week toxicity study in 
cynomolgus monkeys.  Based on protein binding (approximately 99.4%), the IC50 value 
in the hERG assay was 4.2-fold higher than the unbound DS-1205a maximum plasma 
concentration (Cmax) value on Day 1 (approximately 0.02292 μg/mL) in the monkey 4-
week repeated oral dose toxicity study at a dose of 1000 mg/kg, which was a lethal dose 
in males.  Consequently, the possibility of unbound Cmax reaching hERG IC50 levels is 
considered to be low in clinical studies, however, careful ECG monitoring will be 
conducted during clinical trials.  
1.1.2.3. 
Pharmacokinetics and Drug Metabolism 
PK profiles were evaluated in the mouse and monkey during 4-week toxicity studies with 
DS-1205c.  In mice, and where calculable, the terminal elimination half-life (t1/2) ranged 
between 2.28 and 4.97 hours.  At the severely toxic dose in 10% of animals (STD10) of 
1000 mg/kg/day in mice, Cmax and area under the plasma concentration-time curve from 
time 0 to 24 hours (AUC0 24h) mean values were 17.8 μg/mL and 219 μg•h/mL, 
respectively, in males, and 20.8 μg/mL and 240 μg•h/mL, respectively, in females, on 
Day 28.  In monkeys, time to reach Cmax (Tmax) ranged between 4.0 and 6.0 hours after 
dosing in females, and between 2.0 and 6.0 hours after dosing in males.  At the highest 
non-severely toxic dose (HNSTD) of 1000 mg/kg/day in females, Cmax and AUC0 24h 
mean values were 4.42 μg/mL and 63.3 μg•h/mL, respectively, on Day 28.  At the 
HNSTD of 200 mg/kg/day in males, Cmax and AUC0 24h mean values were 2.85 μg/mL 
and 41.1 μg•h/mL, respectively, on Day 28.  Within each species, there were no notable 
differences in exposure between males and females. 
When DS-1205c was administered orally at doses of 100, 400, and 800 mg to male 
beagle dogs under fasted and fed conditions, the mean area under the plasma 
concentration-time curve (AUC) of DS-1205a was higher in fed dogs than in fasted dogs, 
suggesting a positive food effect on the absorption of DS-1205c.  After oral 
administration of [14C]DS-1205b to rats, the radioactivity was distributed to the whole 
body and eliminated rapidly from the tissues and had affinity to melanin.  DS-1205a is 
highly protein bound (> 98.5%) in plasma from mouse, monkey, and human, and showed 
no concentration-dependency in all 3 species.  The metabolism of DS-1205a was 
investigated in mouse, monkey, and human cryopreserved hepatocytes.  A total of 10 
metabolites were produced, all oxidative metabolites except for an N-glucuronide.  The 
major metabolites were: in mouse, a mono-oxygenated form; in monkey, a mono-
oxygenated form and a di-oxygenated form; in human, an N-glucuronide.  On the radio-
high-performance liquid chromatography (radio-HPLC) chromatogram for human 
samples N-glucuronide was the only quantifiable metabolite and no human specific 
metabolite was detected.  The primary uridine 5’-diphosphate-glucuronosyltransferase 
(UDP-glucuronosyltransferase [UGT]) isoform responsible for glucuronidation of 
DS-1205a was identified as UGT1A4, followed by UGT1A1.  When incubated with 


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microsomes containing a recombinant human cytochrome P450 (CYP) isoform, 
[14C]DS-1205a was metabolized by CYP3A4 and CYP3A5. 
1.1.2.4. 
 Toxicology 
In dose range finding studies of the 4-week repeated oral dose toxicity study in 5 male 
mice with DS-1205a (0 [vehicle], 200, and 1000 mg/kg/day) and a single increasing oral 
dose (100 and 300 mg/kg) followed by 7-day repeated oral dose (1000 mg/kg/day) 
toxicity study in 2 cynomolgus monkeys (1 male and 1 female) with DS-1205b, no severe 
toxicity was observed at up to 1000 mg/kg/day.  
Four-week oral toxicity (with toxicokinetics [TK] analysis) studies with daily dosing of 
DS-1205c were conducted in mice and cynomolgus monkeys under compliance with the 
Good Laboratory Practice (GLP). 
In mice (at doses of 100, 300, and 1000 mg/kg/day), the dose level of 1000 mg/kg/day 
caused mortality in 2 males but was well tolerated in all other animals.  In clinical 
pathology, increases in alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase (ALP) and glutamate dehydrogenase (GLDH) activity were 
observed in males at ≥ 300 mg/kg/day and in females at 1000 mg/kg/day, with females 
more affected in terms of severity, and increases in creatine kinase (CK) and lactate 
dehydrogenase (LDH) activity were also observed in females at ≥ 300 and 1000 
mg/kg/day, respectively.  There were histopathological findings in the pancreas at ≥ 100 
mg/kg/day, spleen and liver at 1000 mg/kg/day in both sexes, and an increased liver 
weight in males at 1000 mg/kg/day.  All of the DS-1205c-related findings reversed after a 
4-week treatment-free period, and the STD10  was thus 1000 mg/kg/day in males and 
females.  The STD10 of 1000 mg/kg/day corresponded to Cmax and AUC0 24h mean 
values of 17.8 µg/mL and 219 µgh/mL, respectively, in males, and Cmax and AUC0 24h 
mean values of 20.8 µg/mL and 240 µgh/mL, respectively, in females, on Day 28. 
In cynomolgus monkeys (at doses of 40, 200, and 1000 mg/kg/day), all 5 males given 
1000 mg/kg/day were either found dead (1 animal) or prematurely sacrificed (including 
2 moribund animals).  The dead and moribund-sacrificed animals showed severe clinical 
signs including decreased activity, prostration and cold to touch, and severe degenerative 
changes in the kidneys; in animals sacrificed in extremis, there were also increases in 
blood urea nitrogen (BUN) and creatinine.  In these animals, DS-1205c-related 
histopathological findings were observed in the heart, stomach, duodenum, pancreas, 
lymphoid organs, and liver.  In other clinical pathology parameters, prematurely-
sacrificed animals showed increases in white blood cell, neutrophil, lymphocyte, 
monocyte, eosinophil, basophil, and large unstained cell, and increases in ALT, AST, 
GLDH, LDH, CK, and triglycerides.  In sacrificed animals on schedule including female 
given 1000 mg/kg/day, there were instances of pale or white feces and occasional vomit.  
There were minimal increases in ALT activity at ≥ 200 mg/kg/day, and decreases in 
spleen and thymus weight in males at 200 mg/kg/day.  In females, there was a dose 
related increase in liver weight, and a decrease in thyroid weight at 1000 mg/kg/day.  At 
the end of the treatment-free period, the observed clinical signs and the minimal increases 
in ALT activity completely recovered; a decrease in thymus weight in males at 
200 mg/kg/day was still present but showed tendency toward recovery.  On this basis, the 


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HNSTD was considered to be 200 mg/kg/day in males and 1000 mg/kg/day in females.  
The HNSTD of 200 mg/kg/day in males corresponded to Cmax and AUC0 24h mean 
values of 2.85 µg/mL and 41.1 µgh/mL, respectively, on Day 28, and the HNSTD of 
1000 mg/kg/day in females corresponded to Cmax and AUC0 24h mean values of 
4.42 µg/mL and 63.3 µgh/mL, respectively, on Day 28. 
In an in vitro bacterial reverse mutation study, DS-1205c showed no mutagenic activity.  
In both an in vitro micronucleus study in Chinese hamster lung (CHL) cells and an in 
vivo bone marrow micronucleus studies in rats, DS-1205c showed no induction of 
chromosome aberrations.  Therefore, DS-1205c was considered to have no genotoxic 
potential. 
Additional data describing the use of DS-1205c in nonclinical studies are available in the 
current Investigator’s Brochure (IB).1 
1.1.3. 
Clinical Experience 
There are no clinical data available for DS-1205c to date; periodic updates of clinical 
experience will be included in the Investigator’s Brochure (IB).1 
1.2. 
Background 
Lung cancer is the leading cause of cancer-related death worldwide.2  In addition, lung 
cancer is the second most commonly diagnosed cancer, with estimated 2.2 million new 
cases and 1.6 million deaths per year.3  
1.2.1. 
Metastatic or Unresectable EGFR-Mutant NSCLC 
EGFR-mutant NSCLC represents an important subtype of lung cancer where significant 
advances have been made in first-line treatment but where limited options are available in 
subsequent-line treatment. 
It has been well established through multiple large Phase 3 studies that EGFR tyrosine 
kinase inhibitors (TKIs) represent the first-line treatment of choice in NSCLC with 
EGFR-activating mutations.4, 5, 6, 7, 8, 9, 10 Gefitinib, erlotinib, and afatinib (and more 
recently, osimertinib)11  have demonstrated significant improvements in objective 
response rate (ORR) and progression-free survival (PFS) compared to chemotherapy. 
Despite the often dramatic responses to these agents, however, patients ultimately 
develop resistance to these treatments, usually within a year.  Biopsies performed upon 
disease progression (which have evolved to be considered part of the standard of clinical 
care in the treatment of these patients) have revealed several molecular mechanisms of 
resistance.12 Over half of these patients develop a secondary mutation in EGFR exon 20, 
T790M, in the adenosine triphosphate (ATP)-binding site.13 Patients lacking this 
resistance mutation have exhibited other mutations, amplifications in the EGFR gene, 
activation or up-regulation of other “bypass track” signaling pathways, and phenotypic 
alterations including small cell lung cancer transformation and NSCLC epithelial-to-
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Until recently, the standard of care treatment in the second-line setting has been 
chemotherapy.  The retrospective Phase 3 NEJ002 study, which compared gefitinib with 
carboplatin plus paclitaxel, demonstrated15 that second-line, platinum-based 
chemotherapy followed at progression by gefitinib was similar to first-line, platinum-
based chemotherapy in terms of relative risk (RR) (partial response [PR] with 
chemotherapy second-line vs. first-line treatment: 25.4% vs. 30.7%; odds ratio 1.45; 95% 
CI [0.75, 2.81]; P  0.345) and overall survival (OS) (28.9 vs. 27.6 months; hazard ratio, 
0.77; 95% CI [0.52, 1.14]; P  0.188), with no difference seen for the efficacy of second-
line, platinum-based chemotherapy in the EGFR mutation subtype.  Progression-free 
survival (PFS) was not evaluable in this study. 
Patients with tumors that have acquired the T790M resistance mutation may now be 
treated with osimertinib, a third-generation EGFR TKI that specifically targets the 
T790M mutant-form of EGFR.  In a pivotal Phase 1 study of EGFR-mutant NSCLC 
patients in the second-line setting, 127 T790M-positive subjects who could be evaluated 
for response demonstrated an ORR of 61% and median PFS of 9.6 months.16  
For patients without documented T790M mutation, combination chemotherapy (as used 
in first-line NSCLC treatment) remains the standard treatment, particularly for patients 
who are symptomatic from progressive disease (PD); but again, these responses are 
generally not durable.17 A number of other approaches have been explored with 
achievement of only incremental effectiveness,18 as discussed below. 
Changing to a second-generation TKI does not appear to confer significant benefit.  Two 
Phase 2 trials have tested the efficacy of afatinib in patients with advanced NSCLC who 
progressed after one or two lines of chemotherapy and with at least 12 weeks of erlotinib 
and/or gefitinib.  In the LUX-Lung 1 trial, where 585 patients were randomized to 
afatinib or placebo, a 2-month PFS improvement was seen with afatinib (3.3 vs. 1.1 
months; P < 0.0001), without OS benefit (10.8 vs. 12.0 months; P  0.74).19 The LUX-
Lung 4 single-arm trial showed a median PFS of 4.4 months with afatinib in this 
pretreated population.20 Neither of these trials supports switching to second-generation 
EGFR TKIs; instead, they support continuing inhibition of EGFR pathway beyond EGFR 
TKI progression.  The combination of cetuximab and afatinib could be considered in fit 
patients (because of a relatively higher adverse event [AE] profile) following primary 
TKI and after subsequent chemotherapy, given a response rate of 35% (13 of 37) in 
T790M-negative patients.21  
Tumor flare represents a significant phenomenon in EGFR-mutant NSCLC treated with 
TKI, whereby as many as 23% of patients may develop rapid growth of one or more 
tumor sites following withdrawal of TKI, and this may be associated with significant 
morbidity or even death.  In a meta-analysis22 the median time of tumor flare onset after 
TKI withdrawal was 8 days, with a range of 3 to 21 days.  These and other observations 
have led to the recommendation that patients receiving treatment with TKI in the first-
line setting and demonstrating progression by Response Evaluation Criteria in Solid 
Tumors (RECIST) may continue on their TKI and receive localized treatment (eg, 
radiotherapy or surgical therapy) as needed for site(s) of PD.22  


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Continuation of primary TKI does not appear to be indicated, however, in patients with 
EGFR-mutant NSCLC who experience progression on primary TKI and are given 
chemotherapy in the second-line setting.  Recently updated OS results from the Phase 3 
IMPRESS study23 demonstrate that in 265 EGFR-mutant NSCLC patients who had 
developed acquired resistance to first-line gefitinib, median OS in the gefitinib plus 
chemotherapy (cisplatin/pemetrexed) arm was 13.4 months vs. 19.5 months with placebo 
plus chemotherapy (hazard ratio 1.44; P  0.016).  A subgroup analysis stratifying by 
T790M status showed that of 247 patients for whom T790M status was available, the 
median PFS for the T790M mutation-positive subgroup was 4.6 vs. 5.3 months for the 
gefitinib and placebo groups, respectively (hazard ratio, 0.97; 95% CI [0.67, 1.42]; P  
0.8829).  Median PFS for the T790M mutation-negative subgroup was 6.7 vs. 5.4 months 
for the gefitinib and placebo arms, respectively (hazard ratio, 0.67; 95% CI [0.43, 1.03]; 
P  0.0745).  These results suggest24 that following acquired resistance to first-line 
gefitinib, for T790M-positive patients, gefitinib should not be continued when platinum-
based doublet chemotherapy is available as second-line therapy.  However, for plasma 
T790M-negative patients, the continuation of gefitinib in combination with platinum-
based doublet chemotherapy may potentially offer some clinical benefit, but this requires 
further confirmation in a prospective randomized placebo-controlled study. 
Immune checkpoint inhibitor therapies have been approved for treatment of advanced 
NSCLC in both the first- and second-line settings.  Although patients with EGFR-mutant 
NSCLC are eligible to receive these therapies, data from several studies have not been 
powered to demonstrate a statistically significant benefit for any of these therapies 
compared to chemotherapy in EGFR-mutant patient subgroups.  The meta-analysis of 
these therapies25 from three large randomized trials comparing an immune checkpoint 
inhibitor to docetaxel in NSCLC patients has been conducted.  In total, 1903 patients 
were randomized to receive an immune checkpoint inhibitor (nivolumab [n  292], 
pembrolizumab [n  691], or atezolizumab [n  144]) or docetaxel (n  776), and the 
EGFR mutation status was known for 1548 of these patients (81%).  Treatment with an 
immune checkpoint inhibitor, compared with docetaxel, was associated with a 32% 
reduction in the risk for death in the intention-to-treat population (hazard ratio  0.68, 
95% CI [0.61, 0.77], P < 0.0001; heterogeneity P  0.67).  In the EGFR wild-type 
subgroup (n  1362), the pooled hazard ratio was 0.66 (95% CI [0.58, 0.76], P < 0.0001; 
heterogeneity P  0.96).  In the EGFR-mutant subgroup (n  186), the pooled hazard 
ratio was 1.05 (95% CI [0.70, 1.55], P < 0.81; heterogeneity P  0.80).  There was a 
statistically significant treatment-mutation interaction (P  0.03).  Among the EGFR-
mutant subgroup, there was no significant statistical heterogeneity in treatment effect: 2 
 0.46 (P  0.42) and I2  0%.  However, given the small sample sizes of EGFR-mutant 
subjects in these studies, the hypothesis that immune checkpoint inhibitor is not superior 
to chemotherapy in EGFR-mutant NSCLC is as yet unproven and is a subject of ongoing 
evaluation in the field.  
Patients who experience transformation of tumor histology to small cell lung cancer are 
recommended to receive standard treatments for small cell lung cancer.17 This 
transformation appears to occur with significant frequency (5 to 14%) in small series of 
EGFR-mutant NSCLC patients treated with TKI (reviewed in 26).  It remains unclear 


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whether this incidence of transformation is related primarily to the high frequency of 
serial biopsies in EGFR-mutant NSCLC or whether this is a consequence of genomic 
alterations in EGFR-mutant NSCLC, of TKI treatment, or both.  
1.3. 
Study Rationale and Dose Selection 
1.3.1. 
Study Rationale  
In over half of patients with EGFR-mutant NSCLC acquire resistance to first or second 
generation TKIs (eg, gefitinib, erlotinib, or afatinib), is associated with the development 
of the secondary mutation in EGFR exon 20, T790M.13 Among the remaining cases, a 
number of other proposed mechanisms, including the up-regulation of “bypass track” 
signaling pathways, may be responsible for treatment resistance.  AXL expression was 
observed to be up-regulated in approximately 20% of EGFR-mutant NSCLC patients 
experiencing disease progression on erlotinib.27,28  
Increased expression of AXL has been observed in EGFR-mutant NSCLC tumor biopsies 
obtained from patients with acquired resistance to TKIs.28  As a member of the 
mammalian TYRO-3, AXL, and MER (TAM) receptor kinase family (named for its 
members TYRO3, AXL, and MER), AXL is a cell-surface transmembrane receptor 
containing regulated kinase activity within its cytoplasmic domain, and plays an 
important role in signal transduction in normal and malignant cells.29,30  Overexpression 
or ectopic expression of TAM receptors is known to occur in a wide array of human 
cancers.31  GAS6 is the major ligand for these TAM receptor tyrosine kinases and, in 
particular, is the sole ligand for AXL.29  Its binding to the receptors promotes 
proliferation, survival, and migration of cancer cells in vitro.30,32  Abnormal expression 
and activation of AXL can provide a survival advantage for certain cancer cells, and 
inhibition of AXL may enhance sensitivity of cancer cells to cytotoxic agents.30  
DS-1205c is a novel, specific, small-molecule inhibitor of the receptor tyrosine kinase 
AXL, and is being developed by Daiichi Sankyo as an oral antitumor agent.  Addition of 
DS-1205c restores TKI sensitivity in HCC827 (EGFR exon19deletion, T790M-negative) 
tumor xenograft models.  Additionally, inhibition of acquired resistance to gefitinib 
following the addition of DS-1205c has been demonstrated in non-clinical studies.1 
In summary, DS-1205c is hypothesized to show potential activity in combination with 
gefitinib in T790M mutation-negative EGFR-mutant NSCLC with a manageable safety 
profile. 
1.3.2. 
Study Dose Setting 
1.3.2.1. 
DS-1205c Starting Dose 
The doses of DS-1205c selected for this study are based on nonclinical data and are 
expressed in doses of DS-1205a (free base).  DS-1205c 200 mg capsules contain 
equivalent to 200 mg of DS-1205a (free form).  Nonclinical data showed that a dose of 
1000 mg/kg/day of DS-1205c was the STD10 in the mouse.  The human equivalent dose 
(HED) for 1000 mg/kg, based on allometric scaling by surface area, is approximately 
81.3 mg/kg, and using one-tenth of this value gives a dose of 8.1 mg/kg as the 


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recommended starting dose for the proposed clinical study.  The value of 8.1 mg/kg is 
lower than an alternative starting dose (10.8 mg/kg) calculated using one-sixth of the 
HED for the HNSTD (200 mg/kg/day in males) in the cynomolgus monkey, and thus is 
considered to be the appropriate upper bound for a starting dose for clinical study in 
humans.1  For a 60 kg human, the 8.1 mg/kg dose becomes 488 mg.  Therefore, this study 
will use a starting dose of 400 mg per day of DS-1205c administered orally in 2 divided 
doses (200 mg twice daily [BID]). 
1.3.2.2. 
Gefitinib Dosage 
In this study, DS-1205c will be administered in combination with gefitinib (Iressa®).  
Open-label commercial supplies of gefitinib (Iressa®) will be used and reimbursed by the 
Sponsor.  Gefitinib has been approved (Japan [Standard Commodity Classification 
Number: 874291], July 2002) for the treatment of patients with unresectable or recurrent 
NSCLC harboring EGFR mutations at a recommended dose of one 250 mg tablet 
administered orally once daily (QD). 
1.4. 
Risks and Benefits for Study Subjects 
1.4.1. 
Potential Risks Associated With DS-1205c 
No safety information in humans is available. 
In nonclinical toxicicty studies conducted in mice, elevations in clinical laboratories 
including ALT, AST, ALP GLDH, creatinine kinase (CK), and LDH.  In cynomolgus 
monkeys, DS-1205c-related histopathological findings were observed in the heart, 
stomach, duodenum, pancreas, lymphoid organs, and liver.  In other clinical pathology 
parameters, prematurely-sacrificed animals showed increases in white blood cell, 
neutrophil, lymphocyte, monocyte, eosinophil, basophil, and large unstained cell, and 
increases in ALT, AST, GLDH, LDH, CK, and triglycerides. 
1.4.2. 
Potential Risks Associated With Gefitinib 
Refer to the gefitinib package insert for detailed description of potential risks associated 
with gefitinib.  As for potential risks overlapping with DS-1205c, hepatotoxicity has been 
reported with gefitinib.  In subjects who received gefitinib in clinical trials with 
gefitinib,33 11.4% of subjects had increased ALT, 7.9% of subjects had increased AST, 
and 2.7% of subjects had increased bilirubin.  Grade 3 or higher liver test abnormalities 
occurred in 5.1% (ALT), 3.0% (AST), and 0.7% (bilirubin) of those subjects.  The 
incidence of fatal hepatotoxicity was 0.04%. 
1.4.3. 
Pharmacokinetic Drug Interaction 
In vitro metabolism studies using human hepatocytes indicated that major route of 
metabolism was N-glucuronidation.  The primary UGT isoform responsible for 
glucuronidation of DS-1205a was suggested to be UGT1A4, and the second UGT1A1.  In 
a study using microsomes containing recombinant human CYP isoforms, CYP3A4 was 
the main isoform and CYP3A5 was the minor isoform for the oxidation of DS-1205a. 


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DS-1205a did not show reversible inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, or CYP3A4, and DS-1205a did not show time-dependent inhibition 
of any CYP isoforms tested.  In another in vitro study, DS-1205a had no induction effect 
on mRNA expression levels or specific enzyme activities of CYP3A4, CYP1A2, or 
CYP2B6.   
In a study using Caco-2 cells, DS-1205a inhibited P-glycoprotein (P-gp)-mediated 
digoxin transport in vitro, with an IC50 of 1.20 μM.  The clinical relevance of this 
inhibitory effect will depend on the intestinal and systemic concentration that DS-1205a 
will reach at the therapeutic dose, and on the concomitant drugs in target population. 
1.4.3.1. 
Evaluation of the Potential for PK Interaction Effect on Gefitinib by 
DS-1205c 
Gefitinib is extensively metabolized mainly via CYP3A4 and partially via CYP2D6.34  
However, since in vitro assessment shows that DS-1205c is neither an inhibitor nor an 
inducer of major CYP isoforms, the PK of gefitinib is unlikely to be significantly affected 
by co-administration of DS-1205c in humans.  Although DS-1205c is an in vitro inhibitor 
of P-gp and gefitinib is an in vitro P-gp substrate, it is not expected that such inhibition 
will meaningfully impact the PK of gefitinib, given its high absorption and extensive 
metabolism.  Based on mass balance study results of gefitinib, 80.8% of radioactivity was 
recovered in feces and 3.6% of radioactivity was recovered in urine.  Only 4% of the dose 
recovered in feces was unchanged gefitinib following oral administration of [14C]-
gefitinib.34    
1.4.3.2. 
Evaluation of the Potential for PK Interaction Effect on DS-1205c by 
Gefitinib  
In vitro assessment using human hepatocytes showed that the major metabolic route of 
DS-1205a was N-glucuronidation, and oxidation metabolism was a minor route.  The 
primary UGT isoform responsible for glucuronidation of DS-1205a was suggested to be 
UGT1A4, followed by UGT1A1, by in vitro studies.  It is reported that  gefitinib is 
unlikely to cause clinically significant DDI through inhibition of glucuronidation 
although gefitinib showed inhibition against UGT1A1, UGT1A7, UGT1A9, and 
UGT2B7 in vitro,35 it is unlikely for gefitinib to cause clinically relevant increases in the 
exposure of DS-1205a given that N-glucuronidation of DS-1205a is primarily catalyzed 
by UGT1A4.  Gefitinib is a CYP2D6 inhibitor in vivo, and it also inhibits CYP2C19 in 
vitro.34  The oxidation metabolism of DS-1205a is catalyzed by CYP3A4 and CYP3A5, 
but not by CYP2C19 or CYP2D6.  Therefore, co-administration of gefitinib is not 
expected to cause clinically significant effects on the PK of DS-1205c via UGT and 
CYP-related metabolism. 
1.4.4. 
Potential Benefit Associated with DS-1205c 
No efficacy information in humans is available. 
Nonclinical studies have demonstrated the anti-tumor activity of DS-1205 in combination 
with gefitinib in xenograft models.1  Based on the above rationale, and the nonclinical 


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data, DS-1205c in combination with gefitinib is hypothesized to show activity in 
EGFR-mutant NSCLC. 








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3.2.1. 
Dose Escalation 
3.2.1.1. 
Cycle 0 (Monotherapy, 7 Days) 
To minimize the possibility of developing tumor flare with discontinuation of EGFR TKI, 
subjects who fulfill eligibility criteria will be instructed to continue their current EGFR 
TKI (gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib) during screening.  The last 
dose of gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib must be taken 1 day 
before breakfast in clinic on Cycle 0, Day 1, as depicted in Figure 3.1 above.  This 
schedule provides an 8-day window between the last dose of gefitinib, erlotinib, afatinib, 
dacomitinib, or osimertinib, and the first dose of gefitinib. 
Once eligibility is confirmed, subjects will be assigned by the Sponsor to receive 
DS-1205c at a specific dose level (Table 3.1).  This will be either the current escalation 
dose (as determined by an algorithm described in detail in Section 3.2.1.2 below) or a 
previously assigned lower dose (ie, cohort backfilling).  
Table 3.1: 
Dose Escalation Provisional Cohorts and Provisional Dosages 
 
Cycle 0 
Monotherapy 
(7-day cycle) 
Cycle 1 and Beyond 
Combination Therapy 
(21-day cycles) 
Cohorta 
DS-1205c Dosageb 
DS-1205c Dosageb 
Gefitinib Dosagec 
1 
200 mg BID 
200 mg BID 
250 mg QD 
2 
400 mg BID  
400 mg BID 
250 mg QD 
3 
600 mg BID  
600 mg BID 
250 mg QD 
4 
800 mg BID  
800 mg BID 
250 mg QD 
BID = twice daily; mg = milligrams; QD = once daily 
a. The second subject in each cohort should start dosing at least 24 hours after the initial dosing of the first 
subject. The cohort numbers in this table do not denote actual order of dose transition on the trial. 
b. Administer with a meal, with 240 mL of water.  On the morning of Endpoint ECG days, breakfast 
should be started 30 minutes prior to dosing and should be completed within approximately 20 minutes.  
For all other dosings, it is recommended that meals (breakfast or dinner) be completed within 
approximately 30 minutes; DS‑1205c should be taken immediately after meal completion.  Doses of 
DS-1205c should be taken approximately 12 hours apart. 
c. Co-administer with morning dose of DS-1205c. 
Subjects will report to the clinic on Day 1 before Cycle 0 to obtain ECGs at specified 
time points outlined in the Schedule of Events, Dose Escalation (Cycle 0) (see Table 6.1).  
These time points will be time matched to ECGs obtained on Cycle 0, Day 1. 
Beginning with Cycle 0, Day 1, subjects will receive DS-1205c BID for 7 days.  
DS-1205c should be taken with a meal.  On the morning of Endpoint ECG days, 
breakfast should be started 30 minutes prior to dosing and should be completed within 
approximately 20 minutes.  For all other dosings, it is recommended that meals (breakfast 
or dinner) be completed within approximately 30 minutes; DS‑1205c should be taken 
immediately after meal completion.  Time-matched ECGs will be obtained and blood 
samples for PK will be collected at specified time points (Table 6.1).  Additional safety, 


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PK, and ECG assessments will be performed/obtained on specific days and time points 
over the 7-day run-in period (Section 6.1.2). 
3.2.1.2. 
Cycle 1 and Beyond (Combination Therapy) 
In Cycle 1 and beyond, DS-1205c will be taken BID in combination with 250 mg QD of 
gefitinib in 21-day cycles, as outlined in detail in the Schedule of Events, Dose 
Escalation, (Cycle 1 and Beyond) (Table 6.2). 
Dose escalation of DS-1205c to determine the RDE will be guided by the modified 
Continuous Reassessment Method (mCRM) using a Bayesian logistic regression model 
(BLRM) following the escalation with overdose control (EWOC) principle 
(Section 11.11).  The logistic regression model for the dose-response (DLT rate) 
relationships will include 2 parameters: the intercept and slope.  The DLT-evaluation 
period is defined as the 7 days of Cycle 0 plus the 21 days of Cycle 1 (28 days total).  A 
DLT-evaluable subject is defined as a subject who has received DS-1205c and either has 
completed minimum safety evaluation requirements over the DLT-evaluation period or 
has experienced a DLT during the DLT-evaluation period.  After at least 3 
DLT-evaluable subjects of each cohort complete DLT evaluation, posterior distributions 
of DLT rate will be derived for all dose levels based on the BLRM using DLT outcome 
data from all assessed doses and a pre-specified prior distribution for the model 
parameters.  The EWOC principle requires that the mCRM-recommended dose for the 
next cohort of subjects is the one with the highest posterior probability of the DLT rate in 
the target DLT rate interval with the overdose control constraint for excessive or 
unacceptable toxicity. 
As an exception, the model will be reevaluated before enrollment of any additional 
subjects to the cohort if 2 DLT-evaluable subjects in the cohort experience DLT before 
the enrollment of the third subject.  Enrollment of subjects to a new higher-dose cohort 
requires completion of DLT evaluation of at least 3 subjects treated in the current cohort.  
Subjects who have neither completed DLT evaluation nor experienced DLT will not be 
included in a BLRM update.  In the event when subjects in the previous cohort 
experience DLTs after enrollment of subjects to a new cohort has begun, dose level 
assignment of the next subject in the new cohort will be based on an updated BLRM 
using DLT outcome data from all assessed doses.  Subjects already receiving treatment 
will continue treatment at their assigned dose level or per dosing modification guidelines 
outlined in Section 5.4. 
Subjects can be backfilled (added) to lower doses previously proven to be safe at any 
point during Dose Escalation.  Lower or intermediate dose levels may also be considered 
based on review of available safety, tolerability, and PK data in this and other studies 
with the investigational agent.  There will be no intrasubject dose escalation. 
Any dose cohort may be expanded to include additional subjects for further evaluation of 
safety or PK parameters as required.  The dose level for next cohort will be chosen by the 
Sponsor as outlined in Section 11.11.3  based on the dose recommendation by the 
mCRM, clinical assessment of TEAEs, toxicity profiles, efficacy, PK, and PD 
information observed thus far. 


