Clinical trial NCT03255083
Conditions: Non-small Cell Lung Cancer (NSCLC)
Keywords: Oncology Advanced Non-small Cell Lung Cancer Inoperable Non-small Cell Lung Cancer Metastatic Non-resectable Epidermal growth factor receptor EGFR
Sponsor: Daiichi Sankyo
Start date: 2019-04-10; Completion date: 2020-09-04
Enrollment: 13 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 osimertinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with osimertinib in the study population
* For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with osimertinib 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 until 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, 1200 mg) in combination with daily 80 mg oral dose of osimertinib
Interventions: intervention 1: DS-1205c intervention 2: Osimertinib
Intervention descriptions: intervention 1: DS-1205c 200 mg capsule intervention 2: Osimertinib 80 mg tablet

Protocol documents:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
Page 1 
CLINICAL STUDY PROTOCOL 
 
A MULTICENTER, OPEN-LABEL PHASE 1 STUDY OF 
DS-1205c IN COMBINATION WITH OSIMERTINIB IN 
SUBJECTS WITH METASTATIC OR UNRESECTABLE 
EGFR-MUTANT NON-SMALL CELL LUNG CANCER 
 
DS1205-A-U101 
 
 
VERSION 5.0, 05 MAR 2019 
VERSION 4.0, 22 MAY 2018 
VERSION 3.0, 06 SEP 2017 
VERSION 2.0, 03 MAY 2017 
VERSION 1.0, 22 MAR 2017 
 
DAIICHI SANKYO, INC. 
211 MT. AIRY ROAD 
BASKING RIDGE, NJ 07920-2311, UNITED STATES 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc. (DSI). 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 
DSI. 




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SUMMARY OF CHANGES 
Amendment Rationale: 
The main purposes of this amendment are to update study scope to Taiwan-only, to clarify study 
inclusion requirements surround previous cancer therapy, to update the screening period for 
Dose Escalation and the associated brain scans, and to clarify and correct other study procedures 
and assessments, including laboratory tests and PK sampling. 
Changes to the Protocol: 
Please refer to the comparison document for protocol Version 5.0 (dated 05 Mar 2019) vs. 
protocol Version 4.0 (dated 22 May 2018) for actual changes in-text.  The summary of changes 
below is a top-line summary and rationale of major changes in the DS1205-A-U101 clinical 
study protocol (Version 5.0) by section. 
DESCRIPTION OF EACH HIGH-LEVEL CHANGE 
1 
Rationale:  Updated number of study sites and location, and removed EudraCT and IND 
numbers 
The following sections have been updated: 
 Cover Page 
 Synopsis (EudraCT Number) 
 Synopsis (IND Number) 
 Synopsis (Study and Locations) 
 Section 3.1 (Overall Design Summary) 
2 
Rationale:  Updated title of Dose Escalation cohort dosing table and updated process for 
selecting cohort dose levels for Cycle 1 and beyond 
The following sections have been updated: 
 Protocol Synopsis (Study Design) 
 Table 3.1 (Dose Escalation Cohorts and Provisional Dosages) 
 Section 3.2.1.2 (Cycle 1 and Beyond [Combination Therapy]) 
3 
Rationale:  Updated inclusion criterion regarding existing EGFR TKIs 
The following sections have been updated: 
 Protocol Synopsis (Study Design) 
 Section 4.1 (Inclusion Criteria) 
4 
Rationale:  Updated contraception/pregnancy reporting requirements from 6 months to 
4 months 
The following sections have been updated: 
 Section 4.1 (Inclusion Criteria) 
 Section 9.7 (Exposure In Utero During Clinical Studies) 


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5 
Rationale:  Updated definition of stable disease 
The following sections have been updated: 
 Protocol Synopsis (Study Endpoints) 
 Section 2.3.1 (Dose Escalation) 
 Section 7.1.1 (Efficacy Endpoint[s]) 
 Section 11.4 (Efficacy Analyses) 
6 
Rationale:   Removed verbiage stating first-in-human designation for this study and 
added updated data for DS1205-A-J102 
The following sections have been updated: 
 Section 1.1.3 (Clinical Experience) 
 Section 1.4.1 (Potential Risks Associated with DS-1205c) 
 Section 1.4.3 (Potential Benefits Associated with DS-1205c) 
7 
Rationale:  Updated dose-limiting toxicities (DLT) definitions 
The following section has been updated: 
 Section 3.2.1.3 (Dose-Limiting Toxicities [DLT]) 
8 
Rationale:  Updated screening period for Dose Escalation, with adjustments in timing 
for CT and brain scans 
The following sections have been updated: 
 Section 3.3 3.3 (Duration of Subject Participation) 
 Section 6.1.1.2 (Screening [Dose Escalation]) 
 Table 6.1 (Schedule of Events, Dose Escalation [Cycle 0]) 
9 
Rationale:  Included activated partial thromboplastin time (aPTT) as part of coagulation 
panel and clarified required thyroid function tests 
The following sections have been updated: 
 Section 4.1 (Inclusion Criteria) 
 Table 9.1 (Clinical Laboratory Tests) 
10 
Rationale:  Updated labeling and packaging information 
The following section has been updated: 
 Section 5.2.2 (Labeling and Packaging) 
11 
Rationale:  Updated QTcF to read “mean QTcF” in Dose Interruption/Resumption 
table, and updated definition and action taken for AESI of QTc prolongation 
The following sections have been updated: 
 Table 5.1 (Dose Interruption and Dose Resumption Criteria) 
 Section 9.3.2 (Prolonged QTc Interval [≥Grade 2]) 
 Section 9.10.1 (Safety ECGs) 


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Rationale:  Clarified window for prior medication and updated conditions for 
hematopoietic growth factor use 
The following sections have been updated: 
 Section 5.5.1 (Prior Medication[s], Treatment[s], and Procedure[s]) 
 Section 5.5.2 (Concomitant Medication[s]) 
13 
Rationale:  Updated conditions for tumor tissue testing 
The following sections have been updated: 
 Section 6.1.1.1 (Tissue Requirement [Dose Escalation]) 
 Section 6.2.1.1 (Tissue Screening [Dose Expansion]) 
 Section 8.2.2.1.1 (Epidermal Growth Factor Receptor [EGFR] T790M) 
 Section 8.2.2.2 (Tumor Tissue Biomarker Analysis) 
14 
Rationale:  Updated blood sample size and number for exploratory biomarkers testing 
The following sections have been updated: 
 Section 6.1.2.1 (Cycle 0, Day 1 [Dose Escalation]) 
 Table 6.1 (Schedule of Events, Dose Escalation [Cycle 0]) 
 Table 6.2 (Schedule of Events, Dose Escalation [Cycle 1 and Beyond]) 
15 
Rationale:  Updated vital signs timing and tests being conducted at different visits 
The following sections have been updated: 
 Section 6.1.2 (Cycle 0 [Dose Escalation)]) 
 Section 6.1.3 (Cycle 1 and Beyond [Dose Escalation)]) 
 Table 6.1 (Schedule of Events, Dose Escalation [Cycle 0]) 
16 
Rationale:  Updated the time frame for determining stable disease best response 
The following section has been updated: 
 Section 17.2.2.4.3 (Best Overall Response:  All Time Points) 
17 
Rationale:  Corrected windows for tumor, ophthalmologic, and ECHO/MUGA 
assessments in the Schedule of Events tables and footnotes 
The following sections have been updated: 
 Table 6.2 (Schedule of Events, Dose Escalation [Cycle 1 and Beyond]) 
 Table 6.3 (Schedule of Events, Dose Expansion) 
18 
Rationale:  Updated conditions for biomarker testing and enrollment, and added new 
section for disclosure of biomarker results 
The following sections have been updated: 
 Section 8.2.3 (Additional Biomarker Assessments) 
 Section 8.2.4 (Disclosure of the Results of Biomarker Assessment) 
19 
Rationale:  Added reporting requirements for AESIs and clarified reporting 


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requirements for hepatic AESIs 
The following sections have been updated: 
 Section 9.3 (Adverse Events of Special Interest [AESI]) 
 Section 9.5 (Serious Adverse Events Reporting Procedure For Investigators) 
20 
Rationale:  Added definitions for study drug overdose and hepatic events (Hy’s Law) 
The following sections have been updated: 
 Section 9.4.2 (Serious Adverse Event) 
 Section 9.5 (Serious Adverse Events Reporting Procedure For Investigators) 
21 
Rationale:  Removed lean body mass requirement for calculating estimated creatinine 
clearance rate 
The following section has been updated: 
 Section 17.1 (Cockcroft-Gault Equation) 
22 
Rationale:  Grammatical and editorial updates 
The following sections have been updated: 
 Throughout protocol 


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PROTOCOL SYNOPSIS 
EudraCT Number: 
Not Applicable 
IND Number: 
Not Applicable 
Protocol Number: 
DS1205-A-U101 
Investigational Product: 
DS-1205c in combination with osimertinib 
Active Ingredient(s): 
Study Title: 
A Multicenter, Open-Label Phase 1 Study of DS-1205c in 
Combination with Osimertinib in Subjects with Metastatic or 
Unresectable EGFR-Mutant Non-Small Cell Lung Cancer 
Study Phase: 
Phase 1 
Indication Under Investigation: 
Metastatic or unresectable epidermal growth factor receptor 
(EGFR)-mutant non-small cell lung cancer (NSCLC) subjects who (a) 
are threonine 790 to methionine (T790M) mutation-negative after 
disease progression during treatment with erlotinib, gefitinib, or 
afatinib or (b) develop disease progression while on osimertinib. 
Study Objectives: 
Dose Escalation 
Primary Objective 
 
To assess the safety and tolerability and to determine 
the recommended dose for expansion (RDE) of 
DS-1205c when combined with osimertinib in 
metastatic or unresectable EGFR-mutant NSCLC 
subjects who (a) are T790M mutation-negative after 
disease progression during treatment with erlotinib, 
gefitinib, or afatinib or (b) develop disease 
progression while on osimertinib 
Secondary Objectives 
 
To characterize the pharmacokinetics (PK) of 
DS-1205a (free form of DS-1205c) when DS-1205c is 
administered alone; and of DS-1205a, osimertinib and 
its active metabolites (AZ5104 and AZ7550) when 
DS-1205c is administered in combination with 
osimertinib 
 
To investigate the antitumor activity of DS-1205c in 
combination with osimertinib 
Exploratory Objectives 
 
To evaluate the relationship between the plasma 
concentration of DS-1205a and QT corrected interval 
(QTc) 
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 
To identify biomarkers that correlate with response or 
toxicity to DS-1205c in combination with osimertinib 
 
To assess changes in the profile of EGFR mutations 
and/or other genes in cell-free DNA (cfDNA) or in 
tumor DNA during treatment with DS-1205c in 
combination with osimertinib 
 
To conduct metabolite analysis of DS-1205c 
Study Design: 
This is a multicenter, open-label, Phase 1study of DS-1205c in 
combination with osimertinib in subjects with metastatic or 
unresectable EGFR-mutant NSCLC who (a) are T790M 
mutation-negative after disease progression during treatment with 
erlotinib, gefitinib, or afatinib or (b) develop disease progression while
on osimertinib.  This study has 2 parts:  Dose Escalation and Dose 
Expansion. 
Dose Escalation 
Dose Escalation consists of a DS-1205c monotherapy run-in period 
(Cycle 0) followed by combination treatment of DS-1205c and 
osimertinib (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 erlotinib, gefitinib, afatinib, or 
osimertinib 1 day prior to breakfast in clinic on Cycle 0, Day −1.  
ECGs will be obtained at specified time points over a 10-hour period.  
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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% (the target 
DLT interval is defined as 16% <DLT rate ≤33%), or (c) the starting 
dose is too toxic. 
Study Duration: 
Dose Escalation 
 
Enrollment is planned to occur over approximately 13 months. 
 
Treatment and follow-up will be completed when all subjects 
have either discontinued study treatment or completed last 
study visit. 
Study and Locations: 
Approximately 7 clinical sites in Taiwan.  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, 
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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 is able to discontinue erlotinib, 
gefitinib, or afatinib; or is currently receiving osimertinib at 
the prescribed 80 mg dose and is able to interrupt osimertinib. 
5. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib 
for at least 6 weeks with well-controlled related toxicities less 
than Grade 3 in severity at the time of screening period. 
6. Has radiological documentation of disease progression while 
receiving continuous treatment with erlotinib, gefitinib, 
afatinib, 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 erlotinib, 
gefitinib, afatinib, 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.  No EGFR mutation 
testing is required if treated with osimertinib. 
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. 
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 


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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, and following local treatment or 
undergoing active surveillance) 
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 antiarrhythmic treatment. 
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 QT interval corrected 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. 


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syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years of age in 
first-degree relatives. 
14. Has any history of interstitial lung disease (pulmonary fibrosis 
or severe radiation pneumonitis) or is suspected to have such 
disease by imaging during screening. 
15. Has history of pancreatitis within the past 6 months. 
Dosage Form, Dose, and Route of 
Administration: 
DS-1205c is supplied as 200 mg capsules, white opaque with red 
lines, packaged in high-density polyethylene 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 (8 fluid oz) of water.  It is recommended that 
meals be completed within approximately 30 minutes; DS-1205c 
should be taken immediately after meal completion. 
Osimertinib is supplied as 80 mg tablets, beige oval and biconvex, 
marked with “AZ 80” on one side and plain on the reverse, packaged 
in wallets of 25 film-coated tablets.  Beginning with Day 1 of Cycle 1, 
osimertinib will be co-administered orally QD with the morning dose 
of DS-1205c. 
Study Endpoints:  
Dose Escalation 
Primary Endpoints (ie, Primary Outcome Measures) 
 
To determine the safety and tolerability of DS-1205c in 
combination with osimertinib, 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]), and ECHO 
or MUGA 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 observed analyte concentration (Cmax), the actual 
sampling time to reach Cmax (Tmax), minimum observed 
analyte concentration prior to the beginning, or at the end, of a 
dosing interval (Ctrough), area under the analyte 
concentration (AUC) parameters, and other PK parameters, as 
appropriate. 
 
Cycle 1 and beyond:  To assess the PK of DS-1205a, 
osimertinib, and osimertinib active metabolites (AZ5104 and 
AZ7550), the endpoints will include plasma concentration of 
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(AZ5104 and AZ7550) versus time, and maximum observed 
analyte concentration during a dosing interval (Tau) at steady 
state (Cmax,ss), Tmax, Ctrough, AUC parameters, 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, 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 RNA, DNA, or protein analysis) that correlate 
with response or toxicity to DS-1205c in combination with 
osimertinib may be assessed. 
 
Biomarkers measured in plasma (eg, cfDNA) that correlate 
with response or toxicity to DS-1205c in combination with 
osimertinib will be assessed. 
 
EGFR mutation(s) or mutations in other genes in cfDNA or in 
tumor DNA during treatment with DS-1205c in combination 
with osimertinib will be assessed. 
 
Relation between DS-1205a plasma concentration and 
change-from-baseline QTcF (∆QTcF). 
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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 data by 
analyte/dose/study day/time and for each PK parameter by 
analyte/dose/study day, as appropriate. Evaluation of dose 
proportionality may also be performed using power analysis. 
Efficacy Analyses: 
The efficacy analysis will be performed for the subjects who received 
at least one dose of study drug by dose group.  The analysis will be 
based on subjects dosed at the level of RDE at both the dose escalation 
phase and the dose expansion phase.  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 will be provided.  Time to event variables including DOR, 
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TTR, PFS, and OS will be summarized with median event times with 
2-sided 95% confidence interval (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 RNA, DNA, or protein 
analysis.  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 
SUMMARY OF CHANGES ...........................................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................7 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF TABLES .........................................................................................................................24 
LIST OF FIGURES .......................................................................................................................25 
LIST OF ABBREVIATIONS ........................................................................................................26 
1. 
INTRODUCTION ........................................................................................................31 
1.1. 
Data Summary ...............................................................................................................31 
1.1.1. 
Investigational Product..................................................................................................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 ....................................................................................................33 
1.1.2.3. 
Pharmacokinetics and Drug Metabolism ......................................................................34 
1.1.2.4. 
Toxicology ....................................................................................................................34 
1.1.3. 
Clinical Experience .......................................................................................................35 
1.2. 
Background ...................................................................................................................35 
1.2.1. 
Metastatic or Unresectable EGFR-Mutant NSCLC ......................................................36 
1.3. 
Study Rationale and Dose Selection .............................................................................38 
1.3.1. 
Study Rationale .............................................................................................................38 
1.3.2. 
Dose Selection ...............................................................................................................39 
1.3.2.1. 
DS-1205c Starting Dose ................................................................................................39 
1.3.2.2. 
Osimertinib Dose Selection...........................................................................................39 
1.4. 
Risks and Benefits for Study Subjects ..........................................................................39 
1.4.1. 
Potential Risks Associated with DS-1205c ...................................................................39 
1.4.2. 
Pharmacokinetic Drug Interaction ................................................................................40 
1.4.2.1. 
Evaluation of the Potential for PK Interaction Effect on Osimertinib by 
DS-1205c ......................................................................................................................41 


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1.4.2.2. 
Evaluation of the Potential for PK Interaction Effect on DS-1205c by 
Osimertinib ....................................................................................................................41 
1.4.3. 
Potential Benefit Associated with DS-1205c ................................................................41 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ..............................................................43 
2.1. 
Study Objectives ...........................................................................................................43 
2.1.1. 
Dose Escalation .............................................................................................................43 
2.1.2. 
Dose Expansion .............................................................................................................43 
2.2. 
Study Hypothesis ..........................................................................................................44 
2.3. 
Study Endpoints ............................................................................................................44 
2.3.1. 
Dose Escalation .............................................................................................................44 
2.3.2. 
Dose Expansion .............................................................................................................45 
3. 
STUDY DESIGN ..........................................................................................................47 
3.1. 
Overall Design Summary ..............................................................................................47 
3.2. 
Treatment Groups..........................................................................................................48 
3.2.1. 
Dose Escalation .............................................................................................................48 
3.2.1.1. 
Cycle 0 (Monotherapy, 7 Days) ....................................................................................48 
3.2.1.2. 
Cycle 1 and Beyond (Combination Therapy) ...............................................................49 
3.2.1.3. 
Dose-Limiting Toxicities (DLT) ...................................................................................50 
3.2.1.4. 
Safety Review Meetings ...............................................................................................53 
3.2.1.5. 
Stopping Rule for Recommended Dose for Expansion Determination ........................53 
3.2.1.6. 
Determination of Recommended Dose for Expansion..................................................54 
3.2.2. 
Dose Expansion .............................................................................................................54 
3.2.2.1. 
Stopping Rule for Other Consideration(s) ....................................................................54 
3.3. 
Duration of Subject Participation ..................................................................................54 
3.4. 
Duration of Study ..........................................................................................................54 
4. 
STUDY POPULATION ...............................................................................................56 
4.1. 
Inclusion Criteria ...........................................................................................................56 
4.2. 
Exclusion Criteria..........................................................................................................58 
5. 
STUDY TREATMENT(S) ...........................................................................................61 
5.1. 
Assigning Subjects to Treatments and Blinding ...........................................................61 
5.1.1. 
Treatment Group(s)/Sequence(s) ..................................................................................61 
5.2. 
Study Drug(s) ................................................................................................................61 
5.2.1. 
Description ....................................................................................................................61 


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5.2.2. 
Labeling and Packaging ................................................................................................61 
5.2.3. 
Preparation ....................................................................................................................61 
5.2.4. 
Administration ..............................................................................................................62 
5.2.5. 
Storage...........................................................................................................................62 
5.2.6. 
Drug Accountability ......................................................................................................62 
5.3. 
Treatment Compliance ..................................................................................................63 
5.4. 
Dose Interruptions and Reductions ...............................................................................64 
5.4.1. 
Dose Interruptions .........................................................................................................64 
5.4.2. 
Dose Reductions ...........................................................................................................73 
5.5. 
Prior and Concomitant Medications, Treatments, and Procedures ...............................73 
5.5.1. 
Prior Medication(s), Treatment(s), and Procedure(s) ...................................................73 
5.5.2. 
Concomitant Medication(s) ...........................................................................................73 
5.5.3. 
Prohibited Medications .................................................................................................73 
5.6. 
Subject Withdrawal/Discontinuation ............................................................................74 
5.6.1. 
Reasons for Withdrawal/Discontinuation .....................................................................74 
5.6.2. 
Withdrawal Procedures .................................................................................................75 
5.6.3. 
Subject Re-Screening Procedures .................................................................................75 
6. 
STUDY PROCEDURES ..............................................................................................77 
6.1. 
Dose Escalation .............................................................................................................77 
6.1.1. 
Screening (Dose Escalation) .........................................................................................77 
6.1.1.1. 
Tissue Requirement (Dose Escalation) .........................................................................77 
6.1.1.2. 
Screening (Dose Escalation) .........................................................................................78 
6.1.2. 
Cycle 0 (Dose Escalation) .............................................................................................79 
6.1.2.1. 
Cycle 0, Day 1 (Dose Escalation) ...............................................................................79 
6.1.2.2. 
Cycle 0, Day 1 (Dose Escalation) .................................................................................80 
6.1.2.3. 
Cycle 0, Day 2 (Dose Escalation) .................................................................................81 
6.1.2.4. 
Cycle 0, Day 4 (Dose Escalation) .................................................................................82 
6.1.2.5. 
Cycle 0, Day 6 (Dose Escalation) .................................................................................83 
6.1.2.6. 
Cycle 0, Day 7 (Dose Escalation) .................................................................................84 
6.1.3. 
Cycle 1 and Beyond (Dose Escalation) .........................................................................85 
6.1.3.1. 
Cycle 1, Day 1 (Dose Escalation) .................................................................................85 
6.1.3.2. 
Cycle 1, Day 4, Day 8, and Day 15 (Dose Escalation) .................................................86 
6.1.3.3. 
Cycle 2, Day 1 (Dose Escalation) .................................................................................87 