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The number of treatment cycles is not fixed.  Subjects may continue study treatment until 
PD, unacceptable toxicity, withdrawal of consent, or other reasons detailed in 
Section 5.6.1. 
3.2.1.3. 
Dose-Limiting Toxicities (DLT) 
A DLT is defined as any TEAE not attributable to disease or disease-related processes or 
to concomitant medications or procedures that occurs during the DLT-evaluation period 
(Cycle 0, Day 1 to Cycle 1, Day 21 of Dose Escalation) and is Grade 3 or above, 
according to NCI-CTCAE version 5.0, with the exceptions as defined below.  
For hematological toxicities, a DLT is defined as follows: 
 
For hepatic organ toxicities, a DLT is defined as follows: 
Hematologic Dose-Limiting Toxicities (DLT) NCI-CTCAE version 5.0 
Hematological 
toxicity 
NCI-CTCAE Grade 
CTCAE version 5.0 Definition 
Neutrophil count 
decreased 
4 
(Lasting > 7 days or 
neutrophil count decreased 
that requires supportive 
therapy with myeloid 
growth factors) 
< 500/mm3;  
< 0.5 × 109 /L 
Febrile neutropenia  
≥ 3 
Grade 3: 
ANC < 1000/mm3 with a single 
temperature of > 38.3°C or a 
sustained temperature of ≥38°C for 
more than one hour 
Grade4: 
Life-threatening consequences; urgent 
intervention indicated 
Anemia 
4 
Life-threatening consequences; urgent 
intervention indicated rade4: 
Platelet count 
decreased  
≥ 3 
Lasting > 7 days or with 
clinically significant 
hemorrhage 
Grade 3: 
< 50,000 – 25,000/mm3; < 50.0 – 25.0 
× 109 /L 
Grade 4: 
< 25,000/mm3; < 25.0 × 109 /L 
Lymphocyte count 
decreased  
4 
Lasting > 14 days 
< 200/mm3; < 0.2 × 109 /L 
Any  
5 
Death 


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For pulmonary toxicities, a DLT is defined as any of the following: 
Hepatic Dose-Limiting Toxicities (DLT) NCI-CTCAE version 5.0 
Hepatic Organ Toxicity 
NCI-CTCAE Grade 
CTCAE version 5.0 Definition 
Serum aspartate 
aminotransferase (AST) 
increase 
4 
> 20.0 × the upper limit normal 
(ULN) if baseline was normal;  
> 20.0 × baseline if baseline was 
abnormal 
Serum alanine 
aminotransferase (ALT) 
increase  
4 
> 20.0 × ULN if baseline was normal;  
> 20.0 × baseline if baseline was 
abnormal 
AST or ALT increased  
3 
Lasting >5 days 
> 5.0 – 20.0 × ULN if baseline was 
normal;  
> 5.0 – 20.0 × baseline if baseline 
was abnormal 
ALT or AST increased  
≥ 3.0 × ULN with 
simultaneous TBL 
increased ≥ 2.0 × ULN 
Not applicable 
Not applicable 
Any  
5 
Death 
Pulmonary Dose-Limiting Toxicities (DLT) NCI-CTCAE version 5.0 
Pulmonary Toxicity 
NCI-CTCAE Grade 
CTCAE version 5.0 Definition 
Confirmed interstitial 
lung disease (ILD) 
1 
Asymptomatic; clinical or diagnostic 
observations only; intervention not 
indicated 
 
2 
Symptomatic; medical intervention 
indicated; limiting instrumental 
activities of daily living (ADL) 
 
3 
Severe symptoms; limiting self care 
ADL; oxygen indicated 
 
4 
Life-threatening respiratory 
compromise; urgent intervention 
indicated (eg., tracheotomy or 
intubation) 
 
5 
Death 
Any other pulmonary 
toxicity   
> 3 
Grade 3: 
Severe or medically significant but 
not immediately life-threatening; 
hospitalization or prolongation of 


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For non-hematological, non-hepatic, or non-pulmonary organ toxicities (ie, any other 
Grade ≥3 non-hematologic, non-hepatic, non-pulmonary toxicities including Grade 5 
events), a DLT is defined as any of the following: 
 
 
existing hospitalization indicated; 
limiting self care ADL 
Grade 4: 
Life-threatening consequences; urgent 
intervention indicated 
Grade 5:Death 
Dose-Limiting Toxicities 
(Non-Hematologic, Non-Hepatic, Non-Pulmonary Toxicities) 
DLT 
NCI-CTCAE Grade 
CTCAE version 5.0 Definition 
Symptomatic heart 
failure 
2 
Symptoms with moderate activity or 
exertion 
 
3 
Symptoms at rest or with minimal 
activity or exertion; hospitalization; 
new onset of symptoms 
Left ventricular 
ejection fraction 
(LVEF)  
3 
Resting ejection fraction (EF) 39 – 
20%; >20% drop from baseline 
Endocrine toxicities 
≥ 3 
Which do not resolve in ≤ 14 
days 
Grade 3: 
Severe or medically significant but 
not immediately life-threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
limiting self care ADL 
Grade 4: 
Life-threatening consequences; 
urgent intervention indicated 
The following TEAEs are considered DLTs 
Thrombocytopenia requiring transfusion. 
Anemia  requiring transfusion 
Inability to complete at least 75% of the prescribed doses (ie, at least 42 doses of DS-1205c 
and 16 doses of gefitinib) in the 7 days of Cycle 0 and the 21 days of Cycle 1 as a result of 
Grade ≥ 2 AE not attributed to disease.   


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The following TEAEs are NOT considered DLTs: 
 
Management of study drug-related AEs will be as per treating physician discretion and 
institutional guidelines.  See Section 5.5 for information regarding the use of concomitant 
medications. 
3.2.1.3.1. TEAEs During Cycle 0 
In the event of a TEAE within Cycle 0 that may delay the start of Cycle 1, Day 1, 
Investigators should contact the Sponsor medical monitor or designee for guidance.  
Investigators should refer to Section 5.4 for information on interruptions of dose.  
The following TEAEs are NOT considered Dose Limiting Toxicities 
TEAE 
NCI-CTCAE Grade 
CTCAE version 5.0 Definition 
Fatigue 
3 
Lasting < 7 days 
Fatigue not relieved by rest, limiting 
self care ADL 
Nausea 
3 
That resolves to < grade 2 in 
48 hours 
Inadequate oral caloric or fluid 
intake; tube feeding, TPN, or 
hospitalization indicated 
Vomiting 
3 
That resolves to < grade 2 in 
48 hours 
Tube feeding, TPN, or hospitalization 
indicated 
Diarrhea 
3 
That resolves to < grade 2 in 
48 hours 
Increase of ≥ 7 stools per day over 
baseline; hospitalization indicated; 
severe increase in ostomy output 
compared to baseline; limiting self 
care ADL 
Anorexia 
3 
That resolves to < grade 2 in 
48 hours 
Associated with significant weight 
loss or malnutrition (eg., inadequate 
oral caloric and/or fluid intake); tube 
feeding or TPN indicated 
Isolated laboratory findings not associated with signs or symptoms, including  
● Grade 3 or 4 serum ALP increased, hyperuricemia, serum amylase increased, lipase 
increased, or grade 3 hyponatremia, lasting < 72 hours 
Lymphocyte count 
3 
< 500 – 200/mm3;  
< 0.5 – 0.2 × 109 /L 
 
Subjects missing more than 25% of scheduled doses in Cycle 0 and Cycle 1 for reasons not 
related to AEs (eg, noncompliance) will not be evaluable for DLT. 




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3.2.2.1. 
Stopping Rule for Other Consideration(s) 
The Sponsor has the right to terminate the study at any time, and study termination may 
also be requested by (a) competent authority(-ies). 
3.3. 
Duration of Subject Participation 
The Eligibility Screening period is up to 22 days for Dose Escalation Part and 30 days for 
Dose Expansion Part.  Each cycle of treatment (except for Cycle 0 in Dose Escalation) is 
21 days.  
The number of treatment cycles is not fixed in this study.  Subjects may continue study 
treatment until PD, unacceptable toxicity, withdrawal of consent, or other reasons 
detailed in Section 5.6.1.  
3.4. 
Duration of Study 
This study is expected to last approximately 3 years from the time the first subject is 
enrolled to the time the last subject is off the study.  The end of the study is defined as the 
last subject visit or contact, including telephone contacts, for collection of any study-
related data. 
Dose Escalation 
 Enrollment is planned to occur over approximately 12 months. 
 Treatment and follow-up will be completed when all subjects have either 
discontinued study treatment or completed last study visit. 
CCI


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4. 
STUDY POPULATION 
Subjects must satisfy all of the following inclusion and exclusion criteria to participate in 
either Dose Escalation or Dose Expansion: 
4.1. 
Inclusion Criteria 
1. Male or female subjects aged 20 years and older. 
2. Has histologically or cytologically documented adenocarcinoma NSCLC. 
3. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or 
radiation. 
4. Has acquired resistance to EGFR TKI according to the Jackman criteria.36  
a. Historical confirmation that the tumor harbors an EGFR mutation known to be 
associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, 
L858R, L861Q),  OR 
b. Has experienced clinical benefit from an EGFR TKI, followed by systemic 
progression of disease (RECIST version 1.1 or World Health Organization 
[WHO]) while on continuous treatment with an EGFR TKI.  
5. Is currently receiving and able to interrupt gefitinib or discontinue erlotinib, 
afatinib, dacomitinib, or osimertinib. 
6. Has been receiving gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib for at 
least 6 weeks with well-controlled related toxicities less than Grade 3 in severity 
at the time of screening period.  Subjects who have been receiving gefitinib must 
be taking gefitinib at a dose of 250 mg/day. 
7. Has radiological documentation of disease progression while receiving continuous 
treatment with gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib. 
8. Has at least one measurable lesion per RECIST version 1.1. 
9. Is willing to provide archival tumor tissue from a biopsy performed after 
progression during treatment with gefitinib, erlotinib, afatinib, dacomitinib, or 
osimertinib OR has at least one lesion, not previously irradiated, amenable to core 
biopsy and is willing to undergo screening tumor biopsy. 
10. Demonstrates absence of EGFR T790M mutation in tumor tissue since 
progression during gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib 
treatment. 
11. Has ECOG PS of 0 or 1, with no deterioration over the previous 2 weeks.  A table 
of the ECOG PS scale can be found in Appendix Section 17.4. 
12. Has adequate bone marrow reserve and organ function, defined as: 
a. Platelet count ≥ 100 × 109/L 
b. Hemoglobin (Hb) ≥ 9.0 g/dL  
c. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 


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d. Prothrombin time and activated partial thromboplastin time (aPTT) ≤ 1.5 × the 
upper limit normal (ULN), except for patients on coumarin-derivative 
anticoagulants or other similar anticoagulant therapy, who must have 
prothrombin time-International Normalized Ratio (PT-INR) within therapeutic 
range as deemed appropriate by the Investigator. 
e. Serum creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 50 mL/min as 
calculated using the Cockcroft-Gault equation (Section 17.1); confirmation of 
creatinine clearance is only required when creatinine is > 1.5 × ULN. 
f. AST/ALT ≤ 3.0 × ULN (if liver metastases are present, ≤ 5.0 × ULN). 
g. Total bilirubin ≤ 1.5 × ULN if no liver metastases or < 3.0 × ULN in the 
presence of documented Gilbert’s Syndrome (unconjugated 
hyperbilirubinemia) or liver metastases. 
h. CK  1.5 × ULN. 
i. Lipase  2 × ULN. 
13. Has adequate treatment washout period before first dose of study drug, defined as: 
a. QTc prolonging medications ≥ 10 days (Section 17.6)  
b. CYP3A4 strong inducers ≥ 10 days (Section 17.6)   
c. Proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, and pantoprazole) ≥ 5 days 
14. Female subjects of reproductive/childbearing potential with a male sexual partner 
must agree to use a highly effective form of contraception or avoid intercourse 
during and upon completion of the study and for at least 3 months after the last 
dose of study drug.  For the purpose of this protocol, methods considered as 
highly effective birth control include: 
a. Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal 
delivery). * 
b. Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable delivery). * 
c. Intrauterine device (IUD). 
d. Intrauterine hormone-releasing system (IUS). 
e. Bilateral tubal occlusion. 
f. Vasectomized partner. 
g. Complete sexual abstinence. 
Non-child-bearing potential is defined as pre-menopausal with documented tubal 
ligation or hysterectomy; OR postmenopausal with documented  ≥ 12 months of 
spontaneous amenorrhea (in questionable cases, a blood sample with 
simultaneous follicle-stimulating hormone [FSH] > 40 mIU/mL and estradiol 
< 40 pg/mL [< 147 pmol/L] is confirmatory). 
Females on hormone replacement therapy (HRT) and whose menopausal status is 
in doubt will be required to use one of the contraception methods outlined above 
for women of child-bearing potential if they wish to continue their HRT during 
the study.  Otherwise, they must discontinue HRT to allow confirmation of post-


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menopausal status prior to study enrollment.  For most forms of HRT, at least 2 to 
4 weeks must elapse between the cessation of therapy and the blood draw; this 
interval depends on the type and dosage of HRT.  Following confirmation of their 
post-menopausal status, they can resume use of HRT during the study without use 
of a contraceptive method. 
Female subjects must not retrieve ova or donate from the time of screening and 
throughout the study treatment period, and for ≥ 3 months after the final dose of 
study drug. 
* Only oral agent are approved in Japan. 
15. A male subject with a sexual partner who is a woman of child-bearing potential 
must be willing and able to use a highly effective contraceptive method for the 
entire study treatment period and for ≥ 3 months after the final dose of study drug. 
a. Acceptable forms of contraception include condoms and highly effective 
contraception used by the usual female partner (see above for forms of highly 
effective contraception). 
b. Male subjects must not freeze or donate sperm starting at screening and 
throughout the study period, and ≥ 3 months after the final dose of study drug. 
16. Subjects must be fully informed about their illness and investigational nature of 
the protocol (including foreseeable risks and possible side effects) and sign and 
date an Institutional Review Board (IRB)/Institutional Ethics Committee (IEC)-
approved Informed Consent Form (ICF) before performance of any study-specific 
procedures or tests. 
17. Is willing and able to complete a daily study medication diary. 
4.2. 
Exclusion Criteria 
1. Has any evidence of small cell histology, or combined small cell and non-small 
cell histology, in original tumor biopsy or in screening biopsy performed since 
progression. 
2. Has previously documented evidence of anaplastic lymphoma kinase (ALK) 
fusion, ROS proto-oncogene 1 (ROS1) fusion, BRAF V600E mutation, 
rearranged during transfection (RET) rearrangement, human epidermal growth 
factor receptor 2 (HER2) mutation, or MET exon 14 skipping mutation.  No new 
testing for these genomic alterations is required for Screening. 
3. Has received treatment with any of the following: 
a. Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) 
from a previous cancer treatment regimen or clinical study (other than EGFR 
TKI), within 14 days of the first dose of study treatment 
b. Immune checkpoint inhibitor therapy within 30 days of first dose of 
DS-1205c. 
c. Major surgery (excluding placement of vascular access) within 4 weeks of the 
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d. Radiotherapy treatment to more than 30% of the bone marrow or with a wide 
field of radiation within 4 weeks, or palliative radiation therapy within 2 
weeks of the first dose of study drug treatment. 
4. Has history of other active malignancy within 3 years prior to enrollment, except: 
a. Adequately treated non-melanoma skin cancer OR 
b. Superficial bladder tumors (Tumor stage “a” [Ta], Tumor stage “is” [Tis], 
Tumor stage “1” [T1]) OR 
c. Curatively treated in situ disease OR 
d. Low-risk non-metastatic prostate cancer (with Gleason score < 7 on 
antiandrogen therapy)  
5. Clinically significant malabsorption syndrome or other gastrointestinal disease 
(eg, persistent diarrhea, or known sub-acute bowel obstruction ≥ NCI-CTCAE 
v5.0 Grade 2, despite medical management) that would impact drug absorption. 
6. Presence of retinal disease in the eye that is not due to neovascular age-related 
macular degeneration (nAMD; eg, significant diabetic retinopathy, glaucomatous 
retinal atrophy, retinal detachment). 
7. Has spinal cord compression or clinically active brain metastases, defined as 
untreated and symptomatic, or requiring therapy with corticosteroids or 
anticonvulsants to control associated symptoms.  Subjects with clinically inactive 
brain metastases may be included in the study.  Subjects with treated brain 
metastases that are no longer symptomatic and who require no treatment with 
corticosteroids or anticonvulsants may be included in the study if they have 
recovered from the acute toxic effect of radiotherapy.  A minimum of 2 weeks 
must have elapsed between the end of whole brain radiotherapy and study 
enrollment (1 week for stereotactic radiotherapy). 
8. Has history of myocardial infarction within the past 6 months. 
9. Has symptomatic congestive heart failure (New York Heart Association [NYHA] 
Classes II IV), unstable angina, or cardiac arrhythmia requiring antiarrhythmic 
treatment. 
10. Has LVEF < 45% by either ECHO or MUGA. 
11. Has 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, or PR interval > 250 ms. 
12. Has a mean QTcF prolongation to > 470 ms for females and > 450 ms for males 
in three successive Screening measurements. 
13. Unable or unwilling to discontinue concomitant drug that may influence gefitinib 
or DS-1205c metabolism. 
14. Unable or unwilling to discontinue concomitant use of drugs that are known to 
prolong the QT interval.  (See Section 17.6). 


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15. Has any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events, such as congenital long QT syndrome, family history of long QT 
syndrome or unexplained sudden death under 40 years of age in first-degree 
relatives. 
16. Has a history of (non-infectious) ILD/pneumonitis that required corticosteroid 
treatment, has current ILD/pneumonitis, or has suspected ILD/pneumonitis which 
cannot be ruled out by imaging at screening. 
17. Has history of pancreatitis within the past 6 months. 
18. Has any evidence of severe or uncontrolled systemic diseases including 
uncontrolled hypertension, active bleeding diatheses or active infection (including 
hepatitis B, hepatitis C, and human immunodeficiency virus [HIV]), psychiatric 
illness/social situations, substance abuse, or other factors which in the 
Investigator's opinion makes it undesirable for the subject to participate in the 
study or which would jeopardize compliance with the protocol.  Screening for 
chronic conditions is not required. 
19. Is a lactating mother (women who are willing to temporarily interrupt 
breastfeeding will also be excluded), or pregnant as confirmed by pregnancy tests 
performed within 7 days before enrollment. 




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5.2. 
Study Drug(s) 
5.2.1. 
Description  
The Investigator must ensure that the study drugs will be used only in accordance with 
the protocol. 
DS-1205c is supplied as 200 mg capsules white opaque with red lines.  Each DS-1205c 
200 mg capsule contains a 200 mg equivalent of DS-1205a (free form).  
5.2.2. 
Labeling and Packaging 
DS-1205c will be packaged in high-density polyethylene (HDPE) bottles (32 
capsules/bottle) labeled with the study drug name, strength, batch number, storage 
information, and Sponsor information. 
The study site will dispense the take-home medications and will instruct the subjects on 
their use. 
Local regulations concerning use of study drugs will be followed. 
5.2.3. 
Preparation 
All study drugs will be supplied as capsules or tablets that need no further preparation at 
the study sites.  Procedures for proper handling and disposal of anticancer drugs should 
be followed in accordance with the standard operating procedures (SOPs) of the study 
site. 
5.2.4. 
Administration 
DS-1205c 
 Administer with a meal, with 240 mL of water.  On the morning of Endpoint 
ECG days, breakfast should be started 30 minutes prior to dosing and should 
be completed within approximately 20 minutes.  For all other dosings, it is 
recommended that meals (breakfast or dinner) be completed within 
approximately 30 minutes; DS-1205c should be taken immediately after meal 
completion.  DS-1205c is administered as BID doses to be taken 
approximately 12 hours apart. 
 Doses missed by more than 6 hours should be skipped, and any missed dose 
should be recorded by the subject in the Study Medication Diary. 
When DS-1205c is not be administered as specified in the protocol, such as overdose and 
missed doses, the Investigator will promptly understand the situation and take the 
necessary measures. 
In the event of overdose, the subject should immediately be inspected for any symptoms 
or signs, and the necessary examinations will be performed, including laboratory tests 
and 12-lead ECG. At the same time, the event should be reported to the Sponsor. The 
Sponsor will give instructions as to the dose of DS-1205c on and after the following day. 
Gefitinib 


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 Co-administer with the morning dose of DS-1205c.  
 Doses missed by more than 12 hours should be skipped, and any missed dose 
should be recorded by the subject in the Study Medication Diary. 
If a subject experiences vomiting after a dose of DS-1205c during Cycle 0, the subject 
may receive antiemetic treatment.  If a subject vomits any dose of DS-1205c or gefitinib, 
that dose should not be replaced. 
5.2.5. 
Storage 
Drug supplies must be stored in a secure, limited access storage area under the storage 
conditions listed below: 
DS-1205c 
 Capsules should be stored at up to 25°C.  Excursions permitted up to 30°C in 
HDPE bottles. 
If storage conditions go out of specified requirement, contact the Study Contract 
Research Organization (CRO). 
5.2.6. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label, drug expiration 
date, and sign the Receipt of Shipment Form provided.  The Receipt of Shipment Form 
should be signed, and the original form will be retained at the site.  In addition, the 
Investigator or designee shall contact Sponsor or designee as soon as possible if there is a 
problem with the shipment.  
A Drug Accountability Record will be provided for the study drug.  The record must be 
kept current and should contain the following: 
 Dates and quantities of drug received,  
 Subject’s identification number, subject’s initials, or supply number (as 
applicable),  
 The date and quantity of study drug dispensed and remaining (if from 
individual subject drug units),  
 The initials of the dispenser.  
 Manufacturing number or symbol 
 Expiration Date 
The study monitor will review study drug accountability records during the study and/or 
at the end of the study.  All study drug inventory forms must be made available for 
inspection by a Sponsor-authorized representative or designee and regulatory agency 
inspectors.  The Investigator is responsible for maintaining the accountability of all used 
and unused study supplies at the site.   


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At the end of the study, or as directed, all unused, used, and/or partially used study drug 
will be destroyed at the site per institutional policy (and documented).  As applicable, the 
study site must file a copy of the appropriate institutional destruction policy (and 
documents) and/or Sponsor return documentation in its Investigator site file and provide a 
copy to the Sponsor. 
If the site’s institutional policy does not allow for destruction on site, study drug will be 
returned to a designee as instructed by the Sponsor.  The return of study drug must be 
documented and the documentation included in the shipment.  Study drugs will be 
returned only after the study monitor has completed a final inventory to verify the 
quantity to be returned.  
At the end of the study, a final study drug reconciliation statement must be completed by 
the Investigator or designee and provided to the Sponsor. 
5.3. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance during dosing 
at the clinical site: 
 When study medication is administered in the clinic, it should be administered 
to subjects under the supervision of clinical study personnel at the site.  
 DS-1205c and gefitinib may be dispensed in amounts exceeding the minimum 
amount required for the period of time until the next visit.  Subjects will be 
instructed to return all unused DS-1205c and gefitinib at the next visit.  
Alternatively, to ensure compliance, the site personnel may choose to dispense 
only the adequate amount of study drug required until the next scheduled visit.  
Study medication dispensing should occur as per site’s standard operating 
procedure (SOP) with approval from the Sponsor or CRO.  Compliance with 
the study drug regimen will be determined by counting unused 
capsules/tablets. 
 A Study Medication Diary will be provided to patients at the start of the study 
in order to document the study drug doses taken and the associated meals.  
The Investigator or designee will review the diary and document treatment 
compliance for each subject at each visit.  Clinical research associates (CRAs) 
will review treatment compliance during site visits and at the completion of 
the study. 
5.4. 
Dose Interruptions and Reductions 
Following the DLT evaluation period (Section 3.2.1.3), the Investigator will evaluate 
which toxicities are attributed to the study drug and adjust the administration schedule of 
the drug.Table 5.1 outlines schedule modifications for specific toxicities.  Doses may also 
be interrupted for other toxicities per Investigator discretion, and supportive medication 
may be administered in accordance with local practice guidelines.  All interruptions must 
be recorded on the drug administration electronic Case Report Form (eCRF).  


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In the event of a dose delay occurring prior to completion of a PK blood sampling in the 
study, Investigators should contact Sponsor medical monitor or designee for guidance 
regarding scheduling of these procedures. 
5.4.1. 
Dose Interruptions  
During the DLT evaluation period, the administration of study drugs may be interrupted 
due to DLTs for up to 21 days according to the rules listed in Table 5.1 below.  When a 
DLT triggered interruption is required, both DS-1205c and gefitinib should be held.  If a 
subject requires a dosing delay longer than 21 days, the subject will be withdrawn from 
the study.  
For non-DLT TEAEs Grade 3 and above, study medications will be withheld for up to 3 
weeks until improvement of the TEAE to Grade 2 or below.  Study medications may be 
resumed after discussion and agreement between the Investigator and Sponsor.  If the 
dosing interruption exceeds 21 days, the subject will be withdrawn from the study. 


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Table 5.1: 
Dose Interruption and Dose Resumption Criteria 
 
Worst toxicity 
NCI-CTCAE v5.0 
Grade (unless 
otherwise specified) 
by Definition 
Schedule modification for DS-1205c and 
gefitinib 
General disorders and administration site conditions  
Fatigue/ 
Generalized 
muscle 
weakness 
Grade 3 
(Fatigue not relieved 
by rest, limiting self 
care ADL) 
Delay study medications until resolved to ≤ Grade 
2, then: 
 
If resolved in ≤ 7 days, resume study 
medications. 
 
If resolved in > 7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
 
If not resolved in  21 days, discontinue 
subject from treatment. 
Blood and lymphatic system disorders  
Neutrophil 
count decreased  
Grade 3  
(< 1000-500/mm3;  
< 1.0 - 0.5 × 109/L) 
Grade 4 
(< 500/mm3; 
< 0.5 × 109/L) 
Delay study medications until resolved to ≤ Grade 
2, then: 
 
If resolved in ≤ 7 days, resume study 
medications. 
 
If resolved in > 7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
 
If not resolved in  21 days, discontinue 
subject from treatment. 
Febrile 
neutropenia  
Grade 3 
(ANC < 1000/mm3, 
with a single 
temperature > 38.3°C 
or a sustained 
temperature of ≥ 38°C 
for more than one 
hour) 
Grade 4 
(Life-threatening 
consequences; urgent 
intervention 
indicated) 
Delay study medications until neutrophil count 
decreased resolved to ≤ Grade 2. 
Study medications may be resumed after 
discussion and agreement between the Investigator 
and Sponsor. 


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Table 5.1: 
Dose Interruption and Dose Resumption Criteria (Continued) 
 
Worst toxicity 
NCI-CTCAE v5.0 
Grade (unless 
otherwise specified) 
by Definition 
Schedule modification for DS-1205c and 
gefitinib 
Lymphocyte 
count decreased  
Grade 3 
(500-200/mm3; 
0.5-0.2 × 109/L): 
Grade 4 
(< 200/mm3; 
< 0.2 × 109/L) 
Delay study medications until resolved to ≤ Grade 
2, then:  
 
If resolved in ≤ 7 days, resume study 
medications. 
 
If resolved in > 7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
 
If not resolved in 21 days, discontinue 
subject from treatment. 
Anemia 
Grade 3  
(Hb < 8.0 g/dL; 
< 4.9 mmol/L; 
< 80 g/L; transfusion 
indicated) 
Grade 4 
(Life-threatening 
consequences; urgent 
intervention 
indicated) 
Delay study medications until resolved to ≤ Grade 
2, then  
 
If resolved in ≤ 7 days, resume study 
medications. 
 
If resolved in > 7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
 
If not resolved in  21 days, discontinue 
subject from treatment. 
Platelet count 
decreased 
Grade 3 
(< 50,000 - 
25,000/mm3; < 50 - 
25 × 109/L)  
Grade 4  
(< 25,000/mm3;  
< 25.0 × 109/L) 
Delay study medications until resolved to ≤ Grade 
2, then: 
 
If resolved in ≤ 7 days, resume study 
medications. 
 
If resolved in > 7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
 
If not resolved in  21 days, discontinue 
subject from treatment. 
Consider transfusion per institutional guidelines. 


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Table 5.1: 
Dose Interruption and Dose Resumption Criteria (Continued) 
 
Worst toxicity 
NCI-CTCAE v5.0 
Grade (unless 
otherwise specified) 
by Definition 
Schedule modification for DS-1205c and 
gefitinib 
Cardiac Disorders  
Heart Failure 
Grade 2 
(Symptoms with 
moderate activity or 
exertion) 
Grade 3 
(Symptoms at rest or 
with minimal activity 
or exertion; 
hospitalization; new 
onset of symptoms) 
Grade 4 
(Life-threatening 
consequences; urgent 
intervention indicated 
[eg, continuous IV 
therapy or mechanical 
hemodynamic 
support]) 
Discontinue subject from study treatment. 
Cardiologist consult as necessary. 
Medical intervention as per institutional guidelines. 
Ejection 
fraction (EF) 
decreased 
Grade 3 
(Resting EF 39 - 
20%; ≥ 20% drop 
from baseline) 
Delay study medications until resolved to ≤ Grade 
2, then: 
● If resolved in ≤ 7 days, resume study 
medications. 
● If resolved in > 7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
● If not resolved in  21 days, discontinue 
subject from treatment. 
Repeat LVEF assessment within 3 weeks. 
Cardiologist consult as necessary. 
Grade 4 
(Resting EF < 20 %) 
Discontinue subject from study treatment. 
Cardiologist consult as necessary. 


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Table 5.1: 
Dose Interruption and Dose Resumption Criteria (Continued) 
 
Worst toxicity 
NCI-CTCAE v5.0 
Grade (unless 
otherwise specified) 
by Definition 
Schedule modification for DS-1205c and 
gefitinib 
Electrocardiogr
am QT 
corrected 
interval 
prolonged 
Grade 3 
(Average QTc 
≥ 501 ms; QTc 
[∆QTc] >60 ms 
change from-baseline) 
Delay study medications until resolved to ≤ Grade 
1 (Average QTc 450 - 480 ms). 
Determine if another medication the subject was 
taking may be responsible and can be adjusted or if 
there are any changes in serum electrolytes that can 
be corrected.  If mean QTcF prolongation is 
attributed to study treatment(s), the Investigator 
should have a discussion with the Sponsor before 
resuming study medications. 
Grade 4 
(Torsade de pointes; 
polymorphic 
ventricular 
tachycardia; 
signs/symptoms of 
serious arrhythmia) 
Discontinue subject from study treatment. 
Cardiologist consult as necessary. 
Respiratory, thoracic and mediastinal disorders 
Respiratory, 
thoracic and 
mediastinal 
disorders  
Grade 2 
(Symptomatic; 
medical intervention 
indicated; limiting 
instrumental ADL) 
Grade 3 
(Severe symptoms; 
limiting self care 
ADL; oxygen 
indicated) 
Grade 4 
(Life-threatening 
respiratory 
compromise; urgent 
intervention indicated 
[e.g., tracheotomy or 
intubation]) 
If new or worsening pulmonary symptoms (eg, 
dyspnea, cough, low-grade fever) or radiological 
abnormality suggestive of interstitial lung disease 
(ILD) is observed, an interruption in study 
treatment dosing is recommended, and the Sponsor 
should be informed . 
If a subject is suspected or diagnosed as having 
ILD, the Investigator should consult with a 
pulmonologist as needed, and the subject should be 
treated accordingly. 
The results of the full diagnostic workup (eg, 
high-resolution computed tomography (HRCT), 
blood and sputum culture, hematological 
parameters, arterial blood gas (ABG), pulmonary 
function testing, diffusing capacity of the lungs for 
carbon monoxide [DLCO]) should be recorded 
within the eCRF.  It is strongly recommended to 
perform a full diagnostic workup, to exclude 
alternative causes such as lymphangitic 
carcinomatosis, infection, allergy, cardiogenic 
edema, or pulmonary hemorrhage Unscheduled 
imaging and laboratory results should be included 
in the eCRF. 


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Table 5.1: 
Dose Interruption and Dose Resumption Criteria (Continued) 
 
Worst toxicity 
NCI-CTCAE v5.0 
Grade (unless 
otherwise specified) 
by Definition 
Schedule modification for DS-1205c and 
gefitinib 
 
 
If a non-inflammatory cause is confirmed, this 
should be treated accordingly, and resumption of 
study drug may occur after discussion between the 
Investigator and Sponsor. 
Study treatment will be permanently discontinued 
upon confirmation of drug-induced ILD or drug-
induced pneumonitis. 
Endocrine 
disorders 
Grade 3 
(Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
existing 
hospitalization 
indicated; limiting 
self care ADL) 
Delay dose until resolved to ≤ Grade 2, then: 
● If resolved in ≤ 14 days,  resume study 
medications. 
● If resolved in > 14 days and ≤ 21 days, 
study treatment may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
● If not resolved in  21 days, discontinue 
subject from treatment.  
Grade 4 
(Life-threatening 
consequences; urgent 
intervention 
indicated) 
Discontinue subject from study treatment. 
Nervous system 
disorders 
Grade 3 
(Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
existing 
hospitalization 
indicated; limiting 
self care ADL) 
Grade 4 
(Life-threatening 
consequences; urgent 
intervention 
indicated) 
Delay study medications and monitor at least twice 
a week until resolved to ≤ Grade 2, then: 
● If resolved in ≤7 days, resume study 
medications. 
● If resolved in >7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
● If not resolved in  21 days, discontinue 
subject from treatment. 
 
Unscheduled imaging of the brain or spinal cord 
may also be conducted to evaluate subjects.  


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Table 5.1: 
Dose Interruption and Dose Resumption Criteria (Continued) 
 
Worst toxicity 
NCI-CTCAE v5.0 
Grade (unless 
otherwise specified) 
by Definition 
Schedule modification for DS-1205c and 
gefitinib 
Eye disorders 
Grade 3 
(Severe or medically 
significant but not 
immediately sight-
threatening; decrease 
in visual acuity [best 
corrected visual 
acuity worse than 
20/40 or more than 3 
lines of decreased 
vision from known 
baseline, up to 
20/200]) 
Delay dose until resolved to ≤ Grade 2, then: 
● If resolved in ≤ 7 days, resume study 
medications. 
● If resolved in > 7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
● If not resolved in  21 days, discontinue 
subject from treatment. 
Ophthalmologist consult as necessary. 
Grade 4 
(Sight-threatening 
consequences; urgent 
intervention 
indicated; best 
corrected visual 
acuity of 20/200 or 
worse in the affected 
eye) 
Discontinue subject from study treatment. 
Ophthalmologist consult as necessary. 
Corneal ulceration, 
any Grade 
Discontinue subject from study treatment. 
Ophthalmologist consult as necessary. 
Renal and urinary disorders  
Creatinine 
increased 
Grade 3 
(> 3.0 × baseline;  
> 3.0 - 6.0 × ULN) 
Delay dose until resolved to ≤ Grade 2 (1.5 - 3.0 
× ULN; 1.5 - 3.0 × baseline), then: 
● If resolved in ≤ 7 days, resume study 
medications. 
● If resolved in > 7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
If not resolved in  21 days, discontinue subject 
from treatment. 
Grade 4  
(> 6.0 × ULN) 
Discontinue subject from study treatment. 


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Table 5.1: 
Dose Interruption and Dose Resumption Criteria (Continued) 
 
 
Worst toxicity 
NCI-CTCAE v5.0 
Grade (unless 
otherwise specified) 
by Definition 
Schedule modification for DS-1205c and 
gefitinib 
Hepatobilliary disorders 
AST or ALT 
increased  
Grade 2 
(> 3.0 - 5.0 × ULN if 
baseline was normal; 
>3.0 - 5.0 × baseline 
if baseline was 
abnormal)  
If simultaneous TBL increased ≥ 2.0 × ULN, then 
see “AST or ALT increased with simultaneous 
TBL increased” below.  Otherwise: 
● Continue study medications.  
● Monitor AST/ALT 48 to 72 hours later, and 
continue regular monitoring until 
resolution. 
 
Grade 3 
(> 5.0 - 20.0 × ULN if 
baseline was normal; 
> 5.0 - 20.0 × baseline 
if baseline was 
abnormal)  
If simultaneous TBL increased ≥ 2.0 × ULN, then 
see “AST or ALT increased with simultaneous 
TBL increased” below.  
Otherwise:   
Delay study medications until resolved to ≤ Grade 
2. 
Monitor AST/ALT 48 to 72 hours later, and 
continue regular monitoring until resolved to 
≤Grade 2. 
● If resolved in ≤ 7 days, resume study 
medications. 
● If resolved in > 7 days and ≤21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor.  
● If not resolved in 21 days, discontinue 
subject from treatment. 
 
Grade 4 
(> 20.0 × ULN if 
baseline was normal; 
> 20.0 × baseline if 
baseline was 
abnormal) 
If simultaneous TBL increased ≥ 2.0 × ULN, then 
see “AST or ALT increased with simultaneous 
TBL increased” below.   
Otherwise: 
Discontinue subject from study treatment. 
Monitor AST/ALT 48 to 72 hours later, and 
continue regular monitoring until resolved to 
≤Grade 2. 
Gastroenterologist or hepatologist consult as 
necessary. 


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Table 5.1: 
Dose Interruption and Dose Resumption Criteria (Continued) 
 
Worst toxicity 
NCI-CTCAE v5.0 
Grade (unless 
otherwise specified) 
by Definition 
Schedule modification for DS-1205c and 
gefitinib 
AST or ALT ≥ 
3.0 × ULN with 
simultaneous 
TBL ≥ 2.0 × UL
N 
 
Delay study medication until drug-induced liver 
injury can be ruled out.  The Investigator should 
consult with a gastroenterologist or hepatologist as 
needed, and the subject should be treated 
accordingly. 
Monitor AST/ALT and TBL twice weekly until 
resolution or return to baseline. 
It is strongly recommended to perform a full 
diagnostic workup, to exclude alternative causes 
such as viral or autoimmune hepatitis, alcoholic 
liver injury, biliary tract disorders, or 
hemodynamic abnormalities.  Results from 
diagnostic workup (including, for example: INR, 
direct bilirubin, serologic tests for hepatitis A, B, 
and C; alcohol use, ultrasound, magnetic resonance 
imaging (MRI), computed tomography (CT) scan, 
concomitant medication use, immunoglobulin 
levels, ECHO) should be recorded within the 
eCRF.  
If drug-induced liver injury is ruled out, the subject 
should be treated accordingly, and resumption of 
study drug may occur after discussion between the 
Investigator and Sponsor.Study treatment will be 
permanently discontinued if drug-induced liver 
injury cannot be ruled out from diagnostic workup. 
Gastroenterologist or hepatologist consult as 
necessary. 


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Table 5.1: 
Dose Interruption and Dose Resumption Criteria (Continued) 
 
Worst toxicity 
NCI-CTCAE v5.0 
Grade (unless 
otherwise specified) 
by Definition 
Schedule modification for DS-1205c and 
gefitinib 
TBL increased 
Grade 2 
(> 1.5 – 3.0 × ULN if 
baseline was normal; 
>1.5 – 3.0 × baseline 
if baseline was 
abnormal)  
Continue study medications. 
Grade 3 
(> 3.0 – 10.0 × ULN 
if baseline was 
normal; >3.0 – 10.0 × 
baseline if baseline 
was abnormal),  
 
Delay study medications until resolved to ≤ Grade 
2, then: 
● If resolved in ≤ 7 days, resume study 
medications. 
● If resolved in > 7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
● If not resolved in  21 days, discontinue 
subject from treatment. 
Grade 4 (with or 
without liver 
metastases or 
Gilbert’s syndrome) 
(> 10.0 × ULN if 
baseline was normal; 
>10.0 × baseline if 
baseline was 
abnormal) 
Discontinue subject from study treatment. 
Gastroenterologist or hepatologist consult as 
necessary. 
Skin disorders 
Skin reactions 
Grade 3 
(Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
existing 
hospitalization 
indicated; limiting 
self care ADL) 
Delay study medications until resolved ≤ Grade 2, 
and consider treatment per local 
practice/guidelines, then: 
● If resolved in ≤ 7 days, resume study 
medications. 
● If resolved in > 7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
● Discontinue study drugs if event has not 
resolved in  21 days. 
 


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Table 5.1: 
Dose Interruption and Dose Resumption Criteria (Continued) 
 
Worst toxicity 
NCI-CTCAE v5.0 
Grade (unless 
otherwise specified) 
by Definition 
Schedule modification for DS-1205c and 
gefitinib 
 
Grade 4 
(Life-threatening 
consequences; urgent 
intervention 
indicated) 
Discontinue subject from study treatment. 
Gastrointestinal disorders 
Nausea 
Grade 3 
(Inadequate oral 
caloric or fluid intake; 
tube feeding, TPN, or 
hospitalization 
indicated) 
Delay study medications until resolved ≤ Grade 2, 
and consider anti-nausea treatment per local 
practice/guidelines, then: 
● If resolved in ≤ 7 days, resume study 
medications. 
● If resolved in > 7 days and ≤21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
● If not resolved in  21 days, discontinue 
subject from treatment. 
Diarrhea/Colitis 
Grade 3 
(Increase of  ≥ 7 
stools per day over 
baseline; 
hospitalization 
indicated; severe 
increase in ostomy 
output compared to 
baseline; limiting self 
care ADL) 
Delay study medications until resolved ≤ Grade 2, 
and consider anti-diarrheal treatment per local 
practice/guidelines, then: 
● If resolved in ≤ 7 days, resume study 
medications. 
● If resolved in > 7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
● If not resolved in  21 days, discontinue 
subject from treatment. 
Grade 4 
(Life-threatening 
consequences; urgent 
intervention 
indicated) 
Discontinue subject from study treatment. 


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Table 5.1: 
Dose Interruption and Dose Resumption Criteria (Continued) 
 
Worst toxicity 
NCI-CTCAE v5.0 
Grade (unless 
otherwise specified) 
by Definition 
Schedule modification for DS-1205c and 
gefitinib 
Other 
laboratory AEs 
Grade 3 
Delay study medications until resolved to ≤ Grade 
2, then: 
● If resolved in ≤ 7 days, resume study 
medications 
● If resolved in > 7 days and ≤ 21 days, study 
medications may be resumed after 
discussion and agreement between the 
Investigator and Sponsor. 
● If not resolved in  21 days, discontinue 
subject from treatment. 
Grade 4 
Discontinue subject from study treatment 
 
ABG = arterial blood gas; ANC = absolute neutrophil count; ALT = alanine aminotransferase; AST = 
aspartate aminotransferase; CTCAE: Common Toxicity Criteria for Adverse Events; DLCO = diffusing 
capacity of the lungs for carbon monoxide; ECHO = echocardiogram; eCRF = electronic Case Report 
Form; g/dL = grams per deciliter; Hb = hemoglobin; HRCT = high-resolution computed tomography; 
ILD = interstitial lung disease; L = liter; LVEF = left ventricular ejection fraction; ms = milliseconds; NCI 
= National Cancer Institute; QTcF = corrected QT using Fridericia’s formula; TBL = total bilirubin; ULN = 
upper limit of normal. 
A There will be no dose interruptions for Grade 1 to Grade 3 lymphopenia.  
Possible exceptions to the above may be allowed on a case-by-case basis after discussion 
and agreement between Investigator and Sponsor.  The agreement must be documented. 
5.4.2. 
Dose Reductions 
Dose reductions of DS-1205c and gefitinib may be permitted following a discussion 
between the Investigator and the Sponsor.  The final decision should be documented and 
filed at the site. 
No dose reductions of gefitinib will be allowed for DLT evaluation period of dose 
escalation part. 
5.5. 
Prior and Concomitant Medications, Treatments, and 
Procedures 
5.5.1. 
Prior Medication(s), Treatment(s), and Procedure(s) 
All prior anticancer treatments or procedures (eg, surgery, radiation therapy, TKI therapy, 
chemotherapy, immune checkpoint inhibitor therapy) will be recorded.  All medications 
taken by subjects within 22 days prior to the first dose of DS-1205c will be recorded as 
prior medications. 


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5.5.2. 
Concomitant Medication(s) 
Concomitant medications, ie, medications used from the first dose of DS-1205c until 30 
days after the last dose of study drug or the start of any new anticancer treatment, 
whichever comes first, will be recorded.  All concomitant medications will be recorded 
on the eCRF.  
Management of study drug-related AEs will be as per treating physician discretion and 
institutional guidelines.  
Hematopoietic growth factors (HGFs) may be used for treatment based on the clinical 
judgment of the Investigator.  HGFs (e.g. G-CSF.) should not be used prophylactically 
during the DLT evaluation period. Use of prophylactic HGFs may be considered after 
Cycle 1 following discussion with the Sponsor.  (Treatment with HGFs for anemia 
associated with chemotherapy is not approved in Japan) 
Bisphosphonates (eg, pamidronate or zolendronate) or denosumab for control of bone 
pain, treatment of bony metastases, or treatment of osteoporosis, may be used per clinical 
judgment of the Investigator and according to prescribing information and institutional 
guidelines. 
5.5.3. 
Prohibited Medications 
The following medications, treatments and procedures will be prohibited (with noted 
exceptions below) from enrollment until the End-of-Treatment (EOT) visit, in both Dose 
Escalation and Dose Expansion: 
 Other anticancer therapy, including cytotoxic chemotherapy, targeted agents, 
immunotherapy, endocrine therapy, or TKIs (other than gefitinib) 
 Other investigational therapeutic agents 
 Radiotherapy (except for palliative radiation) 
 Radiotherapy to the thorax 
 Concomitant use of chronic systemic corticosteroids or other 
immunosuppressive medications (inhaled corticosteroids or intra-articular 
steroid injections are permitted in this study) 
 The use of concomitant medications that prolong the QTc (See Section 17.6)   
 Foods containing Hypericum perforatum (St. John’s Wort) 
 Foods or beverages containing grapefruit 
 Use of gastric acid-reducing agents (eg, proton pump inhibitors or histamine 2 
receptor antagonists) 
 Use of antacids is allowed.  Any antacid should be used ≥ 2 hours before 
or after DS-1205c dosing, and should be used ≥ 6 hours before or after 
gefitinib dosing 


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 Strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin). (See 
Section 17.6)   
 Avoid strong CYP3A4 inhibitors (eg, clarithromycin, itraconazole, 
ketoconazole, ritonavir, nefazodone, voriconazole) if possible. Medical 
judgment should be used when administering concomitant strong CYP3A4 
inhibitors. (See Section 17.6)   
 Avoid co-administration of UGT1A1 and UGT1A4 inhibitors (eg, valproic 
acid, probenecid) and inducers (eg, dexamethasone, phenobarbital, rifampicin) 
if possible.  Medical judgment should be used when administering 
concomitant inhibitors or inducers of UGT1A1 and UGT1A4 
 Avoid co-administration of BCRP substrates (eg, rosuvastatin) if possible.  
Medical judgment should be used when administering concomitant substrates 
of BCRP 
 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 subject 
experiences any potentially relevant AEs suggestive of muscle toxicity 
including unexplained muscle pain, tenderness, or weakness, particularly if 
accompanied by malaise or fever, the statin should be stopped, CK level 
should be checked, and any appropriate further management should be taken 
 Avoid co-administration of P-gp substrates (eg, digoxin) if possible.  Medical 
judgment should be used when administering concomitant substrates of P-gp 
Subjects who wear contact lenses must discontinue wearing their lenses if they have any 
mild to moderate eye symptoms (CTCAE Grade ≤ 2) while receiving treatment until at 
least one week after symptoms have resolved.  If a subject has a recurrence of eye 
symptoms or experiences any severe (CTCAE Grade ≥ 3) ocular events they must 
discontinue wearing their contact lenses until at least one week after treatment is 
permanently discontinued.  Subjects must not use any eye drops or ointment for treatment 
of eye symptoms, unless agreed by a study doctor, at any time during the study ≥ 1 week 
after permanent discontinuation of study treatment.  Subject should consult the clinic 
promptly if they have any concerns. 
Subjects taking warfarin should be monitored regularly for changes in prothrombin time 
or PT-INR. 
5.6. 
Subject Withdrawal/Discontinuation 
5.6.1. 
Reasons for Withdrawal/Discontinuation 
Subjects may be withdrawn from the study for the following reasons:  
 PD per criteria set forth in RECIST version 1.1 (Section 17.2)  


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 Clinical progression (definitive clinical signs of disease progression, but a 
recent radiographic assessment did not meet the criteria for PD according to 
RECIST version 1.1) 
 AE 
 Withdrawal of consent by subject 
 Investigator discretion 
 Death 
 Pregnancy 
 Study terminated by Sponsor 
 Lost to follow-up 
 Other, specify 
If the subject is withdrawn due to an AE, the Investigator will follow the subject until the 
AE has resolved or stabilized.  All subjects who are withdrawn from study treatment 
should complete protocol-specified withdrawal procedures (Section 5.6.2). 
Record the reason for treatment discontinuation for any subject who discontinues study 
treatment for any reason. 
Discontinued subjects will be followed for survival, either through direct contacts or by 
collecting public records (eg, death certificates) as allowed by local laws. 
5.6.2. 
Withdrawal Procedures 
If a subject is withdrawn from the study, the Investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal, including the date of 
last treatment and the reason for withdrawal. 
Protocol-specified withdrawal procedures will involve an EOT visit and a follow-up 
phone call 30 days after the last administration of DS-1205c and gefitinib.  If a subject 
begins another anticancer therapy before the end of the 30-day period, all of the EOT 
assessments should be completed prior to commencing the new therapy(-ies).  Protocol-
specified withdrawal procedures are the same as those to be performed at the EOT visit 
(Section 6.1.3.8 or Section 6.2.2.9). 
If the subject is withdrawn due to reasons other than death, withdrawal of consent, loss to 
follow-up, or study closure, and received study treatment, they should be followed for 
survival and subsequent anticancer therapy (Section 6.1.3.10 and Section 6.2.2.11). 
5.6.3. 
Subject Re-Screening Procedures 
The study will allow 1 re-screening for any subject who failed to meet eligibility criteria 
upon initial screening or whose screening window has elapsed.  The Investigator will 
consult with the Sponsor before making the re-screen decision.  The subject identification 
(SID) number must remain the same at the time of re-screening.  The initial screening 
information and the reason why the subject is ineligible for the initial evaluation will be 


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recorded on the Screening Log.  No data from the initial evaluation will be entered into 
the clinical database for re-screening subjects. 
 


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6. 
STUDY PROCEDURES 
6.1. 
Dose Escalation 
In consideration of the subject’s safety, the subjects will be hospitalized from Day 2 
(Cycle 0, Day 2) to Day 30 (Cycle 2, Day 2) in Dose Escalation to allow for careful 
safety monitoring.  However, temporary discharge or leave may be permitted at the 
Investigator’s discretion after Day 15 (Cycle 1, Day 8), taking the subject’s safety into 
consideration.  Investigator should examine the subject carefully before granting 
temporary discharge or leave, and the study site should train the subject about an 
emergency contact. 
6.1.1. 
Screening (Dose Escalation) 
6.1.1.1. 
Tissue Requirement (Dose Escalation) 
All subjects will be required to provide tumor tissue from a biopsy, collected within 6 
months of the date of consent, performed since progression during treatment with 
gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib.  
To meet entry criteria, subjects are required to demonstrate an absence of EGFR T790M 
mutation prior to study entry, assessed in tumor tissue using either cobas® EGFR 
Mutation Test v2 or gene panel testing (FoundationOne CDx™ or OncoGuide™ NCC 
Oncopanel System) performed locally at a College of American Pathologists (CAP) or an 
International Organization for Standardization (ISO)15189 certified laboratory. 
The following procedures should be conducted: 
 Have the subject sign the appropriate ICF before any study-related procedures 
assessments are performed 
 Perform a tumor biopsy OR  
 Request archive tumor tissue sample (if collected within 6 months of the date 
of consent) and confirm that it meets the tumor tissue requirements (eg, 
adequate amount for local and central analyses) for the study as noted in the 
Laboratory Manual 
 If archival tissue does not meet requirements a new core tumor biopsy 
must be obtained 
 Test the EGFR mutation in tumor tissue using either cobas® EGFR Mutation 
Test v2 or gene panel testing (FoundationOne CDx™ or OncoGuide™ NCC 
Oncopanel System) at local CAP or ISO15189-certified laboratory 
 Send the sample(s) to be tested using cobas® EGFR Mutation Test v2 at 
central laboratory and for exploratory biomarker analysis. (The results 
obtained from the analysis are not required for study entry.) 
 Any SAEs directly related to a tumor biopsy procedure should be reported 
according to Section 9.5 


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For additional information regarding EGFR T790M testing and biomarker analysis, refer 
to Section 8.2.2.1 and the Laboratory Manual. 
6.1.1.2. 
Screening (Dose Escalation) 
The duration of the Eligibility Screening period is up to 22 days prior to Cycle 0, Day 1 
in Dose Escalation.  
The following activities and/or assessments should be performed during the screening 
period: 
 Have the subject sign the appropriate ICF before any study-related procedures 
or assessments are performed.  Consent for optional pharmacogenomic (PGx) 
blood sampling is included in the appropriate ICF. 
 Review the subject’s demographics, medical and target disease history, and 
results of tests done as part of routine care and compare against the eligibility 
criteria (Section 4). 
 Perform screening tumor assessments using computed tomography (CT) of the 
chest, abdomen, and pelvis and other areas of known disease or newly 
suspected disease.  Scans of the abdomen, pelvis, and other areas of the body 
may be done with magnetic resonance imaging (MRI) (with ≤ 5 mm cuts) 
instead of CT unless another modality of disease assessment is necessary for 
the lesion(s), but evaluation of the chest should be done with CT.  CT scans 
should be performed with oral and iodinated IV contrast and MRI scans with 
IV gadolinium chelate unless there is a medical contraindication to contrast.  
If iodinated IV contrast is contraindicated, chest CT should be done without 
IV contrast.  Screening brain scans should be performed by MRI pre- and 
post- gadolinium or CT with contrast within 22 days prior to C0D-1.  A bone 
scan (99m-technetium polyphosphonate scintigraphy, whole body bone MRI, 
or 18F-NaF) to assess bone metastases should be performed within 6 weeks 
prior to Cycle0, Day -1 (historical scans within this timeframe are acceptable).  
Tumor assessments should be performed per RECIST version 1.1 
(Section 17.2). 
 Assess AEs/SAEs throughout the screening period from the time the subject 
signed the appropriate ICF (Section 9). 
 Ophthalmologic assessments will include visual acuity testing, slit lamp 
examination, fundoscopy, and tonometry (Section 9.12).  
 Perform either ECHO or MUGA.  The same test must be used for the subject 
throughout the study (Section 9.12). 
 Perform a complete physical examination including weight and height 
(Section 9.11), and assess and record the functional status using the ECOG PS 
scale (Section 17.4). 
 Obtain vital signs (systolic and diastolic blood pressure, HR, respiratory rate, 
and body temperature).  SpO2 (pulse oximetry) should also be obtained.  Vital 