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6.1.3.4. 
Cycle 2, Day 2 and Day 8 (Dose Escalation) ................................................................88 
6.1.3.5. 
Tumor Assessments (Dose Escalation) .........................................................................90 
6.1.3.6. 
Cycle 3 and Subsequent Cycles, Day 1 (Dose Escalation) ...........................................90 
6.1.3.7. 
End-of-Treatment (EOT) Visit (Dose Escalation) ........................................................91 
6.1.3.8. 
Follow-Up Call (Dose Escalation) ................................................................................92 
6.1.3.9. 
New Cancer Treatment and Survival Follow-up (Dose Escalation) .............................93 
6.2. 
Dose Expansion .............................................................................................................93 
6.2.1. 
Screening (Dose Expansion) .........................................................................................93 
6.2.1.1. 
Tissue Screening (Dose Expansion) .............................................................................93 
6.2.1.2. 
Screening (Dose Expansion) .........................................................................................94 
6.2.2. 
Treatment (Dose Expansion).........................................................................................95 
6.2.2.1. 
Cycle 1, Day 9 (Dose Expansion) ...............................................................................95 
6.2.2.2. 
Cycle 1, Day 1 (Dose Expansion) .................................................................................95 
6.2.2.3. 
Cycle 1, Day 8 and Day 15 (Dose Expansion)..............................................................96 
6.2.2.4. 
Cycle 2, Day 1 (Dose Expansion) .................................................................................98 
6.2.2.5. 
Cycle 2, Day 2 and Day 8 (Dose Expansion)................................................................99 
6.2.2.6. 
Tumor Assessments (Dose Expansion) .......................................................................100 
6.2.2.7. 
Cycle 3 and Subsequent Cycles (Dose Expansion) ....................................................100 
6.2.2.8. 
End-of-Treatment (EOT) Visit (Dose Expansion) ......................................................102 
6.2.2.9. 
Follow-Up Call (Dose Expansion) ..............................................................................103 
6.2.2.10. New Cancer Treatment and Survival Follow-up (Dose Expansion) ...........................103 
6.3. 
Schedule of Events ......................................................................................................103 
7. 
EFFICACY ASSESSMENTS .....................................................................................121 
7.1. 
Assessments for Efficacy Endpoint(s) ........................................................................121 
7.1.1. 
Efficacy Endpoint(s) ...................................................................................................121 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ......................122 
8.1. 
Pharmacokinetic (PK) Assessment(s) .........................................................................122 
8.2. 
Biomarkers ..................................................................................................................122 
8.2.1. 
Pharmacodynamic Biomarker Assessments in Blood Samples ..................................122 
8.2.2. 
Biomarker Assessments in Tumor Tissue Samples ....................................................123 
8.2.2.1. 
Tumor Biopsy Sample Collection ...............................................................................123 
8.2.2.2. 
Tumor Tissue Biomarker Analysis .............................................................................124 
8.2.3. 
Additional Biomarker Assessments ............................................................................124 


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8.2.4. 
Disclosure of the Results of Biomarker Assessment ..................................................125 
8.3. 
Pharmacogenomic Analysis ........................................................................................125 
8.3.1. 
Study Subjects for Pharmacogenomic Analysis .........................................................125 
8.3.2. 
Collection of Specimens for Pharmacogenomic Analysis ..........................................125 
8.3.2.1. 
Pharmacogenomic Endpoints ......................................................................................125 
8.3.2.2. 
Disclosure of the Results of Pharmacogenomic Analysis ..........................................125 
8.3.2.3. 
Storage and Disposal of Specimens for Pharmacogenomic Analysis .........................126 
9. 
SAFETY EVALUATION AND REPORTING .........................................................127 
9.1. 
Adverse Events............................................................................................................127 
9.2. 
Safety Endpoints .........................................................................................................128 
9.3. 
Adverse Events of Special Interest (AESI) .................................................................128 
9.3.1. 
Elevations of Aminotransferase(s) and Bilirubin ........................................................128 
9.3.2. 
Prolonged QTc Interval (≥Grade 2) ............................................................................128 
9.3.3. 
Interstitial Lung Disease .............................................................................................128 
9.4. 
Definitions ...................................................................................................................129 
9.4.1. 
Adverse Event .............................................................................................................129 
9.4.2. 
Serious Adverse Event ................................................................................................129 
9.4.3. 
Adverse Event Severity ...............................................................................................130 
9.4.4. 
Causality Assessment ..................................................................................................130 
9.4.5. 
Action Taken Regarding Study Drug(s) .....................................................................131 
9.4.6. 
Other Action Taken for Event .....................................................................................131 
9.4.7. 
Adverse Event Outcome .............................................................................................131 
9.5. 
Serious Adverse Events Reporting Procedure For Investigators ................................131 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Institutional Ethics Committee .........................................................................132 
9.7. 
Exposure In Utero During Clinical Studies ................................................................133 
9.8. 
Clinical Laboratory Evaluations .................................................................................133 
9.9. 
Vital Signs ...................................................................................................................134 
9.10. 
Electrocardiograms .....................................................................................................134 
9.10.1. 
Safety ECGs ................................................................................................................134 
9.11. 
Physical Examinations ................................................................................................135 
9.12. 
Other Examinations .....................................................................................................135 
10. 
OTHER ASSESSMENTS ...........................................................................................137 


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11. 
STATISTICAL METHODS .......................................................................................138 
11.1. 
General Statistical Considerations ..............................................................................138 
11.2. 
Analysis Sets ...............................................................................................................138 
11.3. 
Study Population Data ................................................................................................139 
11.4. 
Efficacy Analyses........................................................................................................139 
11.5. 
Pharmacokinetic Analyses ..........................................................................................140 
11.6. 
Safety Analyses ...........................................................................................................140 
11.6.1. 
Adverse Event Analyses .............................................................................................140 
11.6.2. 
Electrocardiogram Analyses .......................................................................................141 
11.6.3. 
Clinical Laboratory Evaluation Analyses ...................................................................141 
11.6.4. 
Vital Sign Analyses .....................................................................................................141 
11.6.5. 
Physical Examination Analyses ..................................................................................141 
11.6.6. 
Interstitial Lung Disease Analysis and Adjudication ..................................................141 
11.7. 
Interim Analyses .........................................................................................................142 
11.8. 
Data Monitoring Committee .......................................................................................142 
11.9. 
Sample Size Determination .........................................................................................142 
11.10. 
Statistical Analysis Process .........................................................................................142 
11.11. 
Specification of Modified Continuous Reassessment Method with Escalation 
with Overdose Control ................................................................................................142 
11.11.1. Bayesian Logistic Regression Model for Modified Continuous Reassessment 
Method ........................................................................................................................143 
11.11.2. Prior Specification for Bayesian Logistic Regression Model Parameters ..................143 
11.11.3. Escalation with Overdose Control Principle ...............................................................143 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ..............................................145 
12.1. 
Monitoring and Inspections ........................................................................................145 
12.2. 
Data Collection............................................................................................................145 
12.3. 
Data Management .......................................................................................................146 
12.4. 
Study Documentation and Storage ..............................................................................146 
12.5. 
Record Keeping ...........................................................................................................147 
13. 
FINANCING AND INSURANCE .............................................................................148 
13.1. 
Finances.......................................................................................................................148 
13.2. 
Reimbursement, Indemnity, and Insurance .................................................................148 
14. 
PUBLICATION POLICY ...........................................................................................149 


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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION ..............................150 
15.1. 
Ethics and Study Administrative Information.............................................................150 
15.2. 
Compliance Statement, Ethics and Regulatory Compliance.......................................150 
15.3. 
Subject Confidentiality................................................................................................150 
15.4. 
Informed Consent ........................................................................................................150 
15.5. 
Regulatory Compliance ...............................................................................................151 
15.6. 
Protocol Deviations .....................................................................................................152 
15.7. 
Supply of New Information Affecting the Conduct of the Study ...............................152 
15.8. 
Protocol Amendments .................................................................................................152 
15.9. 
Study Termination .......................................................................................................153 
15.10. 
Data and Safety Monitoring Board .............................................................................153 
15.11. 
Address List ................................................................................................................153 
16. 
REFERENCES ............................................................................................................154 
17. 
APPENDICES ............................................................................................................158 
17.1. 
Cockcroft-Gault Equation ...........................................................................................158 
17.2. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 ......................................159 
17.2.1. 
Measurability of Tumor at Baseline ............................................................................159 
17.2.1.1. Definitions ...................................................................................................................159 
17.2.1.2. Specifications by Methods of Measurements .............................................................160 
17.2.2. 
Tumor Response Evaluation .......................................................................................160 
17.2.2.1. Assessment of Overall Tumor Burden and Measurable Disease ................................160 
17.2.2.2. Baseline Documentation of “Target” and “Non-target” Lesions ................................161 
17.2.2.3. Response Criteria ........................................................................................................161 
17.2.2.4. Evaluation of Best Overall Response ..........................................................................164 
17.3. 
New York Heart Association Functional Capacity and Objective Assessment ..........167 
17.4. 
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) .................168 
17.5. 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.044 ...............................................................................................................169 
17.6. 
QT-Prolonging Medications and CYP3A4 Inhibitors/Inducers ..................................170 
17.6.1. 
Potential QT/QTc Prolonging Drugs ..........................................................................170 
17.6.2. 
CYP3A4 Inhibitors and Inducers ................................................................................171 
 


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LIST OF TABLES 
Table 3.1: Dose Escalation Cohorts and Provisional Dosages ....................................................48 
Table 5.1: Dose Interruption and Dose Resumption Criteria ......................................................65 
Table 6.1: Schedule of Events, Dose Escalation (Cycle 0) ........................................................104 
Table 6.2: Schedule of Events, Dose Escalation (Cycle 1 and Beyond) ...................................108 
Table 6.3: Schedule of Events, Dose Expansion .......................................................................114 
Table 9.1: Clinical Laboratory Tests .........................................................................................134 
Table 17.1: Overall Response:  Subjects with Target (±Non-target) Disease .............................164 
Table 17.2: Best Overall Response When Confirmation of CR and PR Is Required ..................165 
Table 17.3: New York Heart Association Functional Capacity and Objective 
Assessment42 .............................................................................................................167 
Table 17.4: Eastern Cooperative Oncology Group Performance Status Scale43 .........................168 
Table 17.5: Potential QT/QTc Prolonging Drugs45 .....................................................................170 
Table 17.6: Partial List of Clinically Relevant Strong CYP3A4 Inhibitors and Inducers46 ........171 
 


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LIST OF FIGURES 
Figure 1.1: Effects of Osimertinib (AZD9291) and DS-1205b on Estimated Tumor 
Volume in HCC827-Bearing Nude Mice ...................................................................33 
Figure 3.1: Study Schema:  Dose Escalation ................................................................................47 
Figure 3.2: Study Schema:  Dose Expansion ................................................................................47 
 












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1. 
INTRODUCTION 
1.1. 
Data Summary 
1.1.1. 
Investigational Product 
1.1.1.1. 
Name 
DS-1205c 
1.1.1.2. 
Description 
DS-1205c is a novel, specific, small-molecule inhibitor of the receptor tyrosine kinase AXL.  
1.1.1.3. 
Intended Use Under Investigation 
DS-1205c will be evaluated in combination with osimertinib in subjects with metastatic or 
unresectable epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer 
(NSCLC) who (a) are threonine 790 to methionine (T790M) mutation-negative after disease 
progression during treatment with erlotinib, gefitinib, or afatinib or (b) develop disease 
progression while on osimertinib. 
1.1.2. 
Nonclinical Studies 
DS-1205b and DS-1205c were used in nonclinical studies as indicated below.  In nonclinical 
studies, the doses and concentrations are expressed as those of DS-1205a (free base) unless 
otherwise stated. 
1.1.2.1. 
Pharmacology 
The inhibitory activity of DS-1205b on AXL kinase receptor phosphorylation in NCI-H1299 and 
AXL cDNA-transfected NIH3T3 (NIH3T3-AXL) cell lines was determined after GAS6 
stimulation.  Cells were pre-treated with DS-1205b and then stimulated with recombinant human 
growth arrest-specific gene 6 (hGAS6) receptor ligand, and the degree of endogenous AXL 
phosphorylation was quantified.  DS-1205b showed potent concentration-dependent inhibition of 
AXL kinase receptor phosphorylation in NCI-H1299 and NIH3T3-AXL cells, with IC50 values 
of 2.8 nM and 3.7 nM, respectively. 
CCI


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An in vivo study evaluated the delay effect of DS-1205b on the acquired resistance of erlotinib in 
nude mice subcutaneously inoculated with human NSCLC cell line HCC827.  Groups of mice 
were administered either erlotinib 25 mg/kg once daily (QD), or DS-1205b (12.5, 25, or 50 
mg/kg twice daily [BID]), or erlotinib 25 mg/kg QD combined with DS-1205b (12.5, 25, or 
50 mg/kg BID).  For some groups, observation was undertaken until estimated tumor volume 
(ETV) reached 1000 mm3 (Day 24); for other groups, observation was extended to Day 100.  The 
mean ETVs on Day 100 for groups receiving erlotinib combined with DS-1205b at 50, 25, or 
12.5 mg/kg BID were 216.8, 321.0, and 541.7 mm3, respectively, compared to group 2 (erlotinib 
25 mg/kg QD) with ETV of 814.5 mm3.  Significantly low values from the erlotinib group were 
found in the erlotinib combined with high dose DS-1205b groups on Days 59 to 80, 98 and 100 
(P  0.0257 to 0.0469).  DS-1205b showed a delay effect on ETV in a dose-dependent trend and 
significantly enhanced the antitumor effect of erlotinib at the dose of 50 mg/kg BID. 
DS-1205b effect on the acquired resistance of osimertinib in an in vivo study in nude mice 
subcutaneously inoculated with the human EGFR-mutant NSCLC cell line HCC827 was also 
examined.  Groups of mice were administered DS-1205b at 12.5, 25, or 50 mg/kg BID.  Other 
groups of mice received osimertinib 3 mg/kg QD, either alone or in combination with DS-1205b 
at 12.5, 25, or 50 mg/kg BID.  All groups were observed to Day 100, and animals were 
euthanized when ETV reached 1000 mm3.  In groups receiving DS-1205b alone, on Day 21, the 
mean ETVs showed no significant difference from control.  The mean ETV on Day 100 for the 
group receiving osimertinib alone was 727.5 mm3.  The mean ETV values of the groups 
receiving osimertinib in combination with DS-1205b at 12.5, 25, or 50 mg/kg BID were 205.1, 
211.3, and 145.8 mm3, respectively.  Significantly low ETV values from the osimertinib group 
were found on occasions in all groups receiving osimertinib in combination with DS-1205b.  In 
conclusion, DS-1205b exhibited significant delay effects on ETV and days to initial ETV in a 
dose-dependent trend at the doses from 12.5 to 50 mg/kg BID on the acquired resistance of 
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Figure 1.1: 
Effects of Osimertinib (AZD9291) and DS-1205b on Estimated Tumor 
Volume in HCC827-Bearing Nude Mice 
 
AZD9291 = osimertinib; BID = twice daily; QD = once daily. 
Points, mean for 5 or 10 animals; vertical bars, SE. 
DS-1205b 25 mg/kg BID plus osimertinib 3 mg/kg QD vs. osimertinib 3mg/kg QD alone: P = 0.0017 to 0.0196; 
Dunnett's test (Day 35 to Day 100). 
DS-1205b 25 mg/kg BID plus osimertinib 3 mg/kg QD vs. osimertinib 3mg/kg QD alone: P = 0.0067 to 0.0314; 
Dunnett's test (Day 25 and from Day 39 to Day 100). 
DS-1205b 50 mg/kg BID plus osimertinib 3 mg/kg QD vs. osimertinib 3mg/kg QD alone: P = 0.0005 to 0.0445; 
Dunnett's test (Day 21 to Day 100). 
No significant difference from the vehicle control, BID group was found for the DS-1205b groups (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 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, electrocardiogram (ECG) parameters 
(PR, QRS, 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 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 would be considered during clinical trials. 


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1.1.2.3. 
Pharmacokinetics and Drug Metabolism 
Pharmacokinetic (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 of 
1000 mg/kg/day in mice, maximum concentration of drug (Cmax) and area under the plasma 
concentration-time curve from time 0 to 24 hours (AUC0 24) 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 maximum concentration of drug (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 24 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 24 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 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 a N-glucuronide.  The major metabolites were: in mouse, a 
mono-oxygenated form; in monkey, a mono-oxygenated form and a di-oxygenated form; and in 
human, an N-glucuronide.  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 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 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 


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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 severely 
toxic dose in 10% of animals (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 highest non-severely toxic dose 
(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. 
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 
DS1205-A-J102 (NCT03599518) is a multicenter, open-label, Phase 1 study being conducted in 
Japan of DS-1205c in combination with gefitinib in subjects with metastatic or unresectable 
EGFR-mutant NSCLC who (a) are T790M-mutation-negative after disease progression during 
treatment with erlotinib, gefitinib, or afatinib or (b) develop disease progression while on 
osimertinib.  This study has 2 parts:  Dose Escalation and Dose Expansion. 
1.2. 
Background 
An estimated 158,080 deaths due to lung cancer are estimated for 2016 in the United States (US).  
In addition, lung cancer is the second most commonly diagnosed cancer, with an estimated 


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224,390 new cases expected in the US in 2016.3   Lung cancer accounts for the greatest number 
of deaths from cancer worldwide.4 
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 kinases 
(TKIs) represent the first-line treatment of choice in NSCLC with EGFR-activating mutations.5, 6, 
7, 8, 9, 10, 11  Gefitinib, erlotinib, and afatinib (and, more recently, osimertinib) 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 
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-mesenchymal transition.14 
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 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 objective 
response rate (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; 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 


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LUX-Lung 1 trial, where 697 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 25% 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 25 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 progressive disease.22 
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, 1907 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 


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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 in26).  It remains unclear 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 non-small cell lung cancer (NSCLC) acquire 
resistance to first generation TKIs (eg, erlotinib, gefitinib, 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 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  
Growth arrest-specific gene 6 (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 osimertinib following the addition of DS-1205 
has been demonstrated in nonclinical studies.1 


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In summary, DS-1205c is hypothesized to show potential activity in combination with 
osimertinib in EGFR-mutant NSCLC with a manageable safety profile. 
1.3.2. 
Dose Selection 
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 severely toxic dose in 10% of animals (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 1/10th of this value gives a dose of 8.1 mg/kg as the 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 1/6th 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 BID). 
1.3.2.2. 
Osimertinib Dose Selection 
In this study, DS-1205c will be administered in combination with osimertinib (Tagrisso®) in an 
investigational use setting.  Osimertinib has been approved (United States [New Drug 
Application:  208065], November 2015; European Union [Agency Product Number:  
EMEA/H/C/004124], February 2016; and Canada [New Drug Submission Control Number:  
188171], July 2016) for the treatment of patients with metastatic EGFR T790M mutation 
positive NSCLC at a recommended dose of one 80 mg tablet administered orally QD. 
1.4. 
Risks and Benefits for Study Subjects 
1.4.1. 
Potential Risks Associated with DS-1205c 
In nonclinical toxicity studies conducted in mice, elevations in clinical laboratories including 
ALT, AST, ALP, GLDH, creatinine kinase (CK), and lactate dehydrogenase (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. 
As of 05 Mar 2019 in the DS1205-A-J102 study, 9 subjects have been enrolled in 2 cohorts and 
8 subjects have been determined to be DLT-evaluable, and the study is enrolling subjects in the 
third cohort.  One subject who was not DLT-evaluable was discontinued from the study due to 
disease progression. 


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1.4.2. 
Pharmacokinetic Drug Interaction 
The direct and metabolism-dependent inhibitory potential of DS-1205a on CYP isoform 
(CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) activities was 
assessed in vitro using pooled human liver microsomes and high-performance liquid 
chromatography mass spectroscopy/mass spectroscopy -based assays.  The test substance used 
was DS-1205b.  Liver microsomes were incubated for 10 minutes with isoform-selective 
substrates at concentrations approximating to the corresponding Michaelis constant (Km) values 
in the absence and presence of DS-1205a (100, 33, 10, 3.3, 1.0, 0.33, 0.1 μM).  All incubations 
were performed in duplicate.  For CYP3A4, midazolam and testosterone were used as probe 
substrates.  For each CYP isoform, a selective direct inhibitor was included as a positive control.  
Assessment of metabolism-dependent inhibition included pre-incubation with nicotinamide 
adenine dinucleotide phosphate (NADPH) for 30 minutes.  The degree of inhibition produced at 
each concentration of DS-1205a was calculated as a percentage of the mean uninhibited control 
rate and used to determine the 50% inhibitory concentration (IC50). 
DS-1205a did not directly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, 
and CYP3A4, as the IC50 values were >100 μM, the highest DS-1205a concentration tested.  DS-
1205a did not show metabolism-dependent inhibition of any CYP isoforms tested, as no IC50 
value showed a decrease of ≥1.5-fold after 30 minutes of pre-incubation with NADPH.  Direct 
and metabolism-dependent IC50 results of the positive control inhibitors were consistent with 
published values, and confirmed the correct performance of the test system.1 
The potential of DS-1205 to induce CYP isoforms (CYP3A4, CYP1A2, and CYP2B6) was 
assessed using primary cultures of fresh human hepatocytes from 3 individuals by incubation at 
concentrations of 0.1, 0.3, 1, 3, 10, and 30 μM for 72 hours.  After treatment, CYP3A4, 
CYP1A2, and CYP2B6 messenger ribonucleic acid (mRNA) levels were determined, along with 
their corresponding enzyme activities.  The test substance used in this study was DS-1205b.  
Rifampicin at 0.1 to 30 μM, omeprazole at 0.3 to 50 μM and phenobarbital at 0.01 to 3 mM were 
used as positive controls for CYP3A4, CYP1A2, and CYP2B6 induction, respectively.  
Dimethylsulfoxide-treated hepatocytes served as solvent control, and cells treated with the 
known non-inducer gatifloxacin served as negative control.  All incubations were performed in 
triplicate.  CYP mRNA levels were determined using quantitative reverse transcription 
polymerase chain reaction technology, while the formation of 6β-hydroxytestosterone from 
testosterone, of acetaminophen from phenacetin, and of hydroxybupropion from bupropion, were 
used as specific reactions to determine CYP3A4, CYP1A2, and CYP2B6 enzyme activity, 
respectively.  Additionally, lactate dehydrogenase (LDH) activity, indicating the cytotoxicity of 
the test articles, was determined. 
DS-1205a had no induction effect on CYP3A4, CYP1A2, and CYP2B6 mRNA expression levels 
as well as enzyme activities at all concentrations tested, as in all cases DS-1205a showed a 
similar fold change in mRNA activity or enzyme activity compared to negative controls.  
Furthermore, DS-1205a showed no cytotoxic effect, with LDH activity showing no notable 
difference from solvent control.1 
The effect of DS-1205a on the P-glycoprotein (P-gp)-mediated transport of digoxin (3 μM) was 
assessed at target concentrations of 0.1, 0.3, 1, 3, 10, 30, and 100 μM DS-1205a by determining 
the apical to basolateral (A to B) and basolateral to apical (B to A) transport of [3H]-digoxin by 