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signs should be measured in the resting state (Section 9.9). This procedure 
should not be conducted during the supine position for ECG measurement. 
 Obtain triplicate ECGs (approximately 1 minute apart).  These ECGs should 
be reviewed and interpreted on-site by the Investigator for eligibility. 
Additionally, the ECGs should be submitted to the central laboratory.  The 
mean QTcF of the triplicate set of ECGs will be used to determine eligibility.  
The ECGs should be measured after the subject has rested supine for at least 
10 minutes. (Section 9.10). 
 Obtain blood and urine samples for safety analysis (hematology, blood 
chemistry, coagulation, and urinalysis) (Section 9.8). As a general rule, this 
procedure should be conducted after ECG measurement. 
 Obtain blood for thyroid function tests (Section 9.8). As a general rule, this 
procedure should be conducted after ECG measurement. 
 Perform Hepatitis B (hepatitis B surface antigen [HBsAg], anti-hepatitis B 
surface antibody [anti-HBs antibody] and anti-hepatitis B core antibody [anti-
HBc antibody]), Hepatitis C (hepatitis C virus [HCV] antibody), and HIV 
antibody tests (HIV antibody test is optional unless required by local 
regulations or IRB/IECs). As a general rule, blood collection should be 
conducted after ECG measurement. 
 Obtain a serum sample for pregnancy testing in women of child-bearing 
potential within 7 days before enrollment.  For postmenopausal subjects (no 
child-bearing potential, as indicated by a lapse of at least 12 months since the 
last menstruation) or female subjects who have no possibility of pregnancy 
due to sterilization surgery, etc, no pregnancy test will be required.  Female 
subjects who have been amenorrheic for 12 months or longer for medical 
reasons other than sterilization surgery (eg, effect of medication) will be 
regarded as women of child-bearing potential and required to undergo 
pregnancy testing. In case of this procedure and ECG measurement is 
conducted in the same day, blood collection should be conducted after ECG 
measurement. 
 Record prior medications. 
 Subjects should be instructed to take their final dose of gefitinib, erlotinib, 
afatinib, dacomitinib, or osimertinib 1 day prior to breakfast in clinic on Cycle 
0, Day 1, as indicated below: 
 2 evenings before breakfast in clinic for Day 1 visit for those subjects 
who regularly take gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib 
in the evening  
 1 morning before breakfast in clinic for Day 1 visit for those subjects 
who regularly take gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib 
in the morning 


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Refer to Schedule of Events, Dose Escalation (Cycle 0) (Table 6.1) for detailed screening 
procedures to be conducted. 
6.1.2. 
Cycle 0 (Dose Escalation) 
6.1.2.1. 
Cycle 0, Day 1 (Dose Escalation) 
Subjects should report to clinic for collection of baseline ECGs.  Refer to Schedule of 
Events, Dose Escalation (Cycle 0) (Table 6.1) for details of procedures to be 
performed/obtained.  
 Verify that the final dose of gefitinib, erlotinib, afatinib, dacomitinib, or 
osimertinib was taken 1 day prior to breakfast in clinic on Cycle 0, Day 1. 
 Obtain blood for hematology, coagulation, and blood chemistry. As a general 
rule, this procedure should be conducted after ECG measurement. 
 Obtain urine for urinalysis. 
 Obtain vital signs (systolic and diastolic blood pressure, HR, respiratory rate, 
and body temperature) at specified time points.  SpO2 (pulse oximetry) should 
also be obtained.  Vital signs should be measured in the resting state 
(Section 9.9). This procedure should not be conducted during the supine 
position for ECG measurement. 
 Obtain blood for biomarker analysis (Section 8.2). As a general rule, this 
procedure should be conducted after ECG measurement. 
 Obtain eight 5-mL blood samples for exploratory blood cfDNA 
biomarker.  Refer to the Laboratory Manual for instruction on collection, 
processing, and shipping of samples. 
 Obtain three 3-mL blood samples for exploratory blood biomarkers 
(osteopontin, IL-8, sAXL) pre-dose as indicated.  Refer to the Laboratory 
Manual for instruction on collection, processing, and shipping of samples. 
 Obtain blood sample for pharmacogenomic (PGx) analysis (if subject has 
consented). As a general rule, this procedure should be conducted after ECG 
measurement. 
 In order to time match with the Cycle 0, Day 1, breakfast should be provided 
to the subject 30 minutes prior to the planned Day 1 dosing time.  Subjects 
should complete breakfast within approximately 20 minutes although no study 
drug will be administered on this day (Cycle 0, Day 1).  In addition to 
breakfast time, breakfast content should be the same for Cycle 0, Day 1 and 
Cycle 0, Day 1. 
 Continuous 12-lead Endpoint ECG recording from Holter for the time-
matched baseline evaluations: 
 ECG extractions will occur as indicated in the Schedule of Events, Dose 
Escalation (Cycle 0) (Table 6.1).  12-lead ECGs will be extracted from a 


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continuous recording at the nominal time points by the ECG central 
laboratory.  
 Subjects should be resting supine for at least 10 minutes prior to and 5 
minutes after each nominal time point for ECG extraction.  
 Lunch should be provided to the subject.  Lunch time and content should be 
the same for Cycle 0, Day 1 and Cycle 0, Day 1.  
 Perform a complete physical examination, including weight (Section 9.11), 
and assess and record the functional status using the ECOG PS scale 
(Section 17.4).  Alternatively, this may be performed pre-dose Cycle 0, Day 1. 
 Chest radiograph should be performed for safety examination 
6.1.2.2. 
Cycle 0, Day 1 (Dose Escalation) 
Day 1 immediately follows Day 1.  Subjects should report to the clinic in the morning 
for pre-dose procedures as indicated in Schedule of Events, Dose Escalation (Cycle 0) 
(Table 6.1).  All procedures should be time matched to procedures obtained/performed on 
Day 1. 
All pre-dose procedures should be completed before breakfast as indicated in Schedule of 
Events (Table 6.1).  The Investigator should review all of the safety laboratories obtained 
from Cycle 0, Day 1 prior to dosing. 
DS-1205c should be administered with 240 mL of water with breakfast.  Breakfast should 
be started 30 minutes prior to dosing and should be completed within approximately 
20 minutes.  In addition to breakfast time, breakfast content should be the same as on 
Cycle 0, Day -1. 
The following procedures should be obtained/performed per the Schedule of Events, 
Dose Escalation (Cycle 0) (Table 6.1): 
 Obtain vital signs (systolic and diastolic blood pressure, HR, respiratory rate, 
and body temperature) at specified time points.  SpO2 (pulse oximetry) should 
also be obtained.  Vital signs should be measured in the resting state 
(Section 9.9). This procedure should not be conducted during the supine 
position for ECG measurement. 
 Continuous 12-lead ECG recording from Holter for the time-matched 
endpoint evaluations and safety: 
 12-lead Endpoint ECGs will be extracted from a continuous recording at 
the nominal time points by the ECG central laboratory.  Subjects should be 
resting supine for at least 10 minutes prior to and 5 minutes after each 
nominal time point for ECG extraction.  Time window for collection time 
points: -2 hours (for pre-dose) and ±15 minutes (for hours 1 to 8 post-
dose). 


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 Safety ECG recordings should be printed for on-site safety assessment by 
the Investigator and for central review.  Subjects should rest supine for at 
least 10 minutes prior to and 5 minutes after each time point. 
 Obtain blood sample for PK analysis of DS-1205a at all specified time points.  
All PK blood draws should be performed as close as possible to scheduled 
time.  When an ECG is performed at the same time point, the PK specimen 
should be taken immediately after completion of the ECG.  Time window for 
collection time points: ±15 minutes of nominal times. 
 If not completed on Cycle 0, Day 1, perform a complete physical 
examination, including weight (Section 9.11), and assess and record the 
functional status using the ECOG PS scale (Section 17.4). 
 Lunch should be provided to the subject approximately 4 hours after dosing.  
Lunch time and content should be the same for Cycle 0, Day 1 and Cycle 0, 
Day 1.  
 Assess AEs/SAEs (Section 9). 
 During the DLT-evaluation period (from Cycle 0, Day 1 to Cycle 1, Day 21 of 
Dose Escalation), determine whether AEs/SAEs represent DLT 
(Section 3.2.1.3). 
 Record concomitant medications. 
After completion of 10-hour post-dose PK blood sample collections, subjects should be 
given dinner in the clinic.  Dinner should be started approximately 30 minutes prior to 
dosing and should be completed before dosing.  Subjects should receive the evening dose 
of DS-1205c in the clinic with 240 mL of water. 
6.1.2.3. 
Cycle 0, Day 2 (Dose Escalation) 
All pre-dose procedures should be completed before breakfast as indicated in Schedule of 
Events, Dose Escalation (Cycle 0) (Table 6.1).  The Investigator should review all of the 
pre-dose results prior to dosing, including safety laboratories results (eg, blood chemistry, 
hematology, and urinalysis). 
DS-1205c should be administered with 240 mL of water following breakfast.  Breakfast 
should be started 30 minutes prior to dosing and should be completed within 
approximately 20 minutes.  In addition to breakfast time, breakfast content should be the 
same as on Cycle 0, Day -1. 
The following procedures should be obtained/performed per the Schedule of Events, 
Dose Escalation (Cycle 0) (Table 6.1): 
 Obtain vital signs (systolic and diastolic blood pressure, HR, respiratory rate, 
and body temperature) pre-dose.  SpO2 (pulse oximetry) should also be 
obtained.  Vital signs should be measured in the resting state (Section 9.9). 
This procedure should not be conducted during the supine position for ECG 
measurement. 


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 12-lead Endpoint ECGs will be extracted from a continuous recording pre-
dose by the ECG central laboratory.  Subjects should be resting supine for at 
least 10 minutes prior to and 5 minutes after each nominal time point for ECG 
extraction.  Time window for collection time points:  -2 hours of nominal 
times (for pre dose). 
 Safety ECG recordings should be printed for on-site safety assessment by the 
Investigator and for central review.  Subjects should rest supine for at least 
10 minutes prior to and 5 minutes after each time point. 
 Obtain blood sample for PK analysis of DS-1205a pre-dose.  All PK blood 
draws should be performed as close as possible to scheduled time. When an 
ECG is performed at the same time point, the PK specimen should be taken 
immediately after completion of the ECG.  Time window for collection time 
points: 2 hours of nominal times (for pre dose). 
 Obtain blood for hematology, coagulation, and blood chemistry pre-dose. As a 
general rule, this procedure should be conducted after ECG measurement. If 
this procedure need to be done before ECG measurement, investigators should 
contact Sponsor for guidance scheduling of these procedures. 
 Obtain urine for urinalysis pre-dose. 
 Perform a complete physical examination (Section 9.11), and assess and 
record the functional status using the ECOG PS scale (Section 17.4). 
 Assess AEs/SAEs (Section 9). 
 During the DLT-evaluation period (from Cycle 0, Day 1 to Cycle 1, Day 21 of 
Dose Escalation), determine whether AEs/SAEs represent DLT 
(Section 3.2.1.3). 
 Record concomitant medications. 
6.1.2.4. 
Cycle 0, Day 4 (Dose Escalation) 
All pre-dose procedures should be completed before breakfast on Day 4 (±1 day) as 
indicated in Schedule of Events, Dose Escalation (Cycle 0) (Table 6.1).  
DS-1205c should be administered with 240 mL of water following breakfast.  Breakfast 
should be started 30 minutes prior to dosing and should be completed within 
approximately 20 minutes.  In addition to breakfast time, breakfast content should be the 
same as on Cycle 0, Day -1. 
The following procedures should be obtained/performed per the Schedule of Events, 
Dose Escalation (Cycle 0) (Table 6.1): 
 Obtain vital signs (systolic and diastolic blood pressure, HR, respiratory rate, 
and body temperature) pre-dose.  SpO2 (pulse oximetry) should also be 
obtained.  Vital signs should be measured in the resting state (Section 9.9). 
This procedure should not be conducted during the supine position for ECG 
measurement. 


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 12-lead Endpoint ECGs will be extracted from a continuous recording pre-
dose by the ECG central laboratory.  Subjects should be resting supine for at 
least 10 minutes prior to and 5 minutes after each nominal time point for ECG 
extraction.  Time window for collection time points: -2 hours of nominal times 
(for pre-dose). 
 Safety ECG recordings should be printed for on-site safety assessment by the 
Investigator and for central review.  Subjects should rest supine for at least 10 
minutes prior to and 5 minutes after each time point. 
 Obtain blood sample for PK analysis of DS-1205a pre-dose.  All PK blood 
draws should be performed as close as possible to scheduled time.  When an 
ECG is performed at the same time point, the PK specimen should be taken 
immediately after completion of the ECG.  Time window for collection time 
points: 2 hours of nominal times (for pre-dose). 
 Assess AEs/SAEs (Section 9). 
 During the DLT-evaluation period (from Cycle 0, Day 1 to Cycle 1, Day 21 of 
Dose Escalation), determine whether AEs/SAEs represent DLT 
(Section 3.2.1.3). 
 Record concomitant medications. 
6.1.2.5. 
Cycle 0, Day 6 (Dose Escalation) 
All pre-dose procedures should be completed before breakfast as indicated in Schedule of 
Events, Dose Escalation (Cycle 0) (Table 6.1).  The Investigator should review all of the 
safety laboratories obtained from Cycle 0, Day 6 (eg, blood chemistry, hematology, and 
urinalysis) prior to dosing. 
DS-1205c should be administered with 240 mL of water following breakfast.  Breakfast 
should be started 30 minutes prior to dosing and should be completed within 
approximately 20 minutes.  In addition to breakfast time, breakfast content should be the 
same as on Cycle 0, Day -1. 
The following procedures should be obtained/performed per the Schedule of Events, 
Dose Escalation (Cycle 0) (Table 6.1): 
 Obtain vital signs (systolic and diastolic blood pressure, and HR) pre-dose.  
SpO2 (pulse oximetry) should also be obtained.  Vital signs should be 
measured in the resting state (Section 9.9). This procedure should not be 
conducted during the supine position for ECG measurement. 
 Obtain blood for hematology, coagulation, and blood chemistry pre-dose. As a 
general rule, this procedure should be conducted after ECG measurement. If 
this procedure need to be done before ECG measurement, investigators should 
contact Sponsor for guidance scheduling of these procedures. 
 Obtain urine for urinalysis pre-dose. 


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 12-lead Endpoint ECGs will be extracted from a continuous recording pre-
dose by the ECG central laboratory.  Subjects should be resting supine for at 
least 10 minutes prior to and 5 minutes after each nominal time point for ECG 
extraction.  Time window for collection time points: 2 hours of nominal 
times (for pre-dose). 
 Safety ECG recordings should be printed for on-site safety assessment by the 
Investigator and for central review.  Subjects should rest supine for at least 10 
minutes prior to and 5 minutes after each time point. 
 Obtain blood sample for PK analysis of DS-1205a pre-dose.  All PK blood 
draws should be performed as close as possible to scheduled time.  When an 
ECG is performed at the same time point, the PK specimen should be taken 
immediately after completion of the ECG.  Time window for collection time 
points: 2 hours of nominal times (for pre dose). 
 Perform a complete physical examination (Section 9.11), and assess and 
record the functional status using the ECOG PS scale (Section 17.4). 
 Assess AEs/SAEs (Section 9). 
 During the DLT-evaluation period (from Cycle 0, Day 1 to Cycle 1, Day 21 of 
Dose Escalation), determine whether AEs/SAEs represent DLT 
(Section 3.2.1.3). 
 Record concomitant medications. 
6.1.2.6. 
Cycle 0, Day 7 (Dose Escalation) 
All pre-dose procedures should be completed before breakfast as indicated in Schedule of 
Events, Dose Escalation (Cycle 0) (Table 6.1).  The Investigator should review all of the 
safety laboratories obtained from Cycle 0, Day 7 prior to dosing. 
DS-1205c should be administered with 240 mL of water following breakfast.  Breakfast 
should be started 30 minutes prior to dosing and should be completed within 
approximately 20 minutes.  In addition to breakfast time, breakfast content should be the 
same as on Cycle 0, Day -1. 
The following procedures should be obtained/performed per the Schedule of Events, 
Dose Escalation (Cycle 0) (Table 6.1): 
 Obtain vital signs (systolic and diastolic blood pressure, and HR) pre-dose.  
SpO2 (pulse oximetry) should also be obtained.  Vital signs should be 
measured in the resting state (Section 9.9). This procedure should not be 
conducted during the supine position for ECG measurement. 
 12-lead Endpoint ECGs will be extracted from a continuous recording at the 
nominal time points by the ECG central laboratory.  Subjects should be resting 
supine for at least 10 minutes prior to and 5 minutes after each nominal time 
point for ECG extraction.  Time window for collection time points: 2 hours 
(for pre dose) and ±15 minutes (for hours 1 to 8 post-dose) of nominal times. 


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 Safety ECG recordings should be printed for on-site safety assessment by the 
Investigator and for central review.  Subjects should rest supine for at least 10 
minutes prior to and 5 minutes after each time point. 
 Obtain blood sample for PK analysis of DS-1205a.  All PK blood draws 
should be performed as close as possible to scheduled time.  When an ECG is 
performed at the same time point, the PK specimen should be taken 
immediately after completion of the ECG.  Time window for collection time 
points: 2 hours (for pre-dose) and ±15 minutes (for hours 1 to 10 post-dose) 
of nominal times. 
 Obtain blood for hematology, coagulation, and blood chemistry pre-dose 
(Section 9.8). As a general rule, this procedure should be conducted after ECG 
measurement. If this procedure needs to be done before ECG measurement, 
investigators should contact Sponsor for guidance in scheduling of these 
procedures. Alternatively, blood for hematology, coagulation, and blood 
chemistry may be obtained Cycle 1, Day 1. 
 Obtain blood for thyroid function tests (Section 9.8). As a general rule, this 
procedure should be conducted after ECG measurement. If this procedure 
needs to be done before ECG measurement, investigators should contact 
Sponsor for guidance in scheduling of these procedures. Alternatively, blood 
for thyroid function tests may be obtained Cycle 1, Day 1. 
 Obtain urine for urinalysis before breakfast. Alternatively, urine for urinalysis 
may be obtained Cycle 1, Day 1. 
 Perform a complete physical examination (Section 9.11), and assess and 
record the functional status using the ECOG PS scale (Section 17.4).  
Alternatively, a complete physical examination and functional status may be 
performed/recorded Cycle 1, Day 1. 
 Lunch should be provided to the subject approximately 4 hours after dosing.  
Lunch time and content should be the same as on Cycle 0, Day -1. 
 Assess AEs/SAEs (Section 9). 
 During the DLT-evaluation period (from Cycle 0, Day 1 to Cycle 1, Day 21 of 
Dose Escalation), determine whether AEs/SAEs represent DLT 
(Section 3.2.1.3). 
 Determine whether AEs/SAEs require delay of Cycle 1 dosing (Section 5.4.1). 
 Record concomitant medications. 
After completion of 10-hour post-dose PK blood sample collections, subjects should be 
given dinner in the clinic.  Dinner should be started approximately 30 minutes prior to 
dosing and should be completed before dosing.  Subjects should receive the evening dose 
of DS-1205c in the clinic with 240 mL of water. 


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6.1.3. 
Cycle 1 and Beyond (Dose Escalation) 
Subjects should continue to take DS-1205c orally BID (approximately 12 hours apart).  
Beginning in Cycle 1, gefitinib 250 mg should be co-administered orally QD with the 
morning DS-1205c dose.  Cycle 1 and subsequent cycles are 21-day cycles (see 
Section 3.2.1.2 for dose selection).  
Procedures to be conducted on each visit day for Dose Escalation are outlined in the 
Schedule of Events, Dose Escalation (Cycle 1 and Beyond) (Table 6.2). 
6.1.3.1. 
Cycle 1, Day 1 (Dose Escalation) 
Cycle 1, Day 1 immediately follows Cycle 0, Day 7.  Subjects should report to the clinic 
in the morning. 
Subjects should be given breakfast in the clinic.  Breakfast should be started 30 minutes 
prior to dosing and should be completed within approximately 20 minutes.  In addition to 
breakfast time, breakfast content should be the same as on Cycle 0, Day -1.  Subjects 
should receive the morning dose of DS-1205c and 250 mg of gefitinib with 240 mL of 
water. 
The following procedures should be obtained/performed per the Schedule of Events, 
Dose Escalation (Cycle 1 and Beyond) (Table 6.2): 
 Vital signs (systolic and diastolic blood pressure, HR, respiratory rate, and 
body temperature) and SpO2 (pulse oximetry), at pre-dose and at 2, 4, 6, and 8 
hours post-dose.  Vital signs should be measured in the resting state 
(Section 9.9). This procedure should not be conducted during the supine 
position for ECG measurement. 
 If not obtained on Cycle 0, Day 7, obtain blood for hematology, coagulation, 
and blood chemistry before breakfast  (Section 9.8). As a general rule, this 
procedure should be conducted after ECG measurement. If this procedure 
needs to be done before ECG measurement, investigators should contact 
Sponsor for guidance in scheduling of these procedures. 
 If not obtained on Cycle 0, Day 7, obtain blood for thyroid function tests 
(Section 9.8). As a general rule, this procedure should be conducted after ECG 
measurement. If this procedure needs to be done before ECG measurement, 
investigators should contact Sponsor for guidance in scheduling of these 
procedures. 
 If not obtained on Cycle 0, Day 7, obtain urine for urinalysis before breakfast . 
 Endpoint ECGs: 12-lead ECGs will be extracted from a continuous recording 
at pre-dose and at 2, 4, 6, and 8 hours post-dose by the ECG central 
laboratory.  Subjects should be resting supine for at least 10 minutes prior to 
and 5 minutes after ECG extraction. 
 Safety ECGs: 12-lead ECG recordings should be printed at pre-dose and at 2, 
4, 6, and 8 hours post-dose for on-site safety assessment by the Investigator 


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and for central review.  Subjects should rest supine for at least 10 minutes 
prior to and 5 minutes after each time point. 
 Obtain blood samples for PK analysis, pre-dose, for both DS-1205a and 
gefitinib.  All PK blood draws should be performed as close as possible to 
scheduled time.  The PK specimen should be taken immediately after 
completion of the Endpoint ECG.  Time window for collection time points: 2 
hours (for pre-dose),  ±15 minutes (for hours 2 to 8 post-dose), and ±2 hours 
(for 24 hours post-dose) of nominal times. 
 Obtain blood sample for Exploratory Blood cfDNA pre-dose. As a general 
rule, this procedure should be conducted after ECG measurement. 
 Obtain blood sample for Exploratory Blood Biomarker pre-dose. As a general 
rule, this procedure should be conducted after ECG measurement. 
 If not performed/recorded on Cycle 0, Day 7, perform a complete physical 
examination (Section 9.11), and assess and record the functional status using 
the ECOG PS scale (Appendix 17.4). 
 Assess AEs/SAEs (Section 9). 
 During the DLT-evaluation period (from Cycle 0, Day 1 to Cycle 1, Day 21 of 
Dose Escalation), determine whether AEs/SAEs represent DLT 
(Section 3.2.1.3). 
 Record concomitant medications. 
6.1.3.2. 
Cycle 1, Day 4, Day 8, and Day 15 (Dose Escalation) 
Subjects should report back to the clinic in the morning to receive breakfast and doses of 
DS-1205c and gefitinib, and procedures should be obtained/performed on Day 4, Day 8, 
and Day 15 (±1 day) as indicated per the Schedule of Events, Dose Escalation (Cycle 1 
and Beyond) (Table 6.2): 
Subjects should be given breakfast in the clinic.  Breakfast should be started 30 minutes 
prior to dosing and should be completed within approximately 20 minutes.  In addition to 
breakfast time, breakfast content should be the same as on Cycle 0, Day -1.  Subjects 
should receive the morning dose of DS-1205c and 250 mg of gefitinib with 240 mL of 
water. 
 Obtain blood for hematology, coagulation, and blood chemistry. As a general 
rule, this procedure should be conducted after ECG measurement. If this 
procedure needs to be done before ECG measurement, investigators should 
contact Sponsor for guidance in scheduling of these procedures. 
 Obtain urine for urinalysis. 
 Vital signs (systolic and diastolic blood pressure, HR) and SpO2 (pulse 
oximetry) pre-dose.  Vital signs should be measured in the resting state 
(Section 9.9). This procedure should not be conducted during the supine 
position for ECG measurement. 


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 Endpoint ECGs: 12-lead ECGs will be extracted from a continuous recording 
pre-dose by the ECG central laboratory.  Subjects should be resting supine for 
at least 10 minutes prior to and 5 minutes after ECG extraction.  Time window 
for collection time points: 2 hours of nominal times. 
 Safety ECGs: 12-lead ECG recordings should be printed pre-dose for on-site 
safety assessment by the Investigator and for central review.  Subjects should 
rest supine for at least 10 minutes prior to and 5 minutes after each time point. 
 Obtain blood samples for PK analysis, pre-dose, for both DS-1205a and 
gefitinib.  All PK blood draws should be performed as close as possible to 
scheduled time.  The PK specimen should be taken immediately after 
completion of the Endpoint ECG.  Time window for collection time points: 2 
hours of nominal times. 
 Obtain blood sample for Exploratory Blood Biomarker pre-dose. As a general 
rule, this procedure should be conducted after ECG measurement. 
 Perform a complete physical examination (Section 9.11), and assess and 
record the functional status using the ECOG PS scale (Appendix 17.4). 
 Assess AEs/SAEs (Section 9). 
 During the DLT-evaluation period (from Cycle 0, Day 1 to Cycle 1, Day 21 of 
Dose Escalation), determine whether AEs/SAEs represent DLT 
(Section 3.2.1.3). 
 Record concomitant medications. 
Day 15 only: 
 An optional On-Study tumor biopsy may also be performed on Cycle 1, Day 
15(+7 days).  Consent for this biopsy should be documented in the tissue 
consent portion of the appropriate ICF.  Tumor biopsy may be obtained from 
primary tumor or metastatic site.  
6.1.3.3. 
Cycle 2, Day 1 (Dose Escalation) 
Subjects should report to the clinic in the morning. 
Subjects should be given breakfast in the clinic.  Breakfast should be started 30 minutes 
prior to dosing and should be completed within approximately 20 minutes.  In addition to 
breakfast time, breakfast content should be the same as on Cycle 0, Day -1.  Subjects 
should receive the morning dose of DS-1205c and 250 mg of gefitinib with 240 mL of 
water. 
The following procedures should be obtained/performed on Day 1 (±1 day) per the 
Schedule of Events, Dose Escalation (Cycle 1 and Beyond) (Table 6.2): 
 Obtain blood for hematology, coagulation, and blood chemistry. As a general 
rule, this procedure should be conducted after ECG measurement. If this 
procedure needs to be done before ECG measurement, investigators should 
contact Sponsor for guidance in scheduling of these procedures. 


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 Obtain blood for thyroid function tests (Section 9.8). As a general rule, this 
procedure should be conducted after ECG measurement. If this procedure 
needs to be done before ECG measurement, investigators should contact 
Sponsor for guidance in scheduling of these procedures. 
 Obtain urine for urinalysis. 
 Vital signs (systolic and diastolic blood pressure, HR, respiratory rate, and 
body temperature) and SpO2 (pulse oximetry), pre-dose.  Vital signs should be 
measured in the resting state (Section 9.9). This procedure should not be 
conducted during the supine position for ECG measurement. 
 Endpoint ECGs: 12-lead ECGs will be extracted from a continuous recording 
at pre-dose and at 2, 4, 6 and 8 hours post-dose by the ECG central laboratory.  
Subjects should be resting supine for at least 10 minutes prior to and 
5 minutes after each nominal time point for ECG extraction. 
 Safety ECGs: 12-lead ECG recordings should be printed at pre-dose and at 2, 
4, 6 and 8 hours post-dose for on-site safety assessment by the Investigator 
and for central review.  Subjects should rest supine for at least 10 minutes 
prior to and 5 minutes after each time point.  Time window for collection time 
points: 2 hours (for pre-dose),  ±15 minutes (for hours 1 to 10 post-dose), 
and ±2 hours (for 24 hours post-dose) of nominal times. 
 Lunch should be provided to the subject approximately 4 hours after dosing.  
Lunch time and content should be the same for Cycle 2, Day 1 as Cycle 0, 
Day 1. 
 Obtain blood samples for PK analysis for both DS-1205a and gefitinib at all 
specified time points within Table 6.2.  All PK blood draws should be 
performed as close as possible to scheduled time.  When an ECG is performed 
at the same time point, the PK specimen should be taken immediately after 
completion of the ECG.  Time window for collection time points: 2 hours 
(for pre-dose), ±15 minutes (for hours 1 to 10 post-dose), and ±2 hours (for 24 
hours post-dose) of nominal times. 
 Obtain blood sample for Exploratory Blood cfDNA pre-dose. As a general 
rule, this procedure should be conducted after ECG measurement. 
 Obtain blood sample for Exploratory Blood Biomarker pre-dose. As a general 
rule, this procedure should be conducted after ECG measurement. 
 Perform a complete physical examination, including weight (Section 9.11), 
and assess and record the functional status using the ECOG PS scale 
(Section 17.4). 
 Ophthalmologic evaluation should be performed within 7 days of the 
scheduled visit.  Assessments should include visual acuity testing, slit lamp 
examination, fundoscopy, and tonometry (Section 9.12).  