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Caco-2 cells (human colon carcinoma cell line) at pH 7.4, and using triplicate wells per 
concentration.  The test substance used in this study was DS-1205b. 
DS-1205a inhibited digoxin transport, with an IC50 value of 1.20 μM.  The integrity of the 
Caco-2 cell monolayer was acceptable in all wells tested.  The efflux ratio of the known P-gp 
substrate digoxin was clearly inhibited by the control inhibitor GF120918 (IC50 0.51 μM), 
demonstrating appropriate test system performance.1 
1.4.2.1. 
Evaluation of the Potential for PK Interaction Effect on Osimertinib by 
DS-1205c 
Based on the absorption, digestion, metabolism and excretion properties of DS-1205c and 
osimertinib, we do not expect that co-administration of DS-1205c will cause clinically 
significant PK interactions with osimertinib.  In vitro assessment shows that DS-1205c is neither 
an inhibitor nor an inducer of major CYP isoforms.  Although DS-1205c is an in vitro inhibitor 
of P-gp and breast cancer resistance protein (BCRP), it is not expected that such inhibition will 
meaningfully impact PK of osimertinib given its high absorption (Fa >0.8) and extensive 
metabolism (unchanged osimertinib accounted for approximately 2% of the elimination).  
Additionally, preliminary nonclinical studies have shown that DS-1205c does not inhibit 
OATP1B1. 
1.4.2.2. 
Evaluation of the Potential for PK Interaction Effect on DS-1205c by 
Osimertinib 
The primary UGT isoform responsible for glucuronidation of DS-1205a was suggested to be 
UGT1A4, followed by UGT1A1, by in vitro studies.  According to the European Medicines 
Agency Assessment Report of osimertinib,2 although osimertinib is a weak inhibitor of UGT1A1 
based on in vitro studies, it does not inhibit UGT1A1 at clinically relevant concentrations 
hepatically.  Although intestinal inhibition of UGT1A1 by osimertinib is possible and the 
associated clinical impact is unknown, it is unlikely that DS-1205a is substantially metabolized 
by intestinal UGT1A1 because the extent of metabolism in the study using human hepatocytes 
was minimal.  Therefore, the drug-drug interaction risk on DS-1205c by osimertinib via UGT 
would be low. 
Based on in vitro assessment, the contribution of CYP3A4/5 to elimination of DS-1205c was 
suggested as minor; DS-1205c is not a substrate of other major CYP isoforms.  Therefore, 
CYP-related drug-drug interaction potential is low.  Osimertinib has no clinically significant 
effect on the exposure of simvastatin (a CYP3A4 substrate).  Evaluation of DS-1205c for its 
potential being a transporter substrate is ongoing, although given its high permeability we do not 
expect that osimertinib (a BCRP inhibitor) will meaningfully impact the PK of DS-1205c. 
Our overall assessment is that co-administration of osimertinib is expected to cause limited effect 
on the PK of DS-1205c. 
1.4.3. 
Potential Benefit Associated with DS-1205c 
Nonclinical studies have demonstrated the anti-tumor activity of DS-1205 in combination with 
osimertinib in xenograft models.1  Based on the above rationale, and the nonclinical data, 
DS-1205c in combination with osimertinib is hypothesized to show activity in EGFR-mutant 
NSCLC. 


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No efficacy information in humans is currently available. 


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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Dose Escalation 
Primary Objective 
 To assess the safety and tolerability and to determine the RDE of DS-1205c when 
combined with osimertinib in metastatic or unresectable EGFR-mutant NSCLC 
subjects who (a) are T790M mutation-negative after disease progression during 
treatment with erlotinib, gefitinib, or afatinib or (b) develop disease progression while 
on osimertinib. 
Secondary Objectives 
 To characterize the PK of DS-1205a (free form of DS-1205c) when DS-1205c is 
administered alone; and of DS-1205a, osimertinib and its active metabolites (AZ5104 
and AZ7550) when DS-1205c is administered in combination with osimertinib 
 To investigate the antitumor activity of DS-1205c in combination with osimertinib 
Exploratory Objectives 
 To evaluate the relationship between the plasma concentration of DS-1205a and QTc 
interval 
 To identify biomarkers that correlate with response or toxicity to DS-1205c in 
combination with osimertinib 
 To assess changes in the profile of EGFR mutations and/or other genes in cell-free 
DNA (cfDNA) or in tumor DNA during treatment with DS-1205c in combination 
with osimertinib 
 To conduct metabolite analysis of DS-1205c 
CCI


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2.2. 
Study Hypothesis 
Dose Escalation 
DS-1205c in combination with osimertinib will be safe and well tolerated and exhibit acceptable 
PK properties in metastatic or unresectable EGFR-mutant NSCLC subjects who (a) are T790M 
mutation-negative after disease progression during treatment with erlotinib, gefitinib, or afatinib 
or (b) develop disease progression while on osimertinib. 
2.3. 
Study Endpoints 
2.3.1. 
Dose Escalation 
Primary Endpoints (ie, Primary Outcome Measures) 
 To determine the safety and tolerability of DS-1205c in combination with 
osimertinib, the endpoints will include dose-limiting toxicities (DLTs), serious 
adverse events (SAEs), treatment-emergent adverse events (TEAEs), physical 
examination findings (including Eastern Cooperative Oncology Group performance 
status [ECOG PS]), vital sign measurements, ophthalmologic findings, standard 
clinical laboratory parameters, ECG parameters (including the change-from-baseline 
ECG parameters:  heart rate [HR]; PR; QT interval corrected using Fridericia’s 
correction (QTcF); and QRS intervals [ΔHR, ΔPR, ΔQTcF, and ΔQRS]), and 
echocardiogram (ECHO)/multigated acquisition (MUGA) scan findings.  Adverse 
events and 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 observed analyte concentration (Cmax), the 
actual sampling time to reach Cmax (Tmax), minimum observed analyte 
concentration prior to the beginning, or at the end, of a dosing interval (Ctrough), area 
CCI
CCI


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under the analyte concentration (AUC) parameters, and other PK parameters, as 
appropriate. 
 Cycle 1 and beyond:  To assess the PK of DS-1205a, osimertinib, and osimertinib 
active metabolites (AZ5104 and AZ7550), the endpoints will include plasma 
concentration of DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 
and AZ7550) versus time, and maximum observed analyte concentration during a 
dosing interval (Tau) at steady state (Cmax,ss), Tmax, Ctrough, AUC parameters, and 
other PK parameters, as appropriate. 
 The efficacy endpoint is 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), DCR (the sum of CR rate, PR rate, 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 that correlate with response or toxicity to 
DS-1205c in combination with osimertinib (eg, AXL immunohistochemistry [IHC], 
AXL and AXL pathway genes measured by RNA, DNA, or protein analysis) may be 
assessed. 
 Biomarkers measured in plasma that correlate with response or toxicity to DS-1205c 
in combination with osimertinib (eg, cfDNA) will be assessed. 
 EGFR mutation(s) or mutations in other genes in cfDNA or in tumor DNA during 
treatment with DS-1205c in combination with osimertinib will be assessed. 
 Relation between DS-1205a plasma concentration and change-from-baseline QTcF 
(∆QTcF). 
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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) over a 12-hour time period following dosing.  Additional safety, 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 80 mg QD of 
osimertinib 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 the 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.  For 


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Dose Expansion, the RDE will be decided based on an overall assessment of available safety and 
tolerability data from Cycle 1 and beyond, all available PK, biomarker, and tumor response data. 
The number of treatment cycles is not fixed.  Subjects may continue study treatment until 
progressive disease (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 that 
occurs during the DLT-evaluation period (C0D1 to C1D21 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 
NCI-CTCAE Version 5.0 Definition 
Neutrophil count decreased 
Grade 4 
(Lasting 7 days or neutrophil count 
decreased that requires supportive 
therapy with myeloid growth factors) 
500/mm3; 0.5 × 109/L 
Febrile neutropenia  
≥Grade 3 
(Grade 3) 
ANC <1000/mm3 with a single temperature of 
>38.3°C (101°F) or a sustained temperature of 
≥38°C (100.4°F) for more than 1 hour 
 
(Grade 4) 
Life-threatening consequences; urgent 
intervention indicated 
Anemia 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
Platelet count decreased  
≥Grade 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  
Grade 4 
(Lasting ≥14 days) 
<200/mm3; <0.2 × 109/L 
Any 
Grade 5 
Death 
Hepatic Dose-Limiting Toxicities (DLT) NCI-CTCAE Version 5.0 
Hepatic Organ Toxicity 
NCI-CTCAE Grade 
NCI-CTCAE Version 5.0 Definition 
Serum aspartate 
aminotransferase (AST) 
Grade 4 
20.0 ×  upper limit normal ULN if baseline 
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For pulmonary toxicities, a DLT is defined as any of the following: 
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: 
increased 
20.0 × baseline if baseline was abnormal 
Serum alanine 
aminotransferase (ALT) 
increased 
Grade 4 
20.0 × ULN if baseline was normal; 
20.0 × baseline if baseline was abnormal 
AST or ALT increased 
Grade 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  
Grade 5 
Death 
Pulmonary Dose-Limiting Toxicities (DLT) NCI-CTCAE Version 5.0 
Pulmonary Toxicity 
NCI-CTCAE Grade 
NCI-CTCAE Version 5.0 Definition 
Confirmed interstitial lung 
disease (ILD) 
Grade 1 
Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated 
Grade 2 
Symptomatic; medical intervention indicated; 
limiting instrumental activities of daily living 
(ADL) 
Grade 3 
Severe symptoms; limiting self-care ADL; 
oxygen indicated 
Grade 4 
Life-threatening respiratory compromise; urgent 
intervention indicated (eg, tracheotomy or 
intubation) 
Grade 5 
Death 
Any other pulmonary toxicity 
≥Grade 3 
(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 
 
(Grade 5) 
Death 
Non-Hematologic, Non-Hepatic, Non-Pulmonary Toxicities (DLT) NCI-CTCAE Version 5.0 


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The following TEAEs are NOT considered DLTs: 
DLT 
NCI-CTCAE Grade 
NCI-CTCAE Version 5.0 Definition 
Symptomatic 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 
intravenous therapy or mechanical 
hemodynamic support) 
Grade 5 
Death 
Left ventricular ejection 
fraction (LVEF) 
Grade 3 
Resting ejection fraction (EF) 39-20%; ≥20% 
drop from baseline 
Grade 4 
Resting EF <20% 
Grade 5 
Not available 
Endocrine toxicities 
≥Grade 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 activities of daily 
living (ADL) 
 
(Grade 4) 
Life-threatening consequences; urgent 
intervention indicated 
 
(Grade 5) 
Death 
The following TEAEs are considered DLTs 
 
Inability to complete at least 75% of the prescribed doses (ie, at least 42 doses of DS-1205c and 16 doses of 
osimertinib) 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 
 
Thrombocytopenia or anemia requiring transfusion 
The following TEAEs are NOT considered Dose Limiting Toxicities 
TEAE 
NCI-CTCAE Grade 
NCI-CTCAE version 5.0 Definition 
Fatigue 
Grade 3 
(Lasting ≤7 days) 
Fatigue not relieved by rest, limiting self-care 
ADL 
Nausea 
Grade 3 
(That resolves to ≤Grade 2 in 
48 hours) 
Inadequate oral caloric or fluid intake; tube 
feeding, total parenteral nutrition (TPN), or 
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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 C1D1, Investigators should 
contact the Sponsor medical monitor or designee for guidance.  Investigators should refer to 
Section 5.4 for information on interruptions of dose. 
3.2.1.4. 
Safety Review Meetings 
Investigators will communicate with the Sponsor any incidence of DLT on a real-time basis. 
Safety review meetings (SRMs) will include at least the Investigators and the Sponsor. 
During Dose Escalation, SRMs will occur as needed to make determinations about enrollment 
and dose escalation according to the DLT-dependent mCRM, and to determine the RDE. 
During Dose Expansion, SRMs will occur as needed to assess safety and tolerability of the 
selected RDE. 
3.2.1.5. 
Stopping Rule for Recommended Dose for Expansion Determination 
Dose Escalation will be stopped if any of the following occur: 
a. at least 6 evaluable subjects have been enrolled at the RDE level 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% (the target DLT interval is 
defined as 16% <DLT rate ≤33% [Section 11.11.3]), OR 
c. the initial dose level is too toxic. 
Vomiting 
Grade 3 
(That resolves to ≤Grade 2 in 
48 hours) 
Tube feeding, TPN, or hospitalization indicated 
Diarrhea 
Grade 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 
Grade 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 alkaline phosphatase (ALP) increased, hyperuricemia, serum amylase increased, or lipase 
increased or Grade 3 hyponatremia lasting 72 hours 
Lymphocyte count 
Grade 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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3.2.1.6. 
Determination of Recommended Dose for Expansion 
Once the dose escalation stopping criteria are met, the RDE determination will be guided by 
mCRM using a BLRM with EWOC (Section 3.2.1.2).  The RDE will be decided based on an 
overall assessment of available safety data from Cycle 1 and beyond, and all available PK, 
biomarker, and tumor response data. 
3.3. 
Duration of Subject Participation 
The Eligibility Screening period is up to 22 days prior to C0D 1 for Dose Escalation and up to 
30 days prior to C1D1 for Dose Expansion.  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 13 months. 
 Treatment and follow-up will be completed when all subjects have either 
discontinued study treatment or completed last study visit. 
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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 18 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.33 
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 (Response Evaluation Criteria in Solid Tumor [RECIST 
version 1.1] or World Health Organization [WHO]) while on continuous treatment 
with an EGFR TKI 
5. Is currently receiving and is able to discontinue erlotinib, gefitinib, or afatinib; or is 
currently receiving osimertinib at the prescribed 80 mg dose and is able to interrupt 
osimertinib. 
6. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with 
well-controlled related toxicities less than Grade 3 in severity at the time of screening 
period. 
7. Has radiological documentation of disease progression while receiving continuous 
treatment with erlotinib, gefitinib, afatinib, 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 erlotinib, gefitinib, afatinib, 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.  No EGFR mutation testing is required 
if treated with osimertinib. 
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 17.4. 
12. Has adequate bone marrow reserve and organ function, defined as: 
a. Platelet count ≥100 × 109/L 
b. Hemoglobin ≥9.0 g/dL (transfusion and/or growth factor support allowed) 
c. Absolute neutrophil count (ANC) ≥1.5 × 109/L 


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d. Prothrombin time and partial thromboplastin time (PTT/aPTT) ≤1.5 × 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. Creatine kinase 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 (Table 17.5) 
b. CYP3A4 strong inducers ≥10 days (Table 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 4 months after the last dose of study drug. 
For the purposes 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-childbearing 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 childbearing potential if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of post-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 


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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 donate or retrieve, for their own use, ova from the time of 
screening and throughout the study treatment period, and for ≥4 months after the final 
dose of study drug. 
15. A male subject with a sexual partner who is a woman of childbearing potential must be 
willing and able to use a highly effective contraceptive method for the entire study 
treatment period and for ≥4 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 ≥4 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), including Health Insurance Portability and Accountability 
Act authorization, if applicable, 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 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 


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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, and following local 
treatment or undergoing active surveillance) 
5. Clinically significant malabsorption syndrome or other gastrointestinal disease 
(eg, persistent diarrhea, or known sub-acute bowel obstruction ≥NCI-CTCAE version 5.0 
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 scan. 
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 use of drugs that are known to prolong 
the QT interval.  A list of drugs can be found in Appendix 17.6.1. 
14. 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. 
15. Has any history of interstitial lung disease (pulmonary fibrosis or severe radiation 
pneumonitis) or is suspected to have such disease by imaging during screening. 
16. 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. 


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17. 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. 
18. Has history of pancreatitis within the past 6 months. 




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5.2.4. 
Administration 
DS-1205c 
 Administer with a meal, with 240 mL (8 fluid oz) 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. 
Osimertinib 
 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 osimertinib, 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 (77°F).  Excursions permitted up to 30°C 
(86°F) in HDPE bottles. 
Osimertinib 
 Tablets should be stored at 25°C (77°F).  Excursions permitted to 15°C to 30°C 
(59°F to 86°F) as indicated in the package insert (see Pharmacy Instructions). 
If storage conditions go out of specified requirement, contact the Study 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 investigational product.  The record must 
be kept current and should contain the following: 
 Dates and quantities of drug received, 


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 Subject’s identification number, subject’s initials, or supply number (as applicable), 
 The date and quantity of investigational product dispensed and remaining (if from 
individual subject drug units), 
 The initials of the dispenser. 
The study monitor will review study drug accountability records during the study and/or at the 
end of the study.  All investigational product 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. 
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 investigational product must be 
documented and the documentation included in the shipment.  Investigational products 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 investigational product 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 osimertinib 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 osimertinib 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 subjects 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. 


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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). 
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 osimertinib 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 21 days 
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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5.4.2. 
Dose Reductions 
Dose reductions of DS-1205c 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 osimertinib will be allowed. 
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 30 days prior to receiving the first dose of DS-1205c will be recorded as prior 
medications. 
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, except during the DLT evaluation period. 
Bisphosphonates (eg, pamidronate or zoledronate) 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 osimertinib) 
 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 Table 17.5 for a list of 
QTc-prolonging medications 
 Foods containing Hypericum perforatum (St. John’s Wort) 


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 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 
 Strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin).  See Table 17.6 
for a partial list of strong CYP3A4 inducers 
 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 Table 17.6 for a 
partial list clinically relevant of strong CYP3A4 inhibitors 
 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, creatine kinase (CK) level should be checked, and any 
appropriate further management should be taken 
 Avoid co-administration of P-glycoprotein (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 (NCI-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 (NCI-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: 


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 Progressive disease per criteria set forth in RECIST version 1.1 (Section 17.2) 
 Clinical progression (definitive clinical signs of disease progression, but a recent 
radiographic assessment did not meet the criteria for Progressive Disease according to 
RECIST version 1.1) 
 AE 
 Withdrawal of consent by subject 
 Investigator discretion 
 Death 
 Pregnancy 
 Study terminated by Sponsor 
 Lost to follow-up 
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 osimertinib.  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 6.1.3.7 or 
Section 6.2.2.8). 
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 6.1.3.9 and Section 6.2.2.10). 
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 number (SID) 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 recorded on the Screening Log.  No 


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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 
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 
prior to enrollment, performed since progression during treatment with erlotinib, gefitinib, 
afatinib, or osimertinib. 
To meet entry criteria, subjects previously treated with erlotinib, gefitinib, or afatinib are 
required to demonstrate an absence of EGFR T790M mutation prior to study entry, assessed in 
tumor tissue by either: 
 cobas® EGFR Mutation Test v2 performed by central laboratory or 
 an EGFR T790M mutation test performed locally by a Clinical Laboratory 
Improvement Amendments (CLIA)-, College of American Pathologists (CAP)-, or 
International Organization for Standardization (ISO) 15189-certified laboratory. 
In the second case, tumor tissue tested locally should also be sent to the central laboratory for 
exploratory biomarker testing.  No EGFR mutation testing is required if treated with osimertinib. 
The following procedures should be conducted: 
 Have the subject sign the appropriate ICF(s)s 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 for the EGFR T790M mutation in tumor tissue using cobas® EGFR Mutation 
Test v2 at the central laboratory or with an EGFR T790M mutation test performed 
locally by a CLIA-, CAP-, or ISO 15189-certified laboratory. 
 Send the sample(s) to be tested 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. 
For additional information regarding EGFR T790M testing and biomarker analysis, refer to 
Section 8.2.2.1 and the Laboratory Manual. 


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6.1.1.2. 
Screening (Dose Escalation) 
The duration of the Eligibility Screening period is up to 22 days prior to C0D 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 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.  
Computed tomography 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 C0D 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) and SpO2 (pulse oximetry).  Vital signs should be measured after 
the subject has rested in a supine position for 5 minutes or more (Section 9.9). 
 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). 