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 Perform either ECHO or MUGA within 7 days of the scheduled visit.  The 
same test must be used for the subject throughout the study (Section 9.12). 
 Assess AEs/SAEs (Section 9). 
 Record concomitant medications. 
After completion of 10-hour post-dose PK blood sample collections, subjects should be 
given dinner in the clinic.  Dinner should be started approximately 30 minutes prior to 
dosing and should be completed before dosing.  Subjects should receive the evening dose 
of DS-1205c in the clinic with 240 mL of water. 
6.1.3.4. 
Cycle 2, Day 2 and Day 8 (Dose Escalation) 
Subjects should report back to the clinic in the morning to receive breakfast and doses of 
DS-1205c and gefitinib, and procedures should be obtained/performed on Day 2, and Day 
8 (± 1 day) as indicated per the Schedule of Events, Dose Escalation (Cycle 1 and 
beyond) (Table 6.2): 
Subjects should be given breakfast in the clinic.  Breakfast should be started 30 minutes 
prior to dosing and should be completed within approximately 20 minutes on Day 2.  In 
addition to breakfast time, breakfast content should be the same as on Cycle 0, Day -1.  
On Day 8, it is recommended to finish breakfast within approximately 30 minutes, and 
DS-1205c should be taken right after meal completion.  Subjects should receive the 
morning dose of DS-1205c and 250 mg of gefitinib with 240 mL of water. 
The following procedures should be obtained/performed per the Schedule of Events, 
Dose Escalation (Cycle 1 and beyond) (Table 6.2): 
 Obtain vital signs (systolic and diastolic blood pressure, and HR) pre-dose.  
SpO2 (pulse oximetry) should also be obtained.  Vital signs should be 
measured in the resting state (Section 9.9). This procedure should not be 
conducted during the supine position for ECG measurement. 
 Safety ECG recordings should be printed for on-site safety assessment by the 
Investigator and for central review.  Subjects should rest supine for at least 10 
minutes prior to and 5 minutes after each time point. 
 Assess AEs/SAEs (Section 9). 
 Record concomitant medications. 
Day 2 only: 
 12-lead Endpoint ECGs will be extracted from a continuous recording pre-
dose by the ECG central laboratory.  Subjects should be resting supine for at 
least 10 minutes prior to and 5 minutes after each nominal time point for ECG 
extraction. 
 Obtain blood samples for PK analysis of DS-1205a and gefitinib pre-dose.  
All PK blood draws should be performed as close as possible to scheduled 
time.  When an ECG is performed at the same time point, the PK specimen 
should be taken immediately after completion of the ECG. 


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Day 8 only: 
 Obtain blood for hematology, and blood chemistry pre-dose. As a general 
rule, this procedure should be conducted after ECG measurement. If this 
procedure needs to be done before ECG measurement, investigators should 
contact Sponsor for guidance in scheduling of these procedures. 
 Perform a complete physical examination (Section 9.11), and assess and 
record the functional status using the ECOG PS scale (Section 17.4). 
After completion of in-clinic procedures of Cycle 2, Day 2, subjects should be discharged 
from the clinic with study medications for at-home dosing and the Study Medication 
Diary.  Subjects should be reminded to bring all study medications and Study Medication 
Diary the following day. 
 Instructions for at-home dosing of DS-1205c and gefitinib (including this 
evening’s dose of DS-1205c) and timing of doses relative to meals.  Refer to 
the Pharmacy Instructions for detailed instructions. 
 Instructions for completion of the Study Medication Diary. 
 Reminder to bring all study medications and Study Medication Diary to every 
subsequent visit.  
Subjects should be instructed to not take morning doses at home on study visit days; they 
will take these doses in clinic instead, coordinated with appropriate pre-dose and post-
dose procedures. 
6.1.3.5. 
Tumor Assessments (Dose Escalation) 
 Investigator determined tumor assessments of the chest, abdomen, and pelvis 
and other areas where scans were performed at screening or newly suspected 
disease should be performed every 6 weeks (±7 days) from Cycle 1, Day 1 for 
the first 24 weeks then every 12 weeks (±7 days) thereafter.  The same 
methodology (CT or MRI) and scan acquisition techniques (including use or 
nonuse of IV contrast) as were used for the screening assessments should be 
used throughout the study for all assessments for each subject unless prior 
approval is obtained from the Sponsor.  Unscheduled tumor assessments may 
be conducted if progression is suspected.  Tumor assessments should not be 
delayed by dose interruptions; they are timed relative to Cycle 1, Day 1 
Tumor assessments should be performed per RECIST version 1.1 
(Section 17.2).  SpO2 should also be measured at the time of tumor assessment 
per Investigator discretion. 
 Objective responses must be confirmed at least 4 weeks later (eg, generally at 
the next tumor assessment time point).  Perform CT or MRI of the brain in 
subjects with baseline brain metastases or if clinically indicated, and within a 
target of 1 week after a subject achieves a CR.  A bone scan (99m-technetium 
polyphosphonate scintigraphy, whole body bone MRI, or 18F-NaF) to assess 
bone metastases should be performed every 24 weeks (within that 24th week) 


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from C1D1, or sooner if clinically indicated.  In subjects whose body CT/MRI 
scans indicate CR has been achieved, a bone scan will be required at 
confirmation of CR to exclude new bone metastases.  Lesions detected on 
bone scans must be followed with cross-sectional imaging. 
6.1.3.6. 
Chest Radiograph for Safety Evaluation (Dose Escalation) 
 Investigator should perform chest radiograph in Cycle 0 Day -1, Cycle 2, Day 
1 and Cycle 4, Day 1 (±2days) for safety evaluation. 
6.1.3.7. 
Cycle 3 and Subsequent Cycles, Day 1 (Dose Escalation) 
Subjects should report to the clinic in the morning. 
Subjects should be given breakfast in the clinic.  It is recommended that breakfast be 
completed approximately 30 minutes; DS-1205c should be taken immediately after meal 
completion.  Subjects should receive the morning dose of DS-1205c and 250 mg of 
gefitinib with 240 mL of water. 
The following procedures should be obtained/performed on Day 1 (±2 day) per the 
Schedule of Events, Dose Escalation (Cycle 1 and Beyond) (Table 6.2): 
 Ophthalmologic evaluation should be performed.  Assessments should include 
visual acuity testing, slit lamp examination, fundoscopy, and tonometry 
(Section 9.12).  Assessments should be conducted on Day 1 of Cycle 4 and 
every 4 cycles (−7 days) thereafter (Cycles 8, 12, 16…). 
 Perform either ECHO or MUGA.  The same test must be used for the subject 
throughout the study (Section 9.12).  Assessments should be conducted on 
Day 1 of Cycle 4 and every 4 cycles ( 7 days) thereafter (Cycles 8, 12, 16…). 
 Obtain blood for hematology and blood chemistry (Section 9.8). As a general 
rule, this procedure should be conducted after ECG measurement. If this 
procedure needs to be done before ECG measurement, investigators should 
contact Sponsor for guidance in scheduling of these procedures.  
 Obtain blood for coagulation (Day 1 of Cycle 3 and every 2 cycles thereafter: 
Cycles 5, 7, 9…) (Section 9.8). As a general rule, this procedure should be 
conducted after ECG measurement. If this procedure needs to be done before 
ECG measurement, investigators should contact Sponsor for guidance in 
scheduling of these procedures.  
 Obtain blood for thyroid function tests (Day 1 of Cycle 3 and every 2 cycles 
thereafter: Cycles 5, 7, 9…) (Section 9.8). As a general rule, this procedure 
should be conducted after ECG measurement. If this procedure needs to be 
done before ECG measurement, investigators should contact Sponsor for 
guidance in scheduling of these procedures.  
 Vital signs (systolic and diastolic blood pressure, HR) and SpO2 (pulse 
oximetry), pre-dose.  Vital signs should be measured in the resting state 


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(Section 9.9). This procedure should not be conducted during the supine 
position for ECG measurement. 
 Safety ECGs: 12-lead ECG recordings should be printed for on-site safety 
assessment by the Investigator and for central review.  Subjects should rest 
supine for at least 10 minutes prior to and 5 minutes after each time point.  
 Obtain blood sample pre-dose for PK analysis for DS-1205a.  When an ECG 
is performed at the same time point, the PK specimen should be taken 
immediately after completion of the ECG.  Time window for collection time 
points: 2 hours of nominal times. 
 Obtain blood sample for Exploratory Blood cfDNA pre-dose (Day 1 of Cycle 
3 and every two cycles thereafter: Cycles 5, 7, 9…). As a general rule, this 
procedure should be conducted after ECG measurement. 
 Obtain blood sample for Exploratory Blood Biomarker pre-dose (Day 1 of 
Cycle 3 and every two cycles thereafter: Cycles 5, 7, 9…). As a general rule, 
this procedure should be conducted after ECG measurement. 
 Perform a complete physical examination, including weight (Section 9.11), 
and assess and record the functional status using the ECOG PS scale 
(Appendix 17.4). 
 Assess AEs/SAEs (Section 9). 
 Record concomitant medications. 
 Instructions for at-home dosing of DS-1205c and gefitinib (including this 
evening’s dose of DS-1205c) and timing of doses relative to meals.  Refer to 
the Pharmacy Instructions for detailed instructions. 
 Instructions for completion of the Study Medication Diary. 
 Reminder to bring all study medications and Study Medication Diary to every 
subsequent visit.  
Subjects should be instructed to not take morning doses at home on study visit days; they 
will take these doses in clinic instead, coordinated with appropriate pre-dose and post-
dose procedures.  
6.1.3.8. 
End-of-Treatment (EOT) Visit (Dose Escalation) 
This visit occurs within 7 days after the final dose of study treatment, or before starting 
new anticancer treatment, whichever comes first. 
The following procedures should be obtained/performed per the Schedule of Events, 
Dose Escalation (Cycle 1 and Beyond) (Table 6.2): 
 Vital signs (systolic and diastolic blood pressure, HR) and SpO2 (pulse 
oximetry), pre-dose.  Vital signs should be measured in the resting state 
(Section 9.9). This procedure should not be conducted during the supine 
position for ECG measurement. 


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 Safety ECGs: 12-lead ECG recordings should be printed for on-site safety 
assessment by the Investigator.  Subjects should be resting supine for at least 
10 minutes prior to and 5 minutes after ECG extraction. 
 Obtain blood for hematology and blood chemistry. As a general rule, this 
procedure should be conducted after ECG measurement. If this procedure 
needs to be done before ECG measurement, investigators should contact 
Sponsor for guidance in scheduling of these procedures. 
 Obtain blood for coagulation (Section 9.8). As a general rule, this procedure 
should be conducted after ECG measurement. If this procedure needs to be 
done before ECG measurement, investigators should contact Sponsor for 
guidance in scheduling of these procedures.  
 Obtain urine for urinalysis. 
 Obtain a urine sample for pregnancy testing in women of child-bearing 
potential. 
 Obtain blood sample for Exploratory Blood cfDNA. As a general rule, this 
procedure should be conducted after ECG measurement. 
 Obtain blood sample for Exploratory Blood Biomarker. As a general rule, this 
procedure should be conducted after ECG measurement. 
 Perform a complete physical examination, including weight (Section 9.11), 
and assess and record the functional status using the ECOG PS scale 
(Appendix 17.4). 
 Perform radiographic tumor assessments (CT/MRI) of the chest, abdomen and 
pelvis and all sites of disease, as per RECIST version 1.1 (Section 17.2).  If 
the previous scan was obtained within the last 6 weeks, this assessment does 
not need to be performed at the EOT visit. 
 Ophthalmologic evaluation should be performed.  Assessments should include 
visual acuity testing, slit lamp examination, fundoscopy, and tonometry 
(Section 9.12).  Assessments may be performed with a window of up to 7 days 
prior.  
 Perform either ECHO or MUGA.  The same test must be used for the subject 
throughout the study (Section 9.12).  Assessments may be performed with a 
window of up to 7 days prior. 
 Assess AEs/SAEs (Section 9).  
 Record concomitant medications. 
 Optional EOT tumor biopsy.  Tumor biopsy should be obtained from primary 
tumor or metastatic site, preferably from a site of recent radiographic 
progression, within 30 days of the last dose of study drug, and prior to starting 
any new anticancer treatment. 


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6.1.3.9. 
Follow-Up Call (Dose Escalation) 
A follow-up telephone call to the subject to review AEs/SAEs (Section 9) should occur 
30 days (+7 days) after the final dose of study treatment, or before starting new 
anticancer treatment, whichever comes first. 
6.1.3.10. New Cancer Treatment and Survival Follow-up (Dose Escalation) 
After discontinuation from study treatment, follow-up information for survival and 
subsequent anticancer therapy, if available, should be obtained every 3 months (±30 
days) from the date of the follow-up visit or Safety Follow-up, whichever is later, until 
death, withdrawal of consent, loss to follow-up, or study closure, whichever occurs first.  
If direct contacts are not possible due to withdrawal of consent or loss to follow-up, the 
site must make every effort to collect survival status from public records (eg, death 
certificates) in accordance with local laws.   
6.2. 
 
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6.3. 
Schedule of Events 
The schedule of study events is provided for Dose Escalation in Table 6.1 andTable 6.2 
and for Dose Expansion in Table 6.3. 
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Table 6.1: 
Schedule of Events, Dose Escalation (Cycle 0) 
Visit Description 
Screen-
ing 
Treatment and Evaluationsa 
Tissue 
Eligi-
bility
CYCLE 
 
 
Cycle 0 
DAY 
 
 
1a 
1a 
2 
4 
6 
7 
HOUR 
 
 
Preb 
0 
2 
4 
6 
8 
Prec 
0 
1 
2 
4 
6 
8 
10 
 
(±1D) 
 
Prec 
0 
1 
2 
4 
6 
8 
10 
Informed Consentd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived Tumor Tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh Tumor Biopsye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Dose of Gefitinib, 
Erlotinib, Afatinib, 
Dacomitinib, or Osimertinib 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO/ 
MUGA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and Blood 
Chemistry Testsg 
 
X 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xc 
 
Xc 
Xi 
 
 
 
 
 
 
 
Coagulation 
 
X 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xc 
 
Xc 
Xi 
 
 
 
 
 
 
 
Thyroid Function Tests 
(T3[FT3], T4[FT4], and 
TSH) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
 
 
 
 
 
 
Pregnancy Test 
 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xc 
 
Xc 
Xi 
 
 
 
 
 
 
 


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Table 6.1: 
Schedule of Events, Dose Escalation (Cycle 0) (Continued) 
Visit Description 
Screen-
ing 
Treatment and Evaluationsa 
Tissue 
Eligi-
bility 
CYCLE 
 
 
Cycle 0 
DAY 
 
 
1a 
1a 
2 
4 
6 
7 
HOUR 
 
 
Preb 
0 
2 
4 
6 
8 
Prec 
0 
1 
2 
4 
6 
8 
10 
 
(±1D) 
 
Prec 
0 
1 
2 
4 
6 
8 
10 
Hepatitis B, Hepatitis C, and 
HIV Antibody Testsk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 Lead Safety ECGl 
 
Xm 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
Xc 
Xc 
Xc 
X 
 
X 
X 
X 
 
X 
 
12 Lead Endpoint ECGn 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
Xc 
Xc 
Xc 
X 
 
 
X 
X 
X 
X 
 
Vital Signs/Pulse Oximetryo 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
Xc 
Xc 
Xc 
X 
 
 
 
 
 
 
 
Height  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
Xp 
 
 
 
 
 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination/ 
ECOG PS 
 
X 
Xp 
 
 
 
 
 
Xp 
 
 
 
 
 
 
 
Xc 
 
X 
Xi 
 
 
 
 
 
 
 
Ophthalmologic Assessments 
q 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breakfast In Clinicr s 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
DS 1205c Administration In 
Clinic (morning dose )t 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
 
 
 
 
 
Lunch In Clinics 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Dinner In Clinicr s 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
DS 1205c Administration In 
Clinic (evening dose) t 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 


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Table 6.1: 
Schedule of Events, Dose Escalation (Cycle 0) (Continued) 
Visit Description 
Screen-
ing 
Treatment and Evaluationsa 
Tissue 
Eligi-
bility 
CYCLE 
 
 
Cycle 0 
DAY 
 
 
D 1a 
D1a 
D
2 
D
4 
D
6 
D7 
HOUR 
 
 
Preb 
0 
2 
4 
6 
8 
Prec 
0 
1 
2 
4 
6 
8 
10 
 
(±1D) 
 
Prec 
0 
1 
2 
4 
6 
8 
10 
Tumor Assessment 
(CT/MRI)u 
 
Xv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest Radiograph for 
Safety Examination 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Scan 
 
Xw 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGx Blood Sample 
(optional)x 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Blood cfDNA 
Sampley 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Blood 
Biomarker Samplez 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DS 1205a PK Blood 
Sampleaa 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X
c 
Xc 
Xc 
X 
 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
bb 
X 
Prior/ 
Concomitant Medications 
 
X 
X 
cfDNA  cell free DNA; CT  computed tomography; D  Day; ECG  electrocardiogram; ECHO  echocardiography; ECOG  Eastern Cooperative Oncology Group; EGFR  
epidermal growth factor receptor; HIV  human immunodeficiency virus; LVEF  left ventricular ejection fraction; MRI  magnetic resonance imaging; MUGA  multigated 
acquisition scan; PGx  pharmacogenomics; PK  pharmacokinetic(s); Pre  pre dose; PS  performance status; SpO2  peripheral capillary oxygen saturation; 
T3  triiodothyronine; T4  thyroxine; TKI  tyrosine kinase inhibitor; TSH  thyroid stimulating hormone  
 


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Table 6.1: 
Schedule of Events, Dose Escalation (Cycle 0) (Continued) 
a. Time points on Day 1 should be time matched to Day 1 (eg, Hour 0 on Day 1 should occur at the same clock time as Hour 0 on Day 1, when study drug is scheduled to be 
administered). Time matched endpoints: pre dose procedures, Endpoint ECGs, and meals. Exception: the Cycle 0, Day 1 10h time point has no match on Cycle 0, Day 1.A 
second subject in each dosing level should start dosing at least 24 hours after the initial dosing of the first subject. 
aa. All PK blood draws should be performed as close as possible to the scheduled time, with windows of 2 hours (for pre dose),and ±15 minutes (for hours 1 to 10 post dose). 
When an ECG is performed at the same time point, the PK specimen should be taken immediately after completion of the ECG. Refer to the Laboratory Manual for 
instructions about collection, processing, and shipping of samples.  
b.  Pre dose on Cycle 0, Day 1 is a time point matched to Cycle 0, Day 1. No study drug is to be administered on Cycle 0, Day 1. The meal time for Day 1 and Day 1 should 
be the same in order to obtain matched time points. Pre dose procedures are to be obtained prior to starting breakfast. Exception: the Cycle 0, Day 1 10h time point has no 
match on Cycle 0, Day 1. 
bb. Any SAEs directly related to a tumor biopsy procedure performed after signing the appropriate ICF should be reported. 
c. Pre dose procedures are to be obtained/performed prior to starting in clinic meal (breakfast). 
d. Informed consent should be obtained at screening prior to performing any study related procedures. Subjects need to sign a separate ICF for tissue screening.  
e. Fresh tumor biopsy is required for subjects who have not had a tumor biopsy since progression while on gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib; and for 
subjects who lack sufficient archival tumor tissue from a tumor biopsy since progression while on gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib.  
f. Subjects must take their final dose of gefitinib, erlotinib, afatinib, dacomitinib, or osimertinib between 20 to 36 hours prior to breakfast in clinic on Cycle 0, Day 1. 
g. Blood samples for safety laboratories should be collected and creatinine clearance will be estimated at the Screening Visit.  As a general rule, blood collection should be 
conducted after ECG measurement. 
h. Results are required prior to dosing on Cycle 0, Day 1. 
i 
May be obtained/performed pre dose on Cycle 1, Day 1. 
j. Within 7 days before enrollment. In case of this procedure and ECG measurement is conducted in the same day, blood collection should be conducted after ECG measurement. 
k. Perform Hepatitis B (HBsAg, anti HBs antibody and anti HBc antibody), Hepatitis C (HCV antibody), and HIV antibody tests (HIV antibody test is optional unless required 
by local regulations or IRB/IECs). As a general rule, blood collection should be conducted after ECG measurement. 
l. Safety ECG recordings should be printed for on site safety assessment by the Investigator and submitted for central review. Subjects should rest supine for at least 10 minutes 
prior to and 5 minutes after each time point. Refer to ECG Manual for additional information.  
m. Obtain triplicate ECGs (approximately 1 minute apart). These ECGs should be reviewed and interpreted on site by the Investigator for eligibility. The mean QTc of the 
triplicate set of ECGs will be used to determine eligibility. Additionally, the ECGs should be submitted to the central laboratory.   
n. At every time point specified for 12 Lead Endpoint ECGs, 3 Holter derived ECGs will be extracted by the central ECG laboratory. Subjects should rest supine for at least 10 
minutes prior to and 5 minutes after each time point. When an ECG is performed at the same study time point as a PK sample, the PK sample should be taken immediately 
afterward. Refer to Investigator Site Manual for additional information.  
o. Vital sign measurements include systolic/diastolic blood pressure and HR. Pulse oximetry should be performed with vital signs. Respiratory rate and body temperature should 
also be measured at Screening and pre dose Day 1 and Day 1; then at 24h post dose (Day 2) and 72h post dose (Day 4). Vital signs should be measured in the resting state. 
This procedure should not be conducted during the supine position for ECG measurement. 
p. Physical examination/ECOG PS and weight need to be obtained/performed on EITHER Cycle 0, Day 1 or Cycle 0, Day 1. 
q. Ophthalmologic assessments: visual acuity, slit lamp examination, fundoscopy, and tonometry. More frequent examinations may be performed at the discretion of the 
Investigator. 
r. On the morning of Endpoint ECG days, breakfast should be started 30 minutes prior to dosing and should be completed within approximately 20 minutes. For all other dosings, 
it is recommended that meals (breakfast or dinner) be completed within approximately 30 minutes; DS 1205c should be taken immediately after meal completion. Doses of 
DS 1205c should be taken approximately 12 hours apart. 
s. Meals administered in the clinic on Days 1, 2, 4, 6, and 7 should be time matched to, and contain similar contents as meals administered on Day 1. Lunch can be given 
approximately 4 hours after dosing. 
t. DS 1205c should be administered BID, with 240 mL of water. DS 1205c should be administered 30 minutes following the start of the meal (breakfast or dinner) and after all 
other pre dose procedures have been performed. 


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Table 6.1: 
Schedule of Events, Dose Escalation (Cycle 0) (Continued) 
u. The same methodology (CT or MRI) and scan acquisition techniques (including use or nonuse of IV contrast) as were used for the screening assessments should be used 
throughout the study for all assessments for each subject unless prior approval is obtained from the Sponsor. Unscheduled tumor assessments may be conducted if progression 
is suspected. Tumor assessments should not be delayed by dose interruptions; they are timed relative to Cycle 1, Day 1. Tumor assessments should be performed per RECIST 
version 1.1. 
v. CT or MRI of the brain should be performed for all subjects.  
w. A bone scan (99m technetium polyphosphonate scintigraphy, whole body bone MRI, or 18F NaF) to assess bone metastases should be performed within 6 weeks prior to 
Cycle 0, Day 1 (historical scans are acceptable). 
x. Consent for pharmacogenomic (PGx) blood sampling is included in the main study ICF. As a general rule, blood collection should be conducted after ECG measurement. 
y. Obtain eight 5 mL samples for exploratory pharmacodynamic biomarkers (cfDNA and exosomes). As a general rule, blood collection should be conducted after ECG 
measurement. Refer to the Laboratory Manual for instructions for collection, processing, and shipping of samples. 
z. Obtain three 3 mL samples for pharmacodynamic biomarkers (osteopontin, IL 8, sAXL) pre dose as indicated. As a general rule, blood collection should be conducted after 
ECG measurement. Refer to the Laboratory Manual for instructions for collection, processing, and shipping of samples. 
 


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Table 6.2: 
Schedule of Events, Dose Escalation (Cycle 1 and Beyond) 
Visit Description 
Treatment and Evaluation 
 
CYCLE 
Cycle 1 
Cycle 2 
Cycle 3 & Subsequent 
Cycles 
EOTa 
q3 mo 
F/U 
Cycle Length (days) 
21 
21 
21 
 
 
DAY 
C1 D1 
C1 D4 
C1 D8 
C1 D15 
C2 D1 
C2 D2 
C2 D8 
Cn D1 
Visit Window (days) 
 
±1 
±1 
±1 
±1 
 
±
1 
±2 
+7 
±30 
HOUR 
 
 
 
 
Pre-
dose 
0 
1 
2 
4 
6 
8 
10 
24 
 
 
 
 
Hematology and Blood Chemistry 
Testsb 
Xc 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Coagulation Testsb 
Xc 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Day 1 of Cycle 3 and every 2 
cycles thereafter (Cycle 5, 7, 9...) 
X 
 
Thyroid Function Tests (T3[FT3], 
T4[FT4], and TSH) 
Xc 
 
 
 
Xb 
 
 
 
 
 
 
 
 
 
Xb 
Day 1 of Cycle 3 and every 2 
cycles thereafter (Cycle 5, 7, 9...) 
 
 
Pregnancy Test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysisb 
Xc 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
12 Lead Safety ECGsd 
Xe 
Xb 
Xb 
Xb 
X 
 
 
X 
X 
X 
X 
 
Xb 
Xb 
Xb 
X 
 
12 Lead Endpoint ECGsf 
Xe 
Xb 
Xb 
Xb 
X 
 
 
X 
X 
X 
X 
 
Xb 
 
 
 
 
Weight 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Xb 
X 
 
Vital Signs/Pulse Oximetryg 
Xe 
Xb 
Xb 
Xb 
X 
 
 
 
 
 
 
 
Xb 
Xb 
Xb 
X 
 
Physical Examination/ECOG PSb 
Xc 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Breakfast In Clinich,i 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
DS 1205c Administration In Clinic 
(morning dose) h 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
 


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Table 6.2: 
Schedule of Events, Dose Escalation (Cycle 1 and Beyond) (Continued) 
Visit Description 
Treatment and Evaluation 
 
CYCLE 
Cycle 1 
Cycle 2 
Cycle 3 & Subsequent 
Cycles 
EOTa 
q3 mo 
F/U
Cycle Length (days) 
21 
21 
21 
 
 
DAY 
C1 D1 
C1 D4 
C1 D8 
C1 D15 
C2 D1 
C2 D2 
C2 D8 
Cn D1 
Visit Window (days) 
 
±1 
±1 
±1 
±1 
 
±
1 
±2 
+7 
±30 
HOUR 
 
 
 
 
Pre-
dose 
0 
1 
2 
4 
6 
8 
10 
24 
 
 
 
 
Lunch In Clinici 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Gefitinib Administration In Clinich 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
Dinner In Clinich,i 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
DS 1205c Administration In Clinic 
(evening dose)h 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
DS 1205a PK Blood Samplej 
Xb 
e 
Xb 
Xb 
Xb 
Xb 
 
X 
X 
X 
X 
X 
Xb 
Xb 
 
Xb 
 
 
Gefitinib PK Blood Samplej 
Xb 
k 
Xb 
Xb 
Xb 
Xb 
 
X 
X 
X 
X 
X 
X 
Xb 
 
 
 
 
Exploratory Blood cfDNA Samplel 
Xb 
 
 
 
Xb 
 
 
 
 
 
 
 
 
 
Xb 
Day 1 of Cycle 3 and every 2 
cycles thereafter (Cycle 5, 7, 9...) 
X 
 
Exploratory Blood Biomarker 
Samplem 
Xb 
Xb 
Xb 
Xb 
Xb 
 
 
 
 
 
 
 
 
 
Xb 
Day 1 of Cycle 3 and every 2 
cycles thereafter (Cycle 5, 7, 9...) 
X 
 
Bone Scann 
X 
Every 24 weeks (±7 days) 
 
 
Tumor Assessment (CT/MRI)o 
Xp 
Every 6 weeks (±7 days) in the first 24 weeks after Day 1 of Cycle 1, and every 12 weeks (±7 days) thereafter 
Xq 
 
Chest Radiograph for Safety 
Examination 
X 
Cycle 2 Day1 and Cycle 4 Day 1 (±2 days) 
 
 


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Table 6.2: 
Schedule of Events, Dose Escalation (Cycle 1 and Beyond) (Continued) 
Visit Description 
Treatment and Evaluation 
 
CYCLE 
Cycle 1 
Cycle 2 
Cycle 3 & Subsequent 
Cycles 
EOTa 
q3 mo 
F/U 
Cycle Length (days) 
21 
21 
21 
 
 
DAY 
C1 D1 
C1 D4 
C1 D8 
C1 D15 
C2 D1 
C2 D2 
C2 D8 
Cn D1 
Visit Window (days) 
 
±1 
±1 
±1 
±1 
 
±
1 
±2 
+7 
±30 
HOUR 
 
 
 
 
Pre-
dose 
0 
1 
2 
4 
6 
8 
10 
24 
 
 
 
 
Ophthalmologic Assessmentsr 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Day 1 of Cycle 4 and every 4 
cycles (  7 days) thereafter 
X 
 
ECHO/MUGAs 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Day 1 of Cycle 4 and every 4 
cycles (  7 days) thereafter 
X 
 
New Cancer Treatment and Survival 
Follow up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tumor Biopsy (optional)  
 
 
 
Xt 
 
 
 
 
 
 
 
 
 
 
 
Xu 
 
Adverse Eventsv 
X 
 
Prior/Concomitant Medications 
X 
 
cfDNA  cell free DNA; C  cycle; CT  computed tomography; D  day; ECG  electrocardiogram; ECHO  echocardiography; ECOG  Eastern Cooperative Oncology Group; 
EGFR  epidermal growth factor receptor; EOT  end of treatment; HIV  human immunodeficiency virus; LVEF  left ventricular ejection fraction; MRI  magnetic resonance 
imaging; MUGA  multigated acquisition scan; n  number; PGx  pharmacogenomics; PK  pharmacokinetic(s); PS  performance status; SpO2  peripheral capillary oxygen 
saturation; T3  triiodothyronine; T4  thyroxine; TKI  tyrosine kinase inhibitor; TSH  thyroid stimulating hormone 
a. This visit occurs within 7 days after the final dose of study treatment, or before starting new anticancer treatment, whichever comes first. A follow up telephone call to the 
subject to review AEs/SAEs should occur 30 days (+7 days) after the final dose of study treatment, or before starting new anticancer treatment, whichever comes first. 
b. To be obtained/performed pre dose. All pre dose procedures should be obtained/performed prior to in clinic meal. As a general rule, blood collection should be conducted after 
ECG measurement. If blood collection need to be done before ECG measurement, investigators should contact Sponsor for guidance scheduling of these procedures. 
c. May be performed Cycle 0, Day 7 
d. Safety ECG recordings should be printed for on site safety assessment by the Investigator and submitted for central review. Subjects should rest supine for at least 10 minutes 
prior to and 5 minutes after each time point. 
e. To be obtained/performed pre dose and at 2, 4, 6, and 8 hours post dose. 