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 Obtain blood and urine samples for safety analysis (hematology, blood chemistry, 
coagulation, and urinalysis) (Section 9.8). 
 Obtain blood for thyroid function tests (Section 9.8). 
 Perform hepatitis B (HBsAg and anti-HBc), hepatitis C (HCV antibody), and HIV 
antibody tests (HIV antibody test is optional unless required by local regulations or 
IRB/IECs). 
 Obtain a serum sample for pregnancy testing in women of childbearing potential 
within 7 days before enrollment.  For postmenopausal subjects (no childbearing 
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 childbearing potential and required to 
undergo pregnancy testing. 
 Record prior medications. 
 Subjects should be instructed to take their final dose of erlotinib, gefitinib, afatinib, or 
osimertinib 1 day prior to breakfast in clinic on C0D 1, as indicated below: 
 2 evenings before breakfast in clinic for Day 1 visit for those subjects who 
regularly take erlotinib, gefitinib, afatinib, or osimertinib in the evening 
 1 morning before breakfast in clinic for Day 1 visit for those subjects who 
regularly take erlotinib, gefitinib, afatinib, or osimertinib in the morning 
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 erlotinib, gefitinib, afatinib, or osimertinib was taken 1 
day prior to breakfast in clinic on C0D 1. 
 Obtain blood for hematology, coagulation, and blood chemistry. 
 Obtain urine for urinalysis. 
 Obtain vital signs (systolic and diastolic blood pressure, HR, respiratory rate, and 
body temperature) at specified time points.  SpO2 should also be obtained.  Vital signs 
should be measured after the subject has rested in a supine position for 5 minutes or 
more (Section 9.9). 
 Continuous 12-lead Endpoint ECG recording from Holter for the time-matched 
baseline evaluations: 


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 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 
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. 
 Obtain blood for biomarker analysis (Section 8.2). 
 Obtain four 10-mL blood samples for exploratory blood cfDNA biomarker.  Refer 
to the Laboratory Manual for instruction on collection, processing, and shipping 
of samples. 
 Obtain one 6-mL and one 3-mL blood sample for exploratory blood biomarkers 
(osteopontin, interleukin 8 [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 PGx analysis (if subject has consented). 
 In order to time match with C0D1, 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 (C0D 1).  In addition to breakfast time, breakfast content should be the same for 
C0D 1 and C0D1. 
 Lunch should be provided to the subject.  Lunch time and content should be the same 
for C0D 1 and C0D1. 
 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 C0D1. 
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 C0D 1 
prior to dosing. 
DS-1205c should be administered with 240 mL (8 fluid oz) 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 C0D 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 should also be obtained.  Vital signs 


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should be measured after the subject has rested in a supine position for 5 minutes or 
more (Section 9.9). 
 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 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.  Time window for collection time points:  
±15 minutes of nominal times. 
 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 pre-dose and at 1, 2, 4, 6, 8, 10, 
and 12 hours post-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 windows 
for collection time points:  2 hours (for pre-dose), ± 15 minutes (for hours 1 to 10 
post-dose), and ± 1 hour (for 12 hours post-dose). 
 If not completed on C0D 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 as on C0D 1. 
 Assess AEs/SAEs (Section 9). 
 During the DLT-evaluation period (from C0D1 to C1D21 of Dose Escalation), 
determine whether AEs/SAEs represent DLT (Section 3.2.1.3). 
 Record concomitant medications. 
Prior to the collection of the 12-hour (pre-evening dose) PK blood sample, subjects should be 
given dinner in the clinic.  Dinner should be started approximately 30 minutes prior to dosing 
and should be completed before dosing.  After sample collection, subjects should receive the 
evening dose of DS-1205c in the clinic with 240 mL (8 fluid oz) 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, chemistry, hematology, and urinalysis). 
DS-1205c should be administered with 240 mL (8 fluid oz) 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 C0D 1. 


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The following procedures should be obtained/performed per the Schedule of Events, Dose 
Escalation (Cycle 0) (Table 6.1): 
 Obtain urine for urinalysis pre-dose. 
 Obtain vital signs (systolic and diastolic blood pressure, HR, respiratory rate, and 
body temperature) and SpO2, pre-dose.  Vital signs should be measured after the 
subject has rested in a supine position for 5 minutes or more (Section 9.9). 
 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:  ± 15 minutes of nominal times. 
 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 (for 
pre-dose). 
 Obtain blood for hematology, coagulation, and blood chemistry 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 C0D1 to C1D21 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 as indicated in Schedule of Events, 
Dose Escalation (Cycle 0) (Table 6.1). 
DS-1205c should be administered with 240 mL (8 fluid oz) 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 C0D 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) and SpO2, pre-dose.  Vital signs should be measured after the 
subject has rested in a supine position for 5 minutes or more (Section 9.9). 
 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 


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prior to and 5 minutes after each nominal time point for ECG extraction.  Time 
window for collection time points:  ± 15 minutes of nominal times. 
 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 (for 
pre-dose). 
 Assess AEs/SAEs (Section 9). 
 During the DLT-evaluation period (from C0D1 to C1D21 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 C0D6 (eg, chemistry, hematology, and urinalysis) prior to dosing. 
DS-1205c should be administered with 240 mL (8 fluid oz) 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 C0D 1. 
The following procedures should be obtained/performed per the Schedule of Events, Dose 
Escalation (Cycle 0) (Table 6.1): 
 Obtain urine for urinalysis pre-dose. 
 Obtain vital signs (systolic and diastolic blood pressure, HR) and SpO2, pre-dose.  
Vital signs should be measured after the subject has rested in a supine position for 
5 minutes or more (Section 9.9). 
 12-lead Endpoint ECGs will be extracted from a continuous 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:  ± 15 minutes of nominal times. 
 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 (for 
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 Obtain blood for hematology, coagulation, and blood chemistry 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 C0D1 to C1D21 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 C0D7 prior to dosing. 
DS-1205c should be administered with 240 mL (8 fluid oz) 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 C0D 1. 
The following procedures should be obtained/performed per the Schedule of Events, Dose 
Escalation (Cycle 0) (Table 6.1): 
 Obtain urine for urinalysis pre-dose.  Alternatively, urine for urinalysis may be 
obtained C1D1. 
 Obtain vital signs (systolic and diastolic blood pressure, HR) and SpO2, pre-dose.  
Vital signs should be measured after the subject has rested in a supine position for 
5 minutes or more (Section 9.9). 
 12-lead Endpoint 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.  Time window for collection time points:  ± 15 minutes of 
nominal times. 
 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 pre-dose and at 1, 2, 4, 6, 8, and 
10 hours post-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 windows for 
collection time points:  2 hours (for pre-dose) and ± 15 minutes (for hours 1 to 10 
post-dose). 
 Obtain blood for hematology, coagulation, and blood chemistry pre-dose 
(Section 9.8).  Alternatively, blood for hematology, coagulation, and blood chemistry 
may be obtained C1D1. 


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 Obtain blood for thyroid function tests (Section 9.8).  Alternatively, blood for thyroid 
function tests may be obtained C1D1. 
 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 C1D1. 
 Lunch should be provided to the subject approximately 4 hours after dosing.  Lunch 
time and content should be the same as on C0D 1. 
 Assess AEs/SAEs (Section 9). 
 During the DLT-evaluation period (from C0D1 to C1D21 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. 
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, osimertinib 80 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 C0D7.  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 C0D 1.  Subjects should receive the morning dose of 
DS-1205c and 80 mg of osimertinib with 240 mL (8 fluid oz) of water. 
The following procedures should be obtained/performed per the Schedule of Events, Dose 
Escalation (Cycle 1 and Beyond) (Table 6.2): 
 If not obtained on C0D7, obtain urine for urinalysis pre-dose. 
 Vital signs (systolic and diastolic blood pressure, HR, respiratory rate, and body 
temperature) and SpO2 at pre-dose and at 2, 4, 6, and 8 hours post-dose.  Vital signs 
should be measured after the subject has rested in a supine position for 5 minutes or 
more (Section 9.9). 
 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. 
 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 


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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 osimertinib.  
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). 
 Obtain blood sample for exploratory blood cfDNA pre-dose. 
 Obtain blood sample for exploratory blood biomarker pre-dose. 
 If not obtained on C0D7, obtain blood for hematology, coagulation, and blood 
chemistry pre-dose (Section 9.8). 
 If not obtained on C0D7, obtain blood for thyroid function tests (Section 9.8). 
 If not performed/recorded on C0D7, 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 C0D1 to C1D21 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 osimertinib, and procedures should be obtained/performed 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 C0D 1.  Subjects should receive the morning dose of 
DS-1205c and 80 mg of osimertinib with 240 mL (8 fluid oz) of water. 
 Obtain urine for urinalysis. 
 Vital signs (systolic and diastolic blood pressure, HR) and SpO2 pre-dose.  Vital signs 
should be measured after the subject has rested in a supine position for 5 minutes or 
more (Section 9.9). 
 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. 
 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. 


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 Obtain blood samples for PK analysis, pre-dose, for both DS-1205a and osimertinib.  
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). 
 Obtain blood sample for exploratory blood biomarker pre-dose. 
 Obtain blood for hematology, coagulation, and blood chemistry. 
 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 C0D1 to C1D21 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 15 days (+ 7 days) after 
the first dose of study drug.  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 C0D 1.  Subjects should receive the morning dose of 
DS-1205c and 80 mg of osimertinib with 240 mL (8 fluid oz) of water. 
The following procedures should be obtained/performed per the Schedule of Events, Dose 
Escalation (Cycle 1 and Beyond) (Table 6.2): 
 Obtain urine for urinalysis. 
 Vital signs (systolic and diastolic blood pressure, HR, respiratory rate and body 
temperature) and SpO2, pre-dose.  Vital signs should be measured after the subject 
has rested in a supine position for 5 minutes or more (Section 9.9). 
 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 
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 Lunch should be provided to the subject approximately 4 hours after dosing.  Lunch 
time and content should be the same as on C0D 1. 
 Obtain blood samples for PK analysis for both DS-1205a and osimertinib at pre-dose 
and at 1, 2, 4, 6, 8, 10, and 12 hours post-dose (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 windows for collection time points:  2 hours (for 
pre-dose), ± 15 minutes (for hours 1 to 10 post-dose), and ± 1 hour (for 12 hours 
post-dose). 
 Obtain blood sample for exploratory blood cfDNA pre-dose. 
 Obtain blood sample for exploratory blood biomarker pre-dose. 
 Obtain blood for hematology, coagulation, and blood chemistry. 
 Obtain blood for thyroid function tests (Section 9.8). 
 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). 
 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. 
Prior to the collection of the 12-hour (pre-evening dose) PK blood sample, subjects should be 
given dinner in the clinic.  Dinner should be started approximately 30 minutes prior to dosing 
and should be completed before dosing.  After sample collection, subjects should receive the 
evening dose of DS-1205c in the clinic with 240 mL (8 fluid oz) of water. 
After completion of in-clinic procedures, subjects should be discharged from the clinic with 
study medications and the Study Medication Diary.  Subjects should be reminded to bring all 
study medications and Study Medication Diary the following day. 
Subjects should be reminded 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. 
6.1.3.4. 
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 osimertinib, and procedures should be obtained/performed 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, 


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breakfast content should be the same as on C0D 1.  Subjects should receive the morning dose of 
DS-1205c and 80 mg of osimertinib with 240 mL (8 fluid oz) of water. 
 Obtain vital signs (systolic and diastolic blood pressure, HR) and SpO2, pre-dose.  
Vital signs should be measured after the subject has rested in a supine position for 
5 minutes or more (Section 9.9). 
 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.  Time 
window for collection time points:  ± 15 minutes of nominal times. 
 Obtain blood samples for PK analysis of DS-1205a and osimertinib 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 (for pre-dose). 
Day 8 only: 
 Obtain blood for hematology, and blood chemistry 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). 
After completion of in-clinic procedures, 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 osimertinib (including that 
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 
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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 C1D1 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 C1D1.  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) 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. 
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.  Breakfast should be started 30 minutes prior to 
dosing and should be completed within approximately 30 minutes.  In addition to breakfast time, 
breakfast content should be the same as on C0D 1.  Subjects should receive the morning dose of 
DS-1205c and 80 mg of osimertinib with 240 mL (8 fluid oz) of water. 
The following procedures should be obtained/performed 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, …). 
 Vital signs (systolic and diastolic blood pressure, HR) and SpO2, pre-dose.  Vital 
signs should be measured after the subject has rested in a supine position for 
5 minutes or more (Section 9.9). 


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 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 for PK analysis, pre-dose, for DS-1205a (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). 
 Obtain blood sample for exploratory blood cfDNA pre-dose (Day 1 of Cycle 3 and 
every two cycles thereafter:  Cycles 5, 7, 9, …). 
 Obtain blood sample for exploratory blood biomarker pre-dose (Day 1 of Cycle 3 and 
every two cycles thereafter:  Cycles 5, 7, 9, …). 
 Obtain blood for hematology and blood chemistry (Section 9.8). 
 Obtain blood for coagulation (Day 1 of Cycle 3 and every 2 cycles thereafter:  Cycles 
5, 7, 9, …) (Section 9.8). 
 Obtain blood for thyroid function tests (Day 1 of Cycle 3 and every two cycles 
thereafter:  Cycles 5, 7, 9, …) (Section 9.8). 
 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. 
After completion of in-clinic procedures, subjects should be discharged from the clinic with 
study medications for at-home dosing and the Study Medication Diary, and the following 
instructions: 
 Instructions for at-home dosing of DS-1205c and osimertinib (including that 
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. 
6.1.3.7. 
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. 


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The following procedures should be obtained/performed per the Schedule of Events, Dose 
Escalation (Cycle 1 and Beyond) (Table 6.2): 
 Obtain urine for urinalysis. 
 Obtain a urine sample for pregnancy testing in women of childbearing potential. 
 Vital signs (systolic and diastolic blood pressure, HR) and SpO2, pre-dose.  Vital 
signs should be measured after the subject has rested in a supine position for 
5 minutes or more (Section 9.9). 
 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 sample for exploratory blood cfDNA. 
 Obtain blood sample for exploratory blood biomarker. 
 Obtain blood for hematology and blood chemistry (Section 9.8). 
 Obtain blood for coagulation (Section 9.8). 
 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. 
6.1.3.8. 
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. 


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6.1.3.9. 
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. 
Dose Expansion 
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6.3. 
Schedule of Events 
The schedule of study events is provided for Dose Escalation in Table 6.1 and Table 6.2, and for 
Dose Expansion in Table 6.3. 
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j Triiodothyronine (T3) may be measured as total T3 or free T3 and thyroxine (T4) as total T4 or free T4. 
k A serum pregnancy test is required for all female subjects of childbearing potential at Screening only (Section 9.8).  Urine pregnancy tests should be performed throughout the 
study as indicated. 
l Perform hepatitis B (HBsAg and anti HBc), hepatitis C (HCV antibody), and HIV antibody tests (HIV antibody test is optional unless required by local regulations or 
IRB/IECs). 
m 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. 
n 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. 
o 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. 
p Vital sign measurements include systolic/diastolic blood pressure and heart rate.  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 after the subject 
has rested in a supine position for 5 minutes or more. 
q Physical examination/ECOG PS and weight need to be obtained/performed on EITHER C0D 1 OR C0D1. 
r Ophthalmologic assessments:  visual acuity, slit lamp examination, fundoscopy, and tonometry.  More frequent examinations may be performed at the discretion of the 
Investigator. 
s 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. 
t 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. 
u DS 1205c should be administered BID, with 240 mL (8 fluid oz) of water, as follows:  200 mg BID (Cohort 1); 400 mg BID (Cohort 2); 600 mg BID (Cohort 3); 800 mg BID 
(Cohort 4).  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 
(Section 3.2.1). 
v 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 C1D1.  Tumor assessments should be performed per RECIST version 1.1 
(Section 17.2). 
w CT or MRI of the brain should be performed for all subjects. 
x 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 C0D 1 
(historical scans are acceptable). 
y Consent for pharmacogenomic (PGx) blood sampling is included in the main study ICF. 
z Obtain four 10 mL samples for exploratory pharmacodynamic biomarkers (cfDNA and exosomes).  Refer to the Laboratory Manual for instructions for collection, processing, 
and shipping of samples. 










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b To be obtained/performed pre dose. All pre dose procedures should be obtained/performed prior to in clinic meal (breakfast). 
c May be performed C0D7. 
d Triiodothyronine (T3) may be measured as total T3 or free T3 and thyroxine (T4) as total T4 or free T4. 
e Urine pregnancy tests should be performed throughout the remainder of the study as indicated (Section 9.8). 
f 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. 
g To be obtained/performed pre dose and at 2, 4, 6, and 8 hours post dose. 
h 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. 
i Vital sign measurements include systolic/diastolic blood pressure and heart rate.  Pulse oximetry should be performed with vital signs.  Respiratory rate and body temperature 
should also be measured pre dose C1D1 and pre dose C2D1.  Vital signs should be measured after the subject has rested in a supine position for 5 minutes or more. 
j Beginning with C1D1, DS 1205c should be administered with a meal, with 240 mL (8 fluid oz) 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.  Osimertinib 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. 
k 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. 
l 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 ± 1 
hour (for 12 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 osimertinib are measured at the same time point, separate 6 mL samples should be obtained.  Refer to the Laboratory Manual for instructions about collection, processing, 
and shipping of samples. 
m Prior to the collection of the 12 hour (pre evening dose) PK blood sample, subjects should be given dinner in the clinic.  Dinner should be started approximately 30 minutes prior 
to dosing and should be completed before dosing. 
n Obtain four 10 mL samples for exploratory pharmacodynamic biomarkers (cell free DNA [cfDNA] and exosomes).  Refer to the Laboratory Manual for instructions for 
collection, processing, and shipping of samples. 
o Obtain one 6 mL and one 3 mL sample for pharmacodynamic biomarkers (osteopontin, interleukin 8, sAXL) pre dose as indicated.  Refer to the Laboratory Manual for 
instructions for collection, processing, and shipping of samples. 
p 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. 
q 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 C1D1.  Tumor assessments should be performed per RECIST version 1.1 
(Section 17.2). 
r 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 C1D1 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. 
s 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 
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t 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 and 
every 4 cycles ( 7 days) thereafter, and at EOT.  Investigators must ensure results of ophthalmologic assessments are available for review prior to dosing on corresponding cycle 
visits. 
u ECHO or MUGA should be performed on C2D1 ( 7 days); C4D1, 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 (Section 9.12).  Investigators must ensure results of ECHO/MUGA are available for review prior to dosing on corresponding cycle visits. 
v On study biopsy is optional.  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.  CBC must be obtained within 2 days of the tumor biopsy and results must be reviewed by the Investigator prior to obtaining a tumor biopsy. 
w 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 
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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 C1D1 for the first 24 weeks then every 12 weeks (± 7 days) thereafter, as indicated in the 
Schedule of Events (Table 6.2 and Table 6.3), until radiological progression or until the subject 
permanently discontinues treatment.  The schedule of efficacy assessments is determined relative 
to C1D1 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 progressive disease.  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 osimertinib (and its active metabolites34 
AZ5104 and AZ7550) 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 blood sample will be collected for 
DS-1205a and/or osimertinib analysis.  If both DS-1205a and osimertinib are measured at the 
same time point, separate samples should be obtained.  Instructions for the collection, handling, 
storing and shipping of the PK samples for DS-1205a and osimertinib 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 osimertinib PK analysis must be recorded on the eCRF. 
If time points coincide for different blood samplings, the PK samples should be taken at the 
exact nominal time point, followed by serum chemistry, hematology, and then biomarker 
samples.  If time points of procedures coincide with blood sampling, vital signs, Safety ECG, 
and Endpoint ECG should be taken immediately prior to PK sampling time. 
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 in Dose 
Escalation 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). 
 Dose Escalation Cycle 0:  Cmax, Tmax, Ctrough, AUC parameters, and other PK 
parameters as appropriate. 
 Dose Escalation/Expansion:  Cmax,ss, Tmax, Ctrough, AUC parameters, 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 osimertinib 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 osimertinib 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 


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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 molecules.  One or more of the aforementioned 
pharmacodynamic biomarkers may also be explored for predictive value. 
Plasma samples for biomarker analysis may 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 osimertinib.  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 RNA, DNA, 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 erlotinib, 
gefitinib, afatinib, or osimertinib AND 
 the tissue biopsy was obtained within 6 months since 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 15 days (+ 7 days) after 
the first dose of study drug.  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 tumor 
biopsy and results must be reviewed by the Investigator prior to obtaining a tumor 
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End-of-Treatment 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 erlotinib, gefitinib, afatinib, or osimertinib. 
Subjects previously treated with erlotinib, gefitinib, or afatinib are required to demonstrate an 
absence of EGFR T790M mutation prior to study entry, assessed in tumor tissue by either: 
 (a) cobas® EGFR Mutation Test v2 performed by central laboratory or 
 (b) an EGFR T790M mutation test performed locally by a CLIA-, CAP-, or ISO 
15189-certified laboratory. 
The in vitro diagnostic product cobas® EGFR Mutation Test v2 should be used in accordance 
with instructions for use in the approved label.  No EGFR mutation testing is required if treated 
with osimertinib. 
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.  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 RNA, DNA, or protein 
analysis.  Additional samples may be requested if the original sample is of insufficient quantity 
or quality to complete planned analyses. 
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 
osimertinib, 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. 
If the subject 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 


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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. 
If a subject withdraws consent for biomarker analysis at any time during or at the end of the 
storage period, their blood and tissue samples will be promptly disposed.  However, any derived 
biomarker data will not be discarded if the analysis is completed before the subject withdraws 
consent. 
If, prior to enrollment, a subject does not consent to providing blood samples or a tumor sample 
for the screening assessment, the subject cannot be enrolled in the study. 
If, prior to enrollment, a subject does not consent to providing optional tumor samples to be 
analyzed after treatment with study drug, the subject can still be enrolled. 
8.2.4. 
Disclosure of the Results of Biomarker Assessment 
The tissue screening results of central laboratory EGFR T790M mutation