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Table 6.2: 
Schedule of Events, Dose Escalation (Cycle 1 and Beyond) (Continued) 
f. At every time point specified for 12 Lead Endpoint ECGs 3 Holter derived ECGs will be extracted by the central ECG laboratory. Subjects should rest supine for at least 10 
minutes prior to and 5 minutes after each time point. When an ECG is performed at the same study time point as a PK sample, the PK sample should be taken immediately 
afterward. Refer to Investigator Site Manual for additional information. 
g. Vital sign measurements include systolic/diastolic blood pressure and HR. Pulse oximetry should be performed with vital signs. Respiratory rate and body temperature should 
also be measured pre dose and at 2, 4, 6, and 8 hours post dose Cycle 1, Day 1 and pre dose Cycle 2, Day 1. Vital signs should be measured in the resting state. This procedure 
should not be conducted during the supine position for ECG measurement. 
h. Beginning with Cycle 1, Day 1, DS 1205c should be administered following a meal, with 240 mL of water. On the morning of Endpoint ECG days, breakfast should be started 
30 minutes prior to dosing and should be completed within approximately 20 minutes. For all other dosings, it is recommended that meals (breakfast or dinner) be completed 
within approximately 30 minutes; DS 1205c should be taken immediately after meal completion. Doses of DS 1205c should be taken approximately 12 hours apart. Gefitinib 
is co administered with the morning dose of DS 1205c. The Schedule of Events table above specifies only those meals and doses to be administered in clinic and does not 
explicitly list the meals and doses to be taken by the subject at home. 
i. Meals administered in the clinic on Days 1, 4, 8, and 15 of Cycle 1 and Days 1 and 2 of Cycle 2 should be time matched to, and contain similar contents as meals administered 
on Day 1 of Cycle 0. Lunch can be given approximately 4 hours after dosing. 
j. All PK blood draws should be performed as close as possible to the scheduled time, with windows of 2 hours (for pre dose), ±15 minutes(for hours 1 to 10 post dose), and 
±2 hours (for 24 hours post dose). When an ECG is performed at the same time point, the PK specimen should be taken immediately after completion of the ECG. If both 
DS 1205a and gefitinib are measured at the same time point, separate 3 mL samples should be obtained. Refer to the Laboratory Manual for instructions about collection, 
processing, and shipping of samples.  
k. To be obtained/performed pre dose and at 2, 4, 6, 8, and 24 hours post dose. 
l. Obtain eight 5 mL samples for exploratory pharmacodynamic biomarkers (cfDNA and exosomes). As a general rule, blood collection should be conducted after ECG 
measurement. Refer to the Laboratory Manual for instructions for collection, processing, and shipping of samples.  
m. Obtain three 3 mL samples for pharmacodynamic biomarkers (osteopontin, IL 8, sAXL) pre dose as indicated. As a general rule, blood collection should be conducted after 
ECG measurement. Refer to the Laboratory Manual for instructions for collection, processing, and shipping of samples. 
n. A bone scan (99m technetium polyphosphonate scintigraphy, whole body bone MRI, or 18F NaF) to assess bone metastases should be performed every 24 weeks (within that 
24th week) from C1D1, or sooner if clinically indicated. In subjects whose body CT/MRI scans indicate CR has been achieved, a bone scan should be required at confirmation 
of CR to exclude new bone metastases. Lesions detected on bone scans must be followed with cross sectional imaging. 
o. The same methodology (CT or MRI) and scan acquisition techniques (including use or nonuse of IV contrast) as were used for the screening assessments should be used 
throughout the study for all assessments for each subject unless prior approval is obtained from the Sponsor. Unscheduled tumor assessments may be conducted if progression 
is suspected. Tumor assessments should not be delayed by dose interruptions; they are timed relative to Cycle 1, Day 1. Tumor assessments should be performed per RECIST 
version 1.1. 
p. Investigator determined tumor assessments of the chest, abdomen, and pelvis and other areas where scans were performed at screening or newly suspected disease should be 
performed every 6 weeks (±7 days) from Cycle 1, Day 1 for the first 24 weeks then every 12 weeks (±7 days) thereafter. Objective responses must be confirmed at least 4 
weeks later (eg, generally at the next tumor assessment time point). Perform CT or MRI of the brain in subjects with baseline brain metastases or if clinically indicated, and 
within a target of 1 week after a subject achieves a CR.  
q. Perform radiographic tumor assessments (CT/MRI) of the chest, abdomen and pelvis and all sites of disease, as per RECIST version 1.1. If the previous scan was performed 
within the last 6 weeks, this assessment does not need to be performed at the EOT visit. 
r. Ophthalmologic assessments (visual acuity, slit lamp examination, fundoscopy, and tonometry) should be performed on Day 1 of Cycle 2 ( 7 days), on Day 1 of Cycle 4 ( 7 
days) and every 4 cycles ( 7 days) thereafter, and at EOT( 7 days). Investigators must ensure results of ophthalmologic assessments are available for review prior to dosing on 
corresponding cycle visits. 
s. ECHO or MUGA should be performed on Cycle 2, Day 1 ( 7 days); Cycle 4, Day 1 ( 7 days), and on Day 1 of every 4 cycles ( 7 days) thereafter, and at EOT ( 7 days). The 
same test must be used for the subject throughout the study. Investigators must ensure results of ECHO/MUGA are available for review prior to dosing on corresponding cycle 
visits. 


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t. On study biopsy is optional on Cycle 1, Day 15 (+7 days). Consent for this biopsy should be documented in the tissue consent portion of the appropriate ICF. Tumor biopsy 
may be obtained from primary tumor or metastatic site.  
u. EOT tumor biopsy is optional. Tumor biopsy should be obtained from primary tumor or metastatic site, preferably from a site of recent radiographic progression, within 30 
days of the last dose of study drug, and prior to starting any new anticancer treatment. 
v. All clinical AEs occurring after the subject signs the Appropriate ICF and up to F/U visit (30 days [+7 days] after the final dose of study treatment, or before starting new 
anticancer treatment, whichever comes first) should be reported. 


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7. 
EFFICACY ASSESSMENTS 
7.1. 
Assessments for Efficacy Endpoint(s) 
7.1.1. 
Efficacy Endpoint(s) 
Efficacy assessments will be determined at Screening and by follow-up imaging using 
RECIST version 1.1 (Section 17.2). Tumor assessments should be conducted every 6 
weeks (±7 days) from Cycle 1, Day 1 for the first 24 weeks then every 12 weeks 
(±7 days) thereafter, as indicated in the Schedule of Events (Table 6.2, Table 6.3), until 
radiological progression or until the subject permanently discontinues treatment. The 
schedule of efficacy assessments is determined relative to Cycle 1, Day 1 and will not be 
altered by interruptions in treatment. The antitumor activity endpoints will include 
percentage change in size of target lesion(s), ORR, DOR, DCR, PFS, and OS. ORR is 
defined as the sum of CR and PR rates. CR includes both confirmed CR (as described in 
Section 6.1.3.5 and Section 6.2.2.6) and unconfirmed CR. DOR is measured from the 
time of first CR or first PR until the first date of PD. TTR is measured from the date of 
first dose of DS-1205c to first objective response (CR or PR). DCR is the sum of CR rate, 
PR rate, and SD rate. PFS is defined as the time from the date of first dose of DS-1205c 
to the earliest date of the first objective documentation of radiographic disease 
progression per RECIST Version 1.1 or death due to any cause. OS is defined as from the 
date of first dose of DS-1205c to death due to any cause. 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS 
8.1. 
Pharmacokinetic (PK) Assessment(s) 
Blood samples for PK analyses of DS-1205a and gefitinib should be obtained at the time 
points specified in the Schedule of Events (Table 6.1, Table 6.2, and Table 6.3). 
Sampling time points may be modified based on available data from PK analyses during 
the study. At each time point, a 3-mL blood sample will be collected for DS-1205a and/or 
gefitinib analysis. If both DS-1205a and gefitinib are measured at the same time point, 
separate 3-mL samples should be obtained. Instructions for the collection, handling, 
storing and shipping of the PK samples for DS-1205a and gefitinib PK analyses will be 
included in the Laboratory Manual. The actual date and exact time of study drug 
administration and of blood sampling for DS-1205a and gefitinib PK analysis must be 
recorded on the eCRF.  
All PK samples should be taken at as the exact nominal time point as possible. If  time 
points of PK sampling coincide with those of Safety or Endpoint ECG, PK samples 
should be taken immediately after ECG measurement.  
Plasma concentrations of study drugs will be measured using validated assays at 
Sponsor-designated bioanalytical laboratories. The samples may be used for bioanalytical 
method development and validation. The leftover PK samples after bioanalysis will be 
used for metabolite profiling, and the results will be reported separately. 
Plasma concentrations will be used to determine the following PK parameters using the 
actual sample collection times and the standard non-compartmental analysis (NCA).  
 Cmax, Tmax, Ctrough, AUCtau, and other PK parameters as appropriate. 
8.2. 
Biomarkers 
Biomarker analyses will be used to investigate the effect of DS-1205c and DS-1205c in 
combination with gefitinib at the molecular and cellular levels as well as to determine 
how changes in the markers may relate to exposure and clinical outcomes. The sample 
collection information as required should be recorded in the eCRF and laboratory 
requisition form(s). Detailed instructions for the collection, handling, and shipping of 
biomarker samples are outlined in the Laboratory Manual. 
8.2.1. 
Pharmacodynamic Biomarker Assessments in Blood Samples 
Pharmacodynamic biomarkers will be analyzed with the intent of monitoring the 
antitumor impact of treatment with DS-1205c and DS-1205c in combination with 
gefitinib as exploratory investigations. The following exploratory pharmacodynamic 
biomarkers that may be measured may include but are not limited to are osteopontin, IL-
8, sAXL, cfDNA, and the composition of exosomes. These biomarkers will be measured 
at specified times in the Schedule of Events (Table 6.1, Table 6.2, and Table 6.3). Other 
pharmacodynamic biomarkers in addition to, or in place of, these may be considered as 
suggested by new scientific findings, and may include DNA, RNA, protein or other 


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molecules. One or more of the aforementioned pharmacodynamic biomarkers may also 
be explored for predictive value. 
Plasma samples for biomarker analysis will also be tested for the presence of EGFR 
mutations known to be associated with EGFR TKI sensitivity (including G719X, exon 19 
deletion, L858R, L861Q) and resistance (T790M) using the cobas® EGFR Mutation Test 
v2. 
Sample collection, preparation, handling, storage, and shipping instructions are provided 
in the Laboratory Manual. 
8.2.2. 
Biomarker Assessments in Tumor Tissue Samples 
Fresh biopsy tissue or an archived tumor specimen will be obtained prior to enrollment to 
assess the baseline expression of biomarkers which may relate to response to DS-1205c 
in combination with gefitinib. Tumor specimens will be used to assess AXL expression 
using IHC and mRNA. In addition, the mRNA analysis of several hundred genes, 
including AXL and AXL pathway genes will be measured using NanoString technology 
and/or other methods (such as next-generation DNA sequencing [NGS] or protein 
analysis). Additional markers or methods may be utilized for testing these samples. 
8.2.2.1. 
Tumor Biopsy Sample Collection 
Study Entry 
All subjects will be asked to provide consent to supply tumor tissue (archival tissue or 
fresh tumor biopsy) after progression during treatment prior to study entry. 
 Archival tumor tissue may be provided for analysis if:  
 tissue has been obtained after progression during treatment with gefitinib, 
erlotinib, afatinib, dacomitinib, or osimertinib, AND 
 the tissue biopsy was obtained within 6 months of the date of consent, 
AND 
 sufficient quantity is available 
 Fresh Tumor Tissue Collection 
 In the event that a subject does not have adequate tumor tissue as required 
per the Laboratory Manual, a fresh tumor biopsy should be obtained. 
 A fresh tumor biopsy should be obtained from a primary tumor or 
metastatic site, not previously irradiated, and preferably from a site of 
disease progression. 
On-Study Biopsy 
 An optional On-Study tumor biopsy may also be performed on Cycle 1, Day 
15 (+7 days). Consent for this biopsy should be documented in the tissue 
consent portion of the appropriate ICF. Tumor biopsy should be obtained from 
primary tumor or metastatic site. CBC must be obtained within 2 days of the 


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tumor biopsy and results must be reviewed by the Investigator prior to 
obtaining a tumor biopsy. 
EOT Biopsy 
 An optional EOT tumor biopsy will also be performed at the time of 
progression or discontinuation from study treatment. Consent for this biopsy 
should be documented in the tissue consent portion of the appropriate ICF. 
Tumor biopsy should be obtained from primary tumor or metastatic site, 
preferably from a site of recent radiographic progression, within 30 days of 
the last dose of study drug, and prior to starting any new anticancer treatment. 
Refer to the Laboratory Manual for instructions regarding archived and fresh tumor tissue 
requirements and shipping. 
8.2.2.1.1. Epidermal Growth Factor Receptor (EGFR) T790M 
All subjects will be required to provide tumor tissue from a biopsy performed since 
progression during treatment with gefitinib, erlotinib, afatinib, dacomitinib, or 
osimertinib.  
Subjects are required to demonstrate an absence of EGFR T790M mutation prior to study 
entry, assessed in tumor tissue using either cobas® EGFR Mutation Test v2 or gene panel 
testing (FoundationOne CDx™ or OncoGuide™ NCC Oncopanel System) performed 
locally at a CAP or an ISO15189 certified laboratory. 
8.2.2.2. 
Tumor Tissue Biomarker Analysis 
Tumor tissue from Screening (fresh tumor biopsy or archived tumor specimen) and from 
the optional EOT biopsy will be used to assess for the presence of EGFR mutations 
known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, 
L858R, L861Q) and resistance (T790M) using the cobas® EGFR Mutation Test v2. Also, 
exploratory biomarker analysis, including, but not limited to, AXL (or other protein) 
expression using IHC, mRNA of several hundred genes (including AXL and AXL 
pathway genes), will be measured using NanoString technology, as well as possibly 
testing for mutations in DNA and/or other methods. Additional samples may be requested 
if the original sample is of insufficient quantity or quality to complete planned analyses.  
These results are not required for study entry. 
8.2.3. 
Additional Biomarker Assessments 
During the study, in addition to the biomarkers specified above, exploratory research may 
be conducted on any tumor or blood sample. These studies would extend the search for 
other potential biomarkers relevant to the effects of DS-1205c and DS-1205c in 
combination with gefitinib, cancer and/or the resistance to the treatment. This may 
include the development of ways to detect, monitor or treat cancer. These additional 
investigations would be dependent upon clinical outcome, and availability of reagents 
and samples. 


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If the patient agrees, the remaining biomarker samples (tumor) may be stored for up to 15 
years, depending on local regulations, and further analyzed to address scientific questions 
related to DS-1205c and/or cancer. This may include the development of methods to 
treat, monitor, or detect cancer. A decision to perform such exploratory biomarker 
research studies would be based on outcome data from this study or from new scientific 
findings related to the drug class or disease, as well as reagent and assay availability. 
At the end of the storage period, or during the storage period, if the subject withdraws 
consent, blood and tissue samples of the subject will be promptly managed regarding 
proper disposition. However, the data will not be discarded if biomarker analysis has 
been completed before the subject withdraws consent. 
If the patient refuses consent to provide blood sample before the enrollment, the subject 
will not be enrolled to the study. If the patient refuses consent to provide tumor sample 
which is corrected for the screening assessment before the enrollment, the subject will not 
be enrolled to the study. If the patient refuses consent to provide optional tumor samples 
which is corrected after the treatment of study drug before the enrollment, the subject will 
be able to be enrolled. 
8.2.4. 
Disclosure of the Results of Biomarker Assessment 
The tissue screening results of EGFR mutation will be disclosed to the subject or 
investigators as they affect the treatment selection. Because the value of future additional 
biomarker assessments is unknown at this time, any individual results obtained from 
exploratory biomarker research will not be disclosed to the subject or investigators. 
8.3. 
Pharmacogenomic Analysis 
8.3.1. 
Study Subjects for Pharmacogenomic Analysis 
Pharmacogenomic samples will be collected from subjects who have given informed 
consent for pharmacogenomic testing as part of the main study ICF. For subjects who 
give informed consent for pharmacogenomic analysis, the Investigator will record the 
date of that consent in the eCRF.  
8.3.2. 
Collection of Specimens for Pharmacogenomic Analysis 
A single 10-mL blood sample for pharmacogenomic analysis will be collected from each 
subject who has provided informed consent, according to the Schedule of Events 
(Table 6.1, Table 6.3). Sample collection, preparation, handling, storage, and shipping 
instructions are provided in the Laboratory Manual. 
8.3.2.1. 
Pharmacogenomic Endpoints 
Pharmacogenomic samples may be analyzed for genes involved in absorption, 
distribution, metabolism, elimination, safety, and efficacy of DS-1205c. Additionally, 
samples may be analyzed for genes involved in DS-1205c-related signaling pathways, or 
to examine diseases or physiologic processes related to DS-1205c action. Subject 
specimens will not be sold to anyone. This information may be useful in identifying 


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genetic differences among individuals that explain variations in response to the study 
drug or elucidating whether such genetic differences are present in germline DNA or 
whether they arise by somatic mutation. 
8.3.2.2. 
Disclosure of the Results of Pharmacogenomic Analysis 
Because the nature and value of future pharmacogenomic research cannot be known at 
this time, any results obtained from research involving pharmacogenomic samples will 
not be disclosed to the subject or Investigators now or in the future. 
8.3.2.3. 
Storage and Disposal of Specimens for Pharmacogenomic Analysis 
Samples will be retained until exhausted, or for up to 15 years if required by local 
regulations, or until the Sponsor requests disposition.  
If the subject withdraws consent, the banked blood samples will be promptly managed 
regarding proper disposition. However, the data will not be discarded if 
pharmacogenomic analysis has been completed before the subject withdraws consent. 


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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Adverse Events 
All clinical AEs (see Section 9.4 for definitions) occurring after the subject signs the 
Appropriate ICF and up to F/U visit (30 days [+7 days] after the final dose of study 
treatment, or before starting new anticancer treatment, whichever comes first) after the 
last dose of study drug, whether observed by the Investigator or reported by the subject, 
will be recorded on the eCRF. In addition, any SAEs directly related to tumor biopsy 
after the subject signs the appropriate ICF should be reported according to Section 9.5.  
Medical conditions (including clinical laboratory values/vital signs that are out of range) 
that were diagnosed or known to exist prior to signing the appropriate ICF will be 
recorded as part of medical history.  
All AEs, SAEs, and adverse events of special interest (AESIs) are to be reported 
according to the procedures in Section 9.5.  
All clinical laboratory results, vital signs, and safety ECG results or findings should be 
appraised by the Investigator to determine their clinical significance. Isolated abnormal 
laboratory results, vital sign findings, or ECG findings (ie, not part of a reported 
diagnosis) should be reported as AEs if they are symptomatic, lead to study drug 
discontinuation, dose reduction, require corrective treatment, or constitute an AE in the 
Investigator’s clinical judgment. 
At each visit, the Investigator will determine whether any AEs have occurred by 
evaluating the subject. AEs may be directly observed, reported spontaneously by the 
subject or by questioning the subject at each study visit. Subjects should be questioned in 
a general way, without asking about the occurrence of any specific symptoms. The 
Investigator must assess all AEs to determine seriousness, severity, and causality, in 
accordance with the definitions in Section 9.4. The Investigator’s assessment must be 
clearly documented in the site’s source documentation with the Investigator’s signature.  
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, 
report the primary sign or symptom as the AE or SAE term with additional details 
included in the narrative until the diagnosis becomes available. If the signs and symptoms 
are distinct and do not suggest a common diagnosis, report them as individual entries of 
AE or SAE.  
For events that are serious due to hospitalization, the reason for hospitalization must be 
reported as the SAE (diagnosis or symptom requiring hospitalization). A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE. Pre-planned (prior 
to signing the ICF) procedures or treatments requiring hospitalization for pre-existing 
conditions that do not worsen in severity should not be reported as SAEs (see 
Section 9.4.2 for Definitions).  
For deaths, the underlying or immediate cause of death should always be reported as an 
SAE. Disease progression is a study endpoint and consequently, should not be reported as 
an AE or SAE. However, when a subject dies from disease progression with no other 
underlying or immediate causes, “disease progression” should be reported as an SAE. 


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Any serious, untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study drug should also be reported and managed as an 
SAE. 
The Investigator should follow subjects with AEs until the event has resolved or the 
condition has stabilized. In case of unresolved AEs, including significant abnormal 
clinical laboratory values at the end of study assessment, these events will be followed 
until resolution or until they become clinically not relevant. 
9.2. 
Safety Endpoints 
Safety endpoints will include SAEs, TEAEs, DLTs, physical examination findings 
(including ECOG PS), vital sign measurements, standard clinical laboratory parameters, 
ECG parameters, ECHO/MUGA findings, and ophthalmologic findings. TEAEs will be 
graded according to the NCI-CTCAE version 5.0.  
9.3. 
Adverse Events of Special Interest (AESI) 
The following AESIs should be reported to the Sponsor by the Investigator in electronic 
data capture (EDC) within 24 hours of awareness. 
9.3.1. 
Elevations of Aminotransferase(s) and Bilirubin 
Combined elevations of aminotransferases and bilirubin, either serious or non-serious and 
whether or not causally related, meeting the laboratory criteria of a potential Hy’s Law 
case (ALT or AST ≥ 3.0 × ULN with simultaneous total bilirubin [TBL] ≥ 2.0 × ULN) 
should always be reported to the Sponsor using a special collection eCRF, with the 
Investigator’s assessment of seriousness, causality, and a detailed narrative. 
If the subject discontinues the study drug due to liver enzyme abnormalities, the subject 
will have additional clinical and laboratory evaluations in order to determine the nature 
and severity of the potential liver injury.  
9.3.2. 
Prolonged QTc Interval（≥ Grade 2） 
Standard ECG parameters will be measured, including RR, PR, QT intervals, and QRS 
duration. Safety ECGs will be reviewed and interpreted on-site by the Investigator and 
evaluated by central reviewer. QTc prolongation more than Grade 2（average QTc 481 - 
500 ms）should be reported as a AESI. For more information regarding collection of 
ECGs, refer to Section 9.10. 
If a subject experiences QTc prolongation of Grade 4 (torsades de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of serious arrhythmia), then the subject should 
be discontinued from study treatment. 
9.3.3. 
Interstitial Lung Disease 
Lung disorders, including interstitial lung disease (ILD), are acknowledged in the current 
reference safety information for gefitinib (see current prescribing information). If a 
subject is suspected or diagnosed as having ILD, the Investigator should consult with a 


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pulmonologist as needed, and the subject will be treated appropriately. The study 
treatments will be interrupted until drug induced pulmonary toxicity can be ruled out. 
Study treatments will be permanently discontinued upon confirmation of drug-induced 
ILD or pneumonitis. It is strongly recommended to perform a full diagnostic workup, to 
exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, 
cardiogenic edema, or pulmonary hemorrhage. See Section 9.12 for details regarding 
pulmonary assessments. 
9.4. 
Definitions 
9.4.1. 
Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product and that does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product (ICH E2A Guideline. Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting, Oct 1994). 
It is the responsibility of Investigators, based on their knowledge and experience, to 
determine those circumstances or abnormal laboratory findings which should be 
considered AEs.  
9.4.2. 
Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity, 
 Is a congenital anomaly/birth defect, or 
 Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject 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 (ICH E2A Guideline. 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
Oct 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias or development of drug dependency or drug abuse. 


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Note:  
 Procedures are not AEs or SAEs, but the reason for the procedure may be an 
AE or SAE.  
 Pre-planned (prior to signing the ICF) procedures or treatments requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are 
not SAEs. 
9.4.3. 
Adverse Event Severity 
The severity of AEs will be graded using the NCI-CTCAE v5.0. For each episode, the 
highest severity Grade attained should be reported. 
The NCI-CTCAE guidelines do not allow certain grades for certain AEs. For example, 
pain can be Grade 1 to 3 only (ie, cannot be life-threatening or fatal), whereas sepsis can 
only be Grade 4 or 5 (ie, can only be life-threatening or fatal). In addition, alopecia can 
only be Grade 1 or 2. The NCI-CTCAE guidelines should be followed closely. 
 Grade 1: Mild AE 
 Grade 2: Moderate AE 
 Grade 3: Severe AE 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 
Severity versus Seriousness: Severity is used to describe the intensity of a specific event 
while the event itself, however, may be of relatively minor medical significance (such as 
severe headache). This is not the same as “seriousness," which is based on subject/event 
outcome at the time of the event. For example, the NCI-CTCAE Grade 4 (life-threatening 
consequences; urgent intervention indicated) is assessed based on unique clinical 
descriptions of severity for each AE, and these criteria may be different from those used 
for the assessment of AE seriousness. An AE assessed as Grade 4 based on the NCI-
CTCAE Grade may or may not be assessed as serious based on the seriousness criteria. 
Overall, the severity of an event may be graded by the Investigator as Grade 1 or 2, but if 
the subject presents to the emergency facility for evaluation and is hospitalized overnight 
for observation, that immediately makes the event serious based upon hospitalization 
without regard to the Investigator assessment of severity. 
9.4.4. 
Causality Assessment 
The Investigator should assess the causal relationship between an AE and the study drugs 
on the basis of his/her clinical judgment and the following definitions. The causality 
assessment must be made based on the available information and can be updated as new 
information becomes available. 
 Related: 
 The AE follows a reasonable temporal sequence from study drug 
administration, and cannot be reasonably explained by the subject’s 


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clinical state or other factors (eg, disease under study, concurrent diseases, 
and concomitant medications), or 
 The AE follows a reasonable temporal sequence from study drug 
administration, and is a known reaction to the drug under study or its 
chemical group, or is predicted by known pharmacology. 
 Not Related: 
 The AE does not follow a reasonable sequence from study drug 
administration, or can be reasonably explained by the subject’s clinical 
state or other factors (eg, disease under study, concurrent diseases, and 
concomitant medications).  
9.4.5. 
Action Taken Regarding Study Drug(s) 
 Dose Not Changed: No change in study drug dosage was made 
 Drug Withdrawn: The study drug was permanently stopped 
 Dose Reduced: The dosage of study drug was reduced 
 Drug Interrupted: The study drug was temporarily stopped 
 Not applicable 
9.4.6. 
Other Action Taken for Event 
 None: No treatment was required 
 Medication required: Prescription and/or over-the-counter (OTC) medication 
was required to treat the AE 
 Hospitalization  
 Other 
9.4.7. 
Adverse Event Outcome 
 Recovered/Resolved: The subject fully recovered from the AE with no 
residual effect observed 
 Recovering/Resolving: The AE improved but has not fully resolved 
 Recovered/Resolved with Sequelae: The residual effects of the AE are still 
present and observable 
 Not Recovered/Not Resolved: The AE itself is still present and observable 
 Fatal should be used when death is a direct outcome of the AE 
 Unknown 
9.5. 
Serious Adverse Events Reporting Procedure For Investigators 
All AEs, AESIs, and SAEs will be reported in the eCRF. 


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Serious events that are also efficacy endpoints (disease progression) will be exempted 
from SAE processing and expedited reporting. Disease progression should not be 
reported as an AE/SAE. However, when a subject dies from disease progression with no 
other immediate causes, “disease progression” should be reported as an SAE and 
captured in the designated eCRF. These events are clinically anticipated events in the 
target treatment population, and will be periodically reviewed to ensure prompt 
identification of any clinically concerning safety issues. 
The following types of events should be reported by the Investigator in electronic data 
capture (EDC) within 24 hours of awareness. In the event that eCRF is unavailable, 
report the folloing types of events by faxing the paper Serious Adverse Event Report 
(SAVER) Form to the CRO using the provided fax transmittal form and the appropriate 
fax number provided for your country. Please enter SAEs reported on the paper SAVER 
Form into the eCRF as soon as possible. Please refer to eCRF Completion Guide for 
additional instructions. 
 SAEs (see Section 9.4.2 for definition) 
 Hepatic events (both serious, non-serious, and clinical laboratory results) 
which meet the potential Hy’s Law criteria defined as an elevated (ALT or 
AST) ≥ 3 x ULN with simultaneously elevated total bilirubin > 2 x ULN 
should be reported as an AE/AESI (see Section 9.3.1 for details) regardless if 
these hepatic events are symptomatic, lead to study drug discontinuation or 
dose reduction, require corrective treatment, constitute an AE in the 
Investigator’s clinical judgment, or are related to disease progression. 
 AESIs: interstitial lung disease (Section 9.3.3) and prolonged QTc interval (≥ 
Grade 2) (Section 9.3.2) 
All events (serious and non-serious) must be reported with Investigator’s assessment of 
the event’s seriousness, severity, and causality to the study drug. A detailed narrative 
summarizing the course of the event, including its evaluation, treatment, and outcome 
should be provided. Specific or estimated dates of event onset, treatment, and resolution 
should be included when available. Medical history, concomitant medications, and 
laboratory data that are relevant to the event should also be summarized in the narrative. 
For fatal events, the narrative should state whether an autopsy was or will be performed, 
and include the results if available. Source documents (including medical reports) will be 
retained at the study site and should not be submitted to the Sponsor for SAE reporting 
purposes. 
Urgent safety queries must be followed up and addressed promptly. Follow-up 
information and response to non-urgent safety queries should be combined for reporting 
to provide the most complete data possible within each follow-up.  
9.6. 
Notifying Regulatory Authorities, Investigators, and 
Institutional Review Board/Institutional Ethics Committee 
The Sponsor and/or CRO will inform Investigators, IRBs/IECs, and regulatory authorities 
of any Suspected Unexpected Serious Adverse Reactions (SUSARs) occurring in other 


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study sites or other studies of the investigational drug, as appropriate per local reporting 
requirements. The Sponsor and/or CRO will comply with any additional local safety 
reporting requirements. 
In Japan, it is the Sponsor’s responsibility to report all the fatal/life-threatening adverse 
reactions to the regulatory authorities regardless of expectedness, and SUSARs to the 
regulatory authorities and IRB/IECs. 
9.7. 
Exposure In Utero During Clinical Studies 
The Sponsor must be notified of any subject who becomes pregnant while receiving, or 
within 3 months of discontinuing, the study drug. Sponsor. must be notified of any male 
subject whose female partner becomes pregnant while the subject is receiving, or within 3 
months of discontinuing, the study drug.  
Although pregnancy is not technically an AE, all pregnancies must be followed to 
conclusion to determine their outcome. This information is important for both drug safety 
and public health concerns. It is the responsibility of the Investigator, or designee, to 
report any pregnancy in a female subject using the Exposure In Utero (EIU) Reporting 
form. Please contact your study monitor to receive the EIU Reporting Form upon 
learning of a pregnancy. The Investigator should make every effort to follow the subject 
until completion of the pregnancy and complete the EIU Reporting Form with complete 
pregnancy outcome information, including normal delivery and induced abortion. The 
adverse pregnancy outcome, either serious or non-serious, should be reported in 
accordance with study procedures. If the outcome of the pregnancy meets the criteria for 
immediate classification as a SAE (ie, post-partum complications, spontaneous or 
induced abortion, stillbirth, neonatal death, or congenital anomaly, including that in an 
aborted fetus), the Investigator should follow the procedures for reporting SAEs outlined 
in Section 9.5.  
9.8. 
Clinical Laboratory Evaluations 
For clinical laboratory parameters, the reference range of the institution that performs the 
measurements will be used.  
Clinical laboratory results will be entered in the eCRF, including whether measurements 
were obtained, date of measurement, and results of measurements. 
Standard clinical laboratory tests listed in Table 9.1 should be performed per the 
Schedule of Events (Table 6.1, Table 6.2, and Table 6.3). 
At Screening, creatinine clearance (mL/min) will be calculated using the Cockcroft-Gault 
equation (Section 17.1).  
In addition, a serum pregnancy test (beta hCG) will be required for all female subjects of 
childbearing potential at Screening. Urine pregnancy tests will be performed throughout 
the remainder of the protocol per the Schedule of Events (Table 6.1, Table 6.2, and 
Table 6.3). A positive urine pregnancy test result must be confirmed immediately using a 
serum test. 


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Table 9.1: 
Clinical Laboratory Tests 
Laboratory Tests 
Parameters 
Hematology 
Red blood cell count, Hb, hematocrit, platelet count, white blood cell 
count, differential white blood cell count (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils) 
Chemistry 
Total protein, albumin, ALP, ALT, AST, TBL, BUN, calcium, 
chloride, CK, serum creatinine, lipase, LDH, magnesium, potassium, 
sodium, FSH (if indicated), estradiol (if indicated), T3[FT3]a, TSHa, 
T4[FT4]a, triglycerides, serum amylase 
Coagulation  
PT-INR, and aPTT 
Urinalysis 
Protein, glucose, blood, microscopy assessments (if indicated), and 
specific gravity 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = 
blood urea nitrogen; LDH = lactate dehydrogenase; FSH = follicle-stimulating hormone; PT-INR = 
prothrombin time–international normalized ratio; T3 = triiodothyronine; FT3 = free triiodothyronine; T4 = 
thyroxine; FT4 = free thyroxine; TBL = total bilirubin; TSH = thyroid stimulating hormone  
a Thyroid function tests (ie, T3[FT3], T4[FT4], and TSH) will be performed as described in the Schedule 
of Events (Table 6.1, Table 6.2, and Table 6.3). More frequent examinations may be performed at the 
discretion of the Investigator and if indicated. 
All clinical laboratory values must be assessed by the Investigator as to clinical 
significance and used to direct appropriate clinical management measures. All abnormal 
clinical laboratory values considered clinically significant by the Investigator should be 
recorded on the AE page of the eCRF. If the abnormal laboratory value constitutes an 
SAE, eCRF should be submitted and other relevant procedures must be followed (see 
Section 9.5). Abnormal clinical laboratory values (NCI-CTCAE Grade 3 or 4) occurring 
during the clinical study will be followed until repeat test results return to normal (or 
baseline), stabilize, or are no longer clinically significant. 
9.9. 
Vital Signs 
Vital sign measurements will include systolic and diastolic blood pressure and HR, 
respiratory rate, and body temperature. Additionally, pulse oximetry (SpO2) will be 
performed as outlined in the Schedule of Events (Table 6.1, Table 6.2, and Table 6.3). 
Blood pressure and HR will be measured in the resting state. 
This procedure should not be conducted during the supine position for ECG 
measurement. 
9.10. 
Electrocardiograms 
9.10.1. 
Safety ECGs 
The corrected QT intervals using Fridericia’s formula will be used for clinical 
assessments and should be calculated as follows:  


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QTcF = QT
√RR
3
 
Electrocardiograms will be performed in triplicate at baseline during Screening and 
evaluated by a central laboratory. Triplicate ECGs (approximately 1 minute apart) will be 
obtained after the subject has rested supine for at least 10 minutes. The mean QTcF of the 
triplicate set of ECGs will be used to determine eligibility. 
12-lead ECGs will be performed at specified time points as described in the Schedule of 
Events (Table 6.1, Table 6.2, and Table 6.3). At each time point, the subject will be 
resting in a supine position for at least 10 minutes prior and 5 minutes after the specified 
times. When vital sign assessments, Safety ECGs, Endpoint ECGs, and blood sampling 
coincide, procedures should be carried out in said order.  
Safety ECGs should be printed for each specified time point and evaluated by the 
Investigator on-site. Safety ECGs will also be submitted to the central laboratory. Other 
unscheduled ECGs may be performed as clinically indicated. 
Standard ECG parameters will be measured, including RR, PR, QT intervals, and QRS 
duration. Please refer to the Investigator Site Manual for additional information on the 
collection of ECGs. 
If a subject experiences QTc prolongation of Grade 4 (torsades de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of serious arrhythmia), then the subject should 
be discontinued from study treatment.  
9.11. 
Physical Examinations 
Physical examinations will include evaluation of the following body systems/organs: 
general appearance; dermatological; head and eyes; ears, nose, mouth, and throat; 
pulmonary; cardiovascular; abdominal; genitourinary (optional); lymphatic; 
musculoskeletal/extremities; and neurological. 
9.12. 
Other Examinations 
Left Ventricular Ejection Fraction (LVEF): 
 LVEF will be measured by either ECHO or MUGA, as described in the 
Schedule of Events (Table 6.1, Table 6.2, and Table 6.3). All ECHO/MUGA 
assessments must be evaluated by the Investigator or delegate. The same 
modality (ECHO or MUGA) should be used for the subject throughout the 
study. 
 Refer to Section 17.3 for NYHA Functional Capacity and Objective 
Assessment.  
Ophthalmologic Assessments: 
 Ophthalmologic assessments will include visual acuity testing, slit lamp 
examination, fundoscopy, and tonometry as described in the Schedule of 
Events (Table 6.1, Table 6.2, and Table 6.3). All ophthalmologic assessments 


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must be evaluated by the Investigator or delegate. More frequent examinations 
may be performed at the discretion of the Investigator and if indicated. A 30-
day follow-up assessment is required if an on treatment assessment was 
abnormal at the time of discontinuation of study therapy, to confirm 
reversibility of the abnormality. 
Pulmonary Assessments: 
 SpO2, will be performed as described in the Schedule of Events (Table 6.1, 
Table 6.2, and Table 6.3). Additional testing to investigate pulmonary 
disorders may be performed, eg, chest radiograph, functional/blood-gas 
examination, pulmonary function testing, or serological examinations, at the 
Investigator’s discretion as described in Table 5.1. An ILD Adjudication 
Committee (AC) will be set up for this study. Additional details regarding the 
ILD AC are available in Section 11.6.6. 
Neurologic Assessments: 
 In a subject who develops new or progressive neurologic symptoms, such as 
peripheral neuropathy NCI-CTCAE Grade 3 to 4, delay dose and subject 
should be monitor at least twice a week until resolved to NCI-CTCAE 
≤ Grade 1. Unscheduled imaging of the brain or spinal cord may also be 
conducted to evaluate subjects with neurologic symptoms. 
Thyroid Assessments: 
 Hypothyroidism has been associated with several TKIs (eg, sunitinib and 
sorafenib), with increases in thyroid stimulating hormone (TSH) reported.41 
Although an association with gefitinib has yet to be established, thyroid 
function tests (ie, T3[FT3], T4[FT4], and TSH) will be performed as 
described in the Schedule of Events (Table 6.1, Table 6.2, and Table 6.3). 
More frequent examinations may be performed at the discretion of the 
Investigator and if indicated. 


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10. 
OTHER ASSESSMENTS 
Not applicable. 


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11. 
STATISTICAL METHODS  
11.1. 
General Statistical Considerations 
Descriptive statistics will be provided for selected demographic, safety, PK, and 
biomarker data from both Dose Escalation and Dose Expansion by dose level within each 
part and visit as appropriate. Descriptive statistics for continuous data will include means, 
medians, standard deviations, and minimum and maximum , while categorical data will 
be summarized using frequency counts and percentages. Graphical summaries of the data 
may be presented. 
Assessments of change from baseline to post-treatment or the ratio of post-treatment to 
baseline will include only those subjects with both baseline and post-treatment 
measurements. The last non-missing value of a variable taken before the first dose of 
study drug will be used as the baseline value, unless otherwise specified. Time-matched 
baseline will be derived from Cycle 0, Day -1 measurements for all ECG.  
Safety analyses will be performed based on the safety analysis sets. Analysis of PK 
parameters will be based on the PK analysis sets, and biomarker analyses will be based 
on the PD biomarker analysis sets.  
Efficacy endpoints will be analyzed based on the Full Analysis Set (FAS). Data from 
Dose Escalation will be summarized by dose level within each part and overall. 
A detailed statistical analysis plan (SAP) describing the methodology to be used in the 
final analysis will be prepared and finalized before database lock. Statistical methods 
described within may be changed based on advances in research. 
11.2. 
Analysis Sets 
 Enrolled Analysis Set will include all subjects who sign the ICF of the study. 
 FAS will include all subjects in the Enrolled Analysis Set who received at 
least one dose of DS-1205c and who had baseline and post-treatment 
evaluable tumor assessments. 
 DLT-Evaluable Set will include subjects enrolled in Dose Escalation who had 
at least one DLT during the 7 days of Cycle 0 or the 21 days of Cycle 1, or did 
not have a DLT but received at least 75% of the doses in the 21 days of Cycle 
1. 
 Safety Analysis Set will include all subjects in the Enrolled Analysis Set, who 
received at least one dose of DS-1205c. Four groups of subjects will be 
identified within the Safety Analysis Set: (1) subjects in Dose Escalation, (2) 
subjects in Dose Expansion, (3) subjects treated at the dose level of RDE, and 
(4) all treated subjects in the study. 
 PK Analysis Set will include all subjects in the Enrolled Analysis Set who 
received any amount of the study drugs and have sufficient plasma 
concentration data to characterize PK of DS-1205a or gefitinib.  


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 Concentration-QTc Analysis Set will include all subjects who are in the Safety 
Analysis Set with at least one pair of postdose plasma concentration data and 
QTc data from the same timepoint. The concentration-QTc Analysis Set will 
be used for the concentration-QTc analysis. 
 Biomarker Analysis Set will include all subjects in the Enrolled Analysis Set 
who received any amount of study drugs and who had the baseline tissue 
biopsy assessment and, where applicable, at least 1 post-treatment blood 
sample assessment for biomarkers. 
11.3. 
Study Population Data 
Disposition and reasons for ending the treatment and discontinuing from the study will be 
summarized and listed for subjects in the Enrolled Analysis Set. 
Demographic and baseline characteristics such as age, sex, race, histology, cancer status 
(metastatic and/or unresectable), molecular mutations (if available), prior treatment 
regimen(s), best response to prior anticancer treatment(s), will be summarized for the 
Enrolled Analysis Set, FAS, and Safety Analysis Set. If 2 analysis sets within a part of 
the study are identical to each other, the table will be presented only once. 
Study drug exposure, treatment duration, and compliance with study therapy will be 
summarized using descriptive statistics for the Safety Analysis Set. 
11.4. 
Efficacy Analyses 
Final data analysis for the clinical study report will occur at the end of the study when all 
subjects have either completed the End-of-Study Follow-up or discontinued from the 
study or have received at least 6 months of therapy. 
Efficacy endpoints will include ORR (the number of subjects with best objective 
response [CR or PR], divided by the number of subjects in the analysis population), 
DOR, DCR (the sum of CR rate, PR rate, and SD rate), TTR, PFS, and OS. CR includes 
both confirmed CR and unconfirmed CR. Tumor responses will be assessed by an 
Investigator according to RECIST version 1.1 (Section 17.2). 
The efficacy endpoints will be listed and summarized using descriptive statistics based on 
the FAS by dose level within each part and overall.  Study data will be analyzed and 
reported based on all subjects’ data from Dose Escalation and Dose Expansion up until 
the time when all subjects have potentially completed at least 6 cycles of treatment. 
Analyses will be performed for each dose level. 
The ORR will be based on Investigator’s assessments. The analysis will be based on 
subjects dosed at the level of RDE at both the dose escalation part and the dose expansion 
part. Subjects with unknown or missing response will be treated as non-responders. Point 
estimates and 2-sided 95% exact binomial confidence intervals (CIs) will be provided  
DOR (the time from documentation of tumor response [either CR or PR] to disease 
progression) will be based on Investigator’s assessments. The DOR will be summarized 
with median event times with 2-sided 95% CI using the Kaplan-Meier method.  


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DCR will be reported as a summary statistic by dose cohort. Point estimates and 2-sided 
95% exact binomial CIs will be provided. 
Time-to-event variables including PFS, TTR, and OS will be summarized with median 
event times with 2-sided 95% CI using the Kaplan-Meier method. PFS is defined as the 
time from the date of the first dose to the earlier of the dates of the first objective 
documentation of radiographic PD or death due to any cause. Censoring rules for the time 
to event endpoints such as PFS analysis will be specified in the SAP.  
Descriptive statistics for the best percentage change from baseline in the sum diameters 
of measurable tumors will be provided. A waterfall plot of the best percentage change in 
the sum of  diameter for each subject will be presented. In addition, sensitivity analyses 
will be performed to include confirmed CR only. 
11.5. 
Pharmacokinetic Analyses  
PK parameters for each subject will be estimated using non-compartmental analysis 
(NCA). Descriptive statistics will be provided for all plasma concentration data by 
analyte/dose/study day/time and for each PK parameter by analyte/dose/study day, as 
appropriate. 
11.6. 
Safety Analyses 
Safety endpoints will include AEs, clinical laboratory measurements, vital sign 
measurements, ECG recordings, physical examination findings, ECHO/MUGA findings, 
and ophthalmologic findings. AEs and abnormal laboratory values will be graded 
according to the NCI-CTCAE version 5.0.  
Safety analyses in general will be descriptive and will be presented in tabular format with 
the appropriate summary statistics. In Dose Escalation, the number of DLTs identified 
among the DLT-evaluable subjects in the DLT-evaluable set will be listed and 
summarized by dose level.  
11.6.1. 
Adverse Event Analyses 
A TEAE is defined as an AE that emerges during the treatment period (from first 
DS-1205c/gefitinib dose date until follow-up call [Section 6.1.3.9 or Section 6.2.2.10] 
after the last dose of study medication), having been absent at pre-treatment; or 
reemerges during treatment, having been present at baseline, but stopped prior to 
treatment; or worsens in severity after starting treatment relative to the pre-treatment 
state, when the AE is continuous. 
The number and percentage of subjects reporting TEAEs will be tabulated by the worst 
NCI-CTCAE Grade, System Organ Class (SOC), and Preferred Term (PT). 
Similarly, the number and percentage of subjects reporting treatment-emergent SAEs will 
be tabulated, as well as TEAEs/SAEs considered related to DS-1205c or gefitinib.  
A by-subject AE (including TEAE) data listing will be provided including, but not 
limited to, verbatim term, PT, SOC, NCI-CTCAE Grade, and relationship to study 
medications. 


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Deaths, other SAEs, and other significant AEs, including those leading to permanent 
discontinuation from study treatment, will be listed.  
AESIs will be added as needed. The details will be described in the SAP.  
11.6.2. 
Electrocardiogram Analyses 
Electrocardiogram parameters (PR, RR, QRS, QT, and QTcF) will be summarized using 
descriptive statistics for actual values and for changes from baseline by scheduled time of 
evaluation, including the EOT visit and the maximum post-treatment value. The corrected 
QT intervals using Fridericia’s formula will be calculated as follows: QTcF  QT/(RR)1/3. 
The incidence of notable ECG changes in maximum absolute QT and QTcF intervals 
over all post-treatment evaluations, as well as in QT and QTcF maximum changes from 
baseline over all post-treatment evaluations will be summarized. A listing of ECG data 
will be provided. 
The Concentration-QTc analysis plan will be presented in a separate document. 
11.6.3. 
Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory results (hematology, 
blood chemistry, coagulation, and urinalysis) by scheduled time of evaluation and by 
treatment group using the Safety Analysis Set, as well as for the change from baseline. 
The baseline value is defined as the last non-missing value before the initial 
administration of study treatment. In addition, mean change from baseline will be 
presented by treatment group for the maximum and minimum post-treatment values and 
the values at the EOT visit. 
Abnormal clinical laboratory results will be graded according to NCI-CTCAE v5.0, if 
applicable, and the Grade will be presented in a by-subject data listing. A shift table, 
presenting by treatment group the two-way frequency tabulation for baseline and the 
worst post-treatment value according to the NCI-CTCAE Grade will be provided for 
clinical laboratory tests. Abnormal clinical laboratory test results deemed of clinical 
significance or of Grade 3 or 4 will be listed.  
11.6.4. 
Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements and changes from 
baseline by scheduled time of evaluation and using the Safety Evaluation Set, as well as 
for the change from baseline. The baseline value is defined as the last non-missing value 
before the initial administration of study treatment. 
11.6.5. 
Physical Examination Analyses 
A listing of physical examination findings will be provided for the Safety Analysis Set. 
11.6.6. 
Interstitial Lung Disease Analysis and Adjudication 
An external ILD AC will be established for this study. Details on the membership, 
responsibilities, and working procedures of the external ILD AC will be described in its 


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own charter, provided as a separate document in the study file. To ensure adequate and 
relevant independent evaluation, systematic additional data collection will be conducted 
for all cases that will be brought for ILD adjudication, these additional data collections 
will cover a more in-depth medical history (eg smoking, radiation, COPD and other 
chronic lung conditions, etc), diagnostic evaluation, treatment and outcome of the event. 
The data collection will be triggered for any safety event reported using a Medical 
Dictionary for Regulatory Activities (MedDRA) PT from the current ILD standardized 
MedDRA query (SMQ) 
The ILD AC will adjudicate ILD cases (including potential ILD) on an ongoing basis.  
Adjudication of ILD cases will be based on evaluation of eCRFs and source documents 
including but not limited to chest high-resolution CT, arterial blood gases, and diffusing 
capacity of lung carbon monoxide (DLCO).  The ILD AC will review ongoing cases of 
ILD to make the final determination of ILD diagnoses to guide Sponsor decisions 
regarding trial suspension or trial discontinuation and to provide assessment of ILD 
prevalence at the end of study. Findings of the ILD AC with its recommendations will be 
provided to the Sponsor. 
11.7. 
Interim Analyses 
No formal interim analysis is planned, except for the assessment of the RDE. 
11.8. 
Data Monitoring Committee 
Not applicable. 
11.9. 
Sample Size Determination 
Phase 1 dose escalation : ≥ 18 subjects 
The Dose Escalation part of this study consists of mCRM with EWOC design with at 
least 3 DLT-evaluable subjects per dose level.  At least 18 DLT-evaluable subjects are 
needed to reach an accurate estimate of the maximum tolerated dose (MTD).  There will 
be at least 18 DLT-evaluable subjects treated to reach an accurate estimate of the RDE in 
Dose Escalation, with at least 6 subjects treated at the final selected dose. 
11.10. 
Statistical Analysis Process 
The clinical study will be analyzed by the Sponsor. 
CCI


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The SAP will provide the statistical methods and definitions for the analysis of the 
efficacy and safety data, as well as describe the approaches to be taken for summarizing 
other clinical study information such as subject disposition, demographic and baseline 
characteristics, study drug exposure, and prior and concomitant medications. The SAP 
will also include a description of how missing, unused, and spurious data will be 
addressed. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP 
will be finalized prior to database lock. 
All statistical analyses will be performed using SAS® Version 9.2 or higher (SAS 
Institute, Cary, North Carolina 27513). 
11.11. 
Specification of Modified Continuous Reassessment Method 
with Escalation With Overdose Control 
In this study mCRM will be based on a 2-parameter BLRM, as defined below. 
11.11.1. 
Bayesian Logistic Regression Model for Modified Continuous 
Reassessment Method 
The dose-toxicity relationship for mCRM with EWOC principle will be described by a 
2-parameter BLRM: 
logit(π(d))  log(α) + β log(d/d*),  
α > 0, β > 0 
where logit(π(d))  ln((d)/(1-[d]), and π(d) is the probability of a DLT or DLT rate at 
dose d. Doses are rescaled as d/d* with the reference dose d*  800 mg. As a 
consequence, α is equal to the odds of toxicity at d*. Note that for a dose equal to zero, 
the probability of toxicity is zero. 
11.11.2. 
Prior Specification for Bayesian Logistic Regression Model Parameters 
The Bayesian approach requires the specification of a prior distribution for the BLRM 
parameters. A minimally-informative bivariate normal prior for the model parameters 
(log(α),log(β)) is obtained as follows: 
 The best guess of the MTD is projected to be around 800 mg in humans. The 
median prior probabilities of DLT are set to be approximately 8% and 24.5% 
at 200 mg (projected starting dose for dose escalation using mCRM) and the 
projected MTD of 800 mg, respectively.  
 For the remaining doses, the prior medians of probability of DLT are assumed 
linear in log-dose on the logit-scale.  
 Based on the above medians for the probability of DLT at each dose and wide 
prior credible intervals (obtained from minimally informative Beta 
distributions), the optimal parameters of the bivariate normal distribution can 
be obtained as follows:  


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Parameters 
Means 
Standard Deviations 
Correlation 
log(α), log(β) 
(−1.1493, −0.5514) 
(2.0739, 1.5228) 
−0.1943 
11.11.3. 
Escalation With Overdose Control Principle 
Dose recommendation for the next cohort of patients will be based on summaries of the 
posterior probability of DLT rate for provisional doses.44 After each cohort of subjects 
completes DLT evaluation during Cycle 1, the joint posterior distribution of the BLRM 
parameters will be generated according to the Bayes' theorem based on the likelihood 
function of the accumulated DLT data from Cycle 1 and the prior distribution. Posterior 
probabilities of DLT rate at different dose levels will then be obtained from updated 
BLRM, and summarized for DTL rate in 4 different ranges: under-dosing (ie, DLT rate 
within [0, 0.16]), target toxicity (ie, DLT rate within [0.16, 0.33]), excessive toxicity (ie, 
DLT rate within [0.33, 0.60]), and unacceptable toxicity (ie, DLT rate within [0.60, 
1.00]). The dose level recommended by mCRM for dosing next cohort will be based on 
these probabilities according to the EWOC principle. The EWOC principle requires that 
the mCRM recommended dose for the next cohort of subjects is the one with the highest 
posterior probability of the DLT rate in the target DLT rate range of [0.16, 0.33] among 
all doses fulfilling the overdose control constraint that there is less than 0.25 of 
probability for DLT rate > 0.33 (probability for excessive or unacceptable toxicity). 


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/study site will permit study-related monitoring, audits, IRB/IEC review, 
and regulatory inspections by providing direct access to source data/documents. Direct 
access includes permission to examine, analyze, verify, and reproduce any records and 
reports that are important to the evaluation of a clinical study. 
12.1. 
Monitoring and Inspections 
The Sponsor, CRO monitor, and regulatory authority inspectors are responsible for 
contacting and visiting the Investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the study (eg, eCRFs, source data, and 
other pertinent documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of 
the data; and adherence to ICH Good Clinical Practice (GCP) and local regulations on the 
conduct of clinical research will be accomplished through a combination of onsite visits 
by the monitor and review of study data remotely. The frequency of the monitoring visit 
will vary based on the activity at each site. The monitor is responsible for inspecting the 
eCRFs and ensuring completeness of the study essential documents. The monitor should 
have access to subject medical records and other study-related records needed to verify 
the entries on the eCRFs. Detailed information is provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, SOPs, GCP, and applicable 
regulations to the Investigator and will ensure that appropriate action(s) designed to 
prevent recurrence of the detected deviations is taken and documented. 
The Investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are addressed to the satisfaction of the 
Sponsor and documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study site may be 
selected for audit by representatives from the Sponsor. Audit of site facilities (eg, 
pharmacy, drug storage areas, laboratories) and review of study related records will occur 
in order to evaluate the study conduct and compliance with the protocol, ICH GCP, and 
applicable regulatory requirements. The Investigator should respond to audit findings. In 
the event that a regulatory authority informs the Investigator that it intends to conduct an 
inspection, the Sponsor shall be notified immediately. 
12.2. 
Data Collection 
An eCRF must be completed for each subject who signs an ICF and undergoes any 
screening procedure. If a subject is not treated, the reason must be recorded on the eCRF.  
All data collected during the study will be recorded in this individual, subject-specific 
eCRF. Instructions will be provided for the completion of the eCRF and any corrections 
made will be automatically documented via an EDC “audit trail.”  
The eCRF completion should be kept current to enable the study monitor to review the 
subject’s status throughout the course of the study. eCRFs will be completed, reviewed 


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and signed off or e-signed by the Investigator as described in the Data Management Plan 
and in the monitoring plan for Clinical Research Associates. 
Upon completion of the subject’s eCRF, it will be reviewed and signed off by the 
Investigator via the EDC system’s electronic signature. This signature will indicate that 
the Investigator inspected or reviewed the data in the eCRF, the data queries, and the site 
notifications and agrees with the eCRF content.  
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
12.3. 
Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by 
the Sponsor.  
To ensure the quality of clinical data across all subjects and study centers, a Clinical Data 
Management review will be performed on subject data. Data will be vetted both 
electronically and manually for eCRFs and the data will be electronically vetted by 
programmed data rules within the application. Queries generated by rules and raised by 
reviewers will be generated within the EDC application. During this review, subject data 
will be checked for consistency, completeness and any apparent discrepancies. 
Data received from external sources such as central laboratories will be reconciled to the 
clinical database.  
SAEs in the clinical database will be reconciled with the safety database.  
All AEs will be coded using the latest version of the MedDRA. 
All concomitant medications and prior cancer therapies will be coded using the latest 
version of the World Health Organization Drug Dictionary (WHODRUG).  
12.4. 
Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to 
whom he/she has delegated study duties. All persons authorized to make entries and/or 
corrections on eCRFs will be included on the Signature List. 
Investigators will maintain a confidential screening log of all potential study candidates 
that includes limited information of the subjects, date, and outcome of screening process. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in 
the study indicating their assigned study number. 
Investigators will maintain a confidential SID number list. This confidential list of names 
of all subjects allocated to study numbers on enrolling in the study allows the Investigator 
to reveal the identity of any subject when necessary. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system (Trial Master File) of all study-related (essential) 
documentation, suitable for inspection at any time by representatives from the Sponsor 
and/or applicable regulatory authorities. Essential documents include: 


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 Subject files containing completed eCRFs, informed consents, and supporting 
copies of source documentation (if kept) 
 Study files containing the protocol with all amendments, IB, copies of relevant 
essential documents required prior to commencing a clinical study, and all 
correspondence to and from the IRB/IEC and Sponsor 
 Records related to the study drug(s) including acknowledgment of receipt at 
site, accountability records and final reconciliation and applicable 
correspondence 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. Source documents are original documents, data, and 
records from which the subject’s eCRF data are obtained. These include but are not 
limited to hospital records, clinical and office charts, laboratory and pharmacy records, 
diaries, microfiches, X-rays, and correspondence. 
12.5. 
Record Keeping 
Records of subjects, source documents, data correction forms, eCRFs, inventory of study 
product, regulatory documents (eg, protocol and amendments, IRB/IEC correspondence 
and approvals, approved and signed ICFs, Investigator’s Agreement, clinical supplies 
receipts, distribution and return records), and other Sponsor correspondence pertaining to 
the study must be kept in appropriate study files at the site. Source documents include all 
recordings and observations or notations of clinical activities and all reports and records 
necessary for the evaluation and reconstruction of the clinical study. These records will 
be retained in a secure file for the period required by the institution or site policy. Prior to 
transfer or destruction of these records, the Sponsor must be notified in writing and be 
given the opportunity to further store such records. 
All study related essential documentation will be retained by the Investigator until at least 
3 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 3 
years have lapsed since the formal discontinuation of clinical development of the study 
drug.  These documents should be retained for a longer period, however, if required by 
the applicable regulatory requirements or by an agreement with the Sponsor.  It is the 
responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. 
Subject’s medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or 
private practice. 
No study document should be destroyed without prior written agreement between 
Sponsor and the Investigator.  Should the Investigator wish to assign the study records to 
another party or move them to another location, he/she must notify Sponsor in writing of 
the new responsible person and/or the new location. 


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13. 
FINANCING AND INSURANCE 
13.1. 
Finances 
Prior to starting the study, the Principal Investigator and/or institution will sign a clinical 
study agreement with Sponsor or a CRO. This agreement will include the financial 
information agreed upon by the parties. 
13.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in 
case of study-related injury. 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on 
terms agreed upon by the parties. 


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14. 
PUBLICATION POLICY 
Sponsor is committed to meeting the highest standards of publication and public 
disclosure of information arising from clinical trials sponsored by the company.  Sponsor  
will comply with US, EU, and Japanese policies for public disclosure of the clinical trial 
protocol and clinical trial results, and for sharing of clinical trial data.  Sponsor follows 
the principles set forward in “Good Publication Practice for Communicating Company-
Sponsored Medical Research (GPP3)”, and publications will adhere to the 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly 
Work in Medical Journals” established by the International Council of Medical Journal 
Editors (ICMJE).   
In order to ensure that Sponsor is in compliance with the public disclosure policies and 
the ICMJE recommendations, and to protect proprietary information generated during the 
study, all publications (manuscripts, abstracts, or other public disclosure) based on data 
generated in this study must be accepted, reviewed, and approved in writing by the 
Sponsor prior to submission. 
 


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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Compliance Statement, Ethics and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that 
have their origin in the Declaration of Helsinki, ICH consolidated Guideline E6 for GCP 
(CPMP/ICH/135/95), and applicable regulatory requirement(s), including the following: 
 US Food and Drug Administration (FDA) GCP Regulations: Code of Federal 
Regulations Title 21, parts 11, 50, 54, 56, and 312 as appropriate 
 Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 of 27 
March, 1997. 
 Other applicable local regulations 
15.2. 
Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking 
part in the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the subject’s anonymity is maintained. On the eCRFs 
or other documents submitted to the Sponsor or the CRO, subjects should be identified by 
a unique subject identifier as designated by the Sponsor. Documents that are not for 
submission to the Sponsor or the CRO (eg, signed ICF) should be kept in strict 
confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and 
institution permit authorized representatives of the company, of the regulatory agency(s), 
and the IRB/IEC direct access to review the subject’s original medical records for 
verification of study-related procedures and data. The Investigator is obligated to inform 
the subject that his/her study-related records will be reviewed by the above named 
representatives without violating the confidentiality of the subject. 
15.3. 
Informed Consent  
Before a subject’s participation in the study, it is the Investigator’s responsibility to 
obtain freely given consent, in writing, from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific procedures or any study drugs are administered. Subjects should be 
given the opportunity to ask questions and receive satisfactory answers to their inquiries, 
and should have adequate time to decide whether or not to participate in the study. The 
written ICF should be prepared in the local language(s) of the potential subject 
population. 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki. The consent form and any 
revision(s) should be approved by the IRB/IEC prior to being provided to potential 
subjects. 


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The subject’s written informed consent should be documented in the subject’s medical 
records. The ICF should be signed and personally dated by the subject and by the person 
who conducted the informed consent discussion (not necessarily the Investigator). The 
original signed ICF should be retained in accordance with institutional policy, and a copy 
of the signed consent form should be provided to the subject. The date and time (if 
applicable) that informed consent was given should be recorded on the eCRF. 
If the subject cannot read, then according to ICH GCP Guideline, Section 4.8.9, an 
impartial witness should be present during the entire informed consent discussion. This 
witness should sign the ICF after the subject has consented to the subject’s participation 
and, if possible, signed the ICF. By signing the ICF, the witness attests that the 
information in the ICF and any other written information was adequately explained to and 
apparently understood by the subject and that informed consent was freely given by the 
subject. 
The consent for screening tumor tissue collection (archival or fresh tumor biopsy) should 
be documented in the tissue consent form.  
Consent for PGx sampling for banking, the on-study biopsy, and the post-treatment tumor 
biopsy should be documented in the main study consent form. Participation for PGx 
sampling for banking, the on-study biopsy, and the post-treatment tumor biopsy are each 
optional for all subjects. Those subjects who choose not to provide a sample for PGx 
sampling for banking or not to provide the post-treatment tumor biopsy may still 
participate in the main portion of the study. 
For studies in the US, an additional consent will be required for the Health Insurance 
Portability and Accountability Act. Subjects are free to withdraw from the study at any 
time, without prejudice to further treatment. 
15.4. 
Regulatory Compliance 
The study protocol, subject information and consent form, the IB, any subject written 
instructions to be given to the subject, available safety information, subject recruitment 
procedures (eg, advertisements), information about payments and compensation available 
to the subjects, and documentation evidencing the Investigator’s qualifications should be 
submitted to the IRB/IEC for ethical review and approval according to local regulations, 
prior to the study initiation. The written approval should identify all documents reviewed 
by name and version. 
The Investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the ICF. The Investigator should 
notify the IRB/IEC of deviations from the protocol or SAEs occurring at the study site 
and other AE reports received from the Sponsor/CRO, in accordance with local 
procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group or 
representative to whom this responsibility has been delegated will ensure all legal aspects 
are covered, and approval from the appropriate regulatory bodies obtained, prior to study 
initiation. If changes to the initial protocol and other relevant study documents are made, 


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this representative will also ensure that any revised documents required for submission 
are submitted to regulatory authorities and implementation of these changes happen only 
after approval by the relevant regulatory bodies, as required. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
regulatory authority(-ies) in any area of the world, or if the Investigator is aware of any 
new information which might influence the evaluation of the benefits and risks of the 
investigational drug, the Sponsor should be informed immediately.  
In addition, the Investigator will inform the Sponsor immediately of any urgent safety 
measures taken by the Investigator to protect the study subjects against any immediate 
hazard, and of any suspected/actual serious GCP non-compliance that the Investigator 
becomes aware of. 
15.5. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by 
Sponsor and, if required, by the regulatory authority(-ies), and which was given 
approval/favorable opinion by the IRBs/IECs. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed 
in this study except where necessary to eliminate immediate hazard(s) to the subject. 
Sponsor must be notified of all intended or unintended deviations to the protocol (eg, 
inclusion/exclusion criteria, dosing, missed study visits) on an expedited basis. 
The Investigator, or person designated by the Investigator, should document and explain 
any deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or study treatment, and had at 
least 1 administration of study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the IRB/IEC of deviations from the protocol 
in accordance with local procedures. 
15.6. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects 
or the conduct of the study, the Sponsor will inform all Investigators involved in the 
clinical study, IRBs/IECs, and regulatory authorities of such information, and when 
needed, will amend the protocol and/or subject information. 
The Investigator should immediately inform the subject whenever new information 
becomes available that may be relevant to the subject’s consent or may influence the 
subject’s willingness to continue participation in the study. The communication should be 
documented on medical records, and it should be confirmed whether the subject is willing 
to remain in the study.  
If the subject information is revised, it must be re-approved by the IRB/IEC. The 
Investigator should obtain written informed consent to continue participation with the 
revised written information even if subjects were already informed of the relevant 


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information. The Investigator or other responsible personnel who provided explanations 
and the subject should sign and date the revised ICF. 
15.7. 
Protocol Amendments 
Any amendments to the study protocol that are deemed necessary as the study progresses 
will be communicated to the Investigator by the Sponsor or the CRO. All protocol 
amendments will undergo the same review and approval process as the original protocol. 
A protocol amendment may be implemented after it has been approved by the IRB/IEC, 
unless immediate implementation of the change is necessary for subject safety. The 
Sponsor will assure the timely submission of amendments to regulatory authorities in 
accordance with the governing regulations.  
Changes made by protocol amendments will be documented in a Summary of Changes 
document. 
15.8. 
Study Termination 
The Sponsor has the right to terminate the study at any time and study termination may 
also be requested by (a) competent authority(-ies). 
15.9. 
Data and Safety Monitoring Board 
Not applicable. 
15.10. 
Address List 
A list of key study personnel (including personnel at the sponsor, CRO, laboratories, and 
other vendors) and their contact information (address, telephone, fax, email) will be kept 
on file and regularly updated as necessary. 
15.10.1. 
Sponsor 
Japan 
Daiichi Sankyo Company, Limited  
3-5-1, Nihonbashi-honcho, Chuo-ku, Tokyo 103-8426, Japan  


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16. 
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4. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in 
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6. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy 
as first-line treatment for European patients with advanced EGFR mutation-
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7. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line 
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8. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin 
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9. Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-
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harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 
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in patients with non-small-cell lung cancer harbouring mutations of the epidermal 
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11. Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated 
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13. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas 
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14. Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to 
tyrosine kinase inhibitors in lung cancer. J Clin Oncol. 2013;31(31):3987-96. 
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carboplatin plus paclitaxel (NEJ002). Jpn J Clin Oncol. 2015;45(7):670-6. 
16. Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-
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17. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in 
Oncology (NCCN Guidelines): Non-Small Cell Lung Cancer 2018 [Internet]. 
2018. Available from: nccn.org. 
18. Piotrowska Z, Sequist LV. Treatment of EGFR-Mutant Lung Cancers After 
Progression in Patients Receiving First-Line EGFR Tyrosine Kinase Inhibitors : A 
Review. JAMA Oncol. 2016;2(7):948-54. 
19. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with 
advanced, metastatic non-small-cell lung cancer after failure of erlotinib, 
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2b/3 randomised trial. Lancet Oncol. 2012;13(5):528-38. 
20. Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in 
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21. Janjigian YY, Smit EF, Groen HJ, et al. Dual inhibition of EGFR with afatinib 
and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and 
without T790M mutations. Cancer Discov. 2014;4(9):1036-45. 
22. Chaft JE, Oxnard GR, Sima CS, et al. Disease flare after tyrosine kinase inhibitor 
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23. Mok TS, Kim SW, Wu YL, et al. Gefitinib Plus Chemotherapy Versus 
Chemotherapy in Epidermal Growth Factor Receptor Mutation Positive Non
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24. Yap TA, Macklin-Doherty A, Popat S. Continuing EGFR inhibition beyond 
progression in advanced non-small cell lung cancer. Eur J Cancer. 2017;70:12-21. 
25. Lee CK, Man J, Lord S, et al. Checkpoint Inhibitors in Metastatic EGFR-Mutated 
Non-Small Cell Lung Cancer-A Meta-Analysis. J Thorac Oncol. 2017;12(2):403-
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26. Oser MG, Niederst MJ, Sequist LV, et al. Transformation from non-small-cell 
lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet 
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27. Ji W, Choi CM, Rho JK, et al. Mechanisms of acquired resistance to EGFR-
tyrosine kinase inhibitor in Korean patients with lung cancer. BMC Cancer. 
2013;13:606. 
28. Zhang Z, Lee JC, Lin L, et al. Activation of the AXL kinase causes resistance to 
EGFR-targeted therapy in lung cancer. Nat Genet. 2012;44(8):852-60. 
29. Park IK, Giovenzana C, Hughes TL, et al. The Axl/Gas6 pathway is required for 
optimal cytokine signaling during human natural killer cell development. Blood. 
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30. Verma A, Warner SL, Vankayalapati H, et al. Targeting Axl and Mer kinases in 
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31. Wu X, Liu X, Koul S, et al. AXL kinase as a novel target for cancer therapy. 
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32. D'Arcangelo D, Gaetano C, Capogrossi MC. Acidification prevents endothelial 
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33. U.S. Food and Drug Administration: FDA Approved Drug Products on NDA 
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34. U.S. Food and Drug Administration: FDA Approved Drug Products on NDA 
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PharmR.pdf 
35. Liu Y, Ramirez J, House L, et al. Comparison of the drug-drug interactions 
potential of erlotinib and gefitinib via inhibition of UDP-glucuronosyltransferases. 
Drug Metab Dispos. 2010;38(1):32-9. 
36. Jackman D, Pao W, Riely GJ, et al. Clinical definition of acquired resistance to 
epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung 
cancer. J Clin Oncol. 2010;28(2):357-60. 
37. Dickinson PA, Cantarini MV, Collier J, et al. Metabolic Disposition of 
Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind 
Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor. Drug 
Metab Dispos. 2016;44(8):1201-12. 
38. Tornøe CW, Garnett CE, Wang Y, et al. Creation of a knowledge management 
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39. Cleveland WS. Robust Locally Weighted Regression and Smoothing Scatterplots. 
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41. Ahmadieh H, Salti I. Tyrosine kinase inhibitors induced thyroid dysfunction: a 
review of its incidence, pathophysiology, clinical relevance, and treatment. 
Biomed Res Int. 2013;2013:725410. 
42. Cho BC, Im CK, Park MS, et al. Phase II study of Erlotinib in advanced non
small-cell lung cancer after failure of Gefitinib. J Clin Oncol. 2007;25(18):2528-
33. 
43. Asami K, Okuma T, Hirachima T, et al. Continued treatment with gefitinib 
beyond progressive disease benefits patients with activating EGFR mutations. 
Lung Cancer, 2013;79(3):276-82. 
44. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian 
approach to phase I cancer trials. Stat Med. 2008;27(13):2420-39. 
45. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron. 1976;16(1):31-41. 
46. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47. 
47. The Criteria Committee of the New York Heart Association. Nomenclature and 
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Little, Brown & Co; 1994. 
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E_v5_Quick_Reference_8.5x11.pdf  


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17. 
APPENDICES 
17.1. 
Cockcroft-Gault Equation 
The estimated creatinine clearance rate (CrCl; mL/min) will be calculated using the 
Cockcroft-Gault equation45 based on actual weight in kilograms (1 kilogram  2.2 
pounds): 
Conventional (serum creatinine in mg/dL): 
Male: 
CrCl (mL/min)  
72
 
 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
 
years)]
(in 
 
age
 - 
[140


 
Female: 
CrCl (mL/min)  
72
 
 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
 
years)]
(in 
 
age
 - 
[140


  0.85 
 
International System of Units (SI) (serum creatinine in μmol/L): 
Male: 
CrCl (mL/min)  
0.0113
 
 
72
 
 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
 
years)]
(in 
 
age
 - 
[140




 
 
Female: 
CrCl (mL/min)  
0.0113
 
 
72
 
 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
 
years)]
(in 
 
age
 - 
[140




  0.85 
 


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17.2. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
Assessment of tumor responses will be performed according to revised RECIST guidelines, 
Version 1.1.46 Some of these definitions and criteria are highlighted below. 
17.2.1. 
Measurability of Tumor at Baseline 
17.2.1.1. Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
17.2.1.1.1. Measurable 
 Tumor lesions: Must be accurately measured in at least 1 dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
 Measurable malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be  15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. See 
also notes below on “Baseline documentation of target and non-target lesions” for 
information on lymph node measurement. 
17.2.1.1.2. Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with  10 to < 15 mm short axis), as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
and abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
17.2.1.1.3. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment. 
17.2.1.1.3.1. Bone Lesions 
 Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 


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 Blastic bone lesions are non-measurable. 
17.2.1.1.3.2. Cystic Lesions 
 Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 “Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same subject, these are preferred 
for selection as target lesions. 
17.2.1.1.3.3. Lesions with Prior Local Treatment 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion.  
17.2.1.2. Specifications by Methods of Measurements 
17.2.1.2.1. Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
NEVER more than 22 days (Dose Escalation) or 30 days (Dose Expansion) before the first 
dose of study drug administration. 
17.2.1.2.2. Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be performed rather than clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (eg, for body scans).  
17.2.2. 
Tumor Response Evaluation 
17.2.2.1. Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements.  
Only subjects with measurable disease at baseline should be included in the study. 
17.2.2.2. Baseline Documentation of “Target” and “Non-target” Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (representative of all involved organs) should be identified as target lesions and 


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will be recorded and measured at baseline (this means in instances where subjects have only 
1 or 2 organ sites involved a maximum of 2 and 4 lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves 
to reproducible repeated measurements. It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumor. As noted above, pathological nodes 
which are defined as measurable and may be identified as target lesions must meet the 
criterion of a short axis of  15 mm by CT scan. Only the short axis of these nodes will 
contribute to the baseline sum. The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as 2 
dimensions in the plane in which the image is obtained (for CT scan this is almost always the 
axial plane; for MRI the plane of acquisition may be axial, sagittal, or coronal). The smaller 
of these measures is the short axis. For example, an abdominal node which is reported as 
being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable 
node. In this example, 20 mm should be recorded as the node measurement. All other 
pathological nodes (those with short axis  10 mm but < 15 mm) should be considered non-
target lesions. Nodes that have a short axis < 10 mm are considered non-pathological and 
should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. 
The baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression.” In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the case record form (eg, “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).  
17.2.2.3. Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
17.2.2.3.1. Evaluation of Target Lesions 
CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm. 
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
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 


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of at least 5 mm. (Note: the appearance of 1 or more new lesions is also considered 
progression). 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
17.2.2.3.2. Special Notes on the Assessment of Target Lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the “sum” of lesions may not be zero even if CR 
criteria are met, since a normal lymph node is defined as having a short axis of < 10 mm. For 
PR, SD, and PD, the actual short axis measurement of the nodes is to be included in the sum 
of target lesions. 
Target lesions that become “too small to measure”: While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measure and may report them as 
being “too small to measure.” When this occurs, it is important that a value be recorded on 
the eCRF. If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned (Note: It is less 
likely that this rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the retroperitoneum; however, if 
a lymph node is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned in this circumstance as well). This default value is derived 
from the 5 mm CT slice thickness (but should not be changed with varying CT slice 
thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon 
measurement error. To reiterate, however, if the radiologist is able to provide an actual 
measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the target 
lesion sum. Similarly, as lesions coalesce, a plane between them may be maintained that 
would aid in obtaining maximal diameter measurements of each individual lesion. If the 
lesions have truly coalesced such that they are no longer separable, the vector of the longest 
diameter in this instance should be the maximal longest diameter for the “coalesced lesion.” 
17.2.2.3.3. Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-target lesions. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the time 
points specified in the protocol.  
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All 
lymph nodes must be non-pathological in size (< 10 mm short axis). 


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Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
PD: Unequivocal progression (see comments below) of existing non-target lesions (Note: the 
appearance of 1 or more new lesions is also considered progression). 
17.2.2.3.4. Special Notes on Assessment of Progression of Non-target Disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the subject also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the 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 1 or more non-target lesions is usually not 
sufficient to quality for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare.  
When the subject has only non-measurable disease: The same general concepts apply here 
as noted above, however, in this instance there is no measurable disease assessment to factor 
into the interpretation of an increase in non-measurable disease burden. Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly non-
measurable) a useful test that can be applied when assessing subjects for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease (ie, an increase in tumor burden representing an additional 
73% increase in “volume” [which is equivalent to a 20% increase diameter in a measurable 
lesion]). If “unequivocal progression” is seen, the subject should be considered to have had 
overall PD at that point. While it would be ideal to have objective criteria to apply to non-
measurable disease, the very nature of that disease makes it impossible to do so: therefore, 
the increase must be substantial. 
17.2.2.3.5. New Lesions 
The appearance of new malignant lesions denotes disease progression. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new 
lesion should be unequivocal: ie, not attributable to differences in scanning technique, change 
in imaging modality or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions). This is particularly important when the subject’s baseline lesions show PR or CR. 
For example, necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic 
lesion, which it is not. 
A lesion identified on an F/U study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the 
subject who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The subject’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline.  
If a new lesion is equivocal, for example because of its small size, continued therapy and F/U 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan.  


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17.2.2.4. Evaluation of Best Overall Response 
17.2.2.4.1. Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs. 
Table 17.1 provides a summary of the overall response status calculation at each time point 
for subjects who have measurable disease at baseline.  
Table 17.1: 
Overall Response: Subjects with Target (±Non-target) Disease 
Time Point Response: Subjects with Target (±Non-target) Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response;  
SD = stable disease. 
17.2.2.4.2. Missing Assessments and Inevaluable Designation 
When no imaging/measurement is performed at all at a particular time point, the subject is 
not evaluable (NE) at that timepoint. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that timepoint, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response.  This would be most likely to happen in the case of 
PD.  For example, if a subject had a baseline sum of 50 mm with 3 measured lesions and at 
F/U only 2 lesions were assessed, but those gave a sum of 80 mm, the subject will have 
achieved PD status, regardless of the contribution of the missing lesion.  
17.2.2.4.3. Best Overall Response: All Time Points 
Best response determination in trials where confirmation of CR or PR is required: When SD 
is believed to be best response, it must also meet the protocol-specified minimum time from 
baseline, 6 weeks. If the minimum time is not met when SD is otherwise the best time point 
response, the subject’s best response depends on the subsequent assessments.  CR or PR may 
be claimed only if the criteria for each are met at a subsequent time point as specified in the 
protocol.  In this circumstance, the best overall response can be interpreted as in Table 17.2.   


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Table 17.2: 
Best Overall Response When Confirmation of CR and PR Is Required 
Overall Response, 
First Time Point 
Overall Response, 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria 
for SD duration met otherwise, 
PD 
CR 
PD 
SD provided minimum criteria 
for SD duration met otherwise, 
PD 
CR 
NE 
SD provided minimum criteria 
for SD duration met otherwise, 
NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria 
for SD duration met otherwise, 
PD 
PR 
NE 
SD provided minimum criteria 
for SD duration met otherwise, 
NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not 
evaluable. 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even 
disease meeting PR criteria relative to baseline, makes the disease PD at that point (since 
disease must have reappeared after CR). Best response would depend on whether minimum 
duration for SD (6 weeks) was met. However, sometimes ‘CR’ may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the subject had PR, 
not CR at the first time point. Under these circumstances, the original CR should be changed 
to PR and the best response is PR. 
17.2.2.4.4. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes.  As noted earlier, this means 
that subjects with CR may not have a total sum of “zero” on the eCRF. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 


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objective response: it is a reason for stopping study therapy.  The objective response status of 
such subjects is to be determined by evaluation of target and non-target disease. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
17.2.2.4.5. Frequency of Tumor Re-evaluation 
In this study, tumor measurement will be conducted every 6 weeks in the first 24 weeks after 
Day 1 of Cycle 1 and thereafter every 12 weeks while the subject remains on study until 
progression of disease, withdrawal of consent, death, or loss to F/U.  Scan dates should not be 
adjusted or rescheduled due to dose interruption of any type. 
Baseline tumor assessments must be performed within 22 days of the first dose of study drug 
administration. 
All efforts should be made to ensure consistency between the baseline measurements and all 
subsequent measurements in reference to utilization of scanning method, equipment, 
technique (including slice thickness and field of view), and radiographic interpreter. 
The radiographic evaluation must include CT or MRI scanning of the brain, chest, abdomen, 
and pelvis at screening period.  Any additional suspected sites of disease should also be 
imaged.  Every effort should be made to use the same assessment modality for all 
assessments for each subject.  However, if there is no brain metastasis at the time of 
screening, CT or MRI should only be done when symptoms associated with brain metastasis 
occur during study period.  If no clinical symptoms are observed, brain CT or MRI is not 
mandatory during study period.  All evaluations should meet the standard of care for imaging 
of lesions in the respective organ(s) and should conform to the image acquisition guidelines 
according to institutional standards. 
All target and non-target sites are evaluated at each time point of tumor assessment. 


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17.3. 
New York Heart Association Functional Capacity and Objective 
Assessment 
The ninth edition, revised by the Criteria Committee of the American Heart Association, New 
York City Affiliate, was released March 14, 1994. The new classifications are summarized 
below for the many physicians and scientists who use them to describe the status of 
individual patients. 
Table 17.3: 
New York Heart Association Functional Capacity and Objective 
Assessment47 
Functional Capacity  
Objective Assessment  
Class I. Patients with cardiac disease but without resulting limitation 
of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
A. No objective evidence 
of cardiovascular disease. 
Class II. Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
B. Objective evidence of 
minimal cardiovascular 
disease. 
Class III. Patients with cardiac disease resulting in marked limitation 
of physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
C. Objective evidence of 
moderately severe 
cardiovascular disease. 
Class IV. Patients with cardiac disease resulting in inability to carry 
on any physical activity without discomfort. Symptoms of heart 
failure or the anginal syndrome may be present even at rest. If any 
physical activity is undertaken, discomfort is increased. 
D. Objective evidence of 
severe cardiovascular 
disease. 
 


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17.4. 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status (PS)  
Table 17.4: 
Eastern Cooperative Oncology Group Performance Status Scale48 
Grade Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (eg, light housework, office 
work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5 
Dead. 


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17.5. 
National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.049 
1. Toxicity Grade should reflect the most severe degree occurring during the evaluated 
period, not an average. 
2. When 2 different criteria grades might be applicable for rating a particular toxicity, or 
similar toxicities, the more severe Grade should be used. 
3. Any toxicity resulting in death is defined as Grade 5. 
4. The evaluator must attempt to discriminate between disease/treatment and related 
signs/symptoms. 
5. The NCI-CTCAE v5.0 is accessible online at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v
5_Quick_Reference_8.5x11.pdf  
 


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17.6. 
QT-Prolonging Medications and CYP3A4 Inhibitors/Inducers 
Lists of medications that potentially prolong QT/QTc and medications and foods that are 
common inhibitors/inducers of CYP3A4 are provided as supplements.  Those lists should not 
be considered all inclusive. Consult individual drug labels for specific information on a 
compound’s propensity to prolong QT/QTc and/or inhibit/induce CYP3A4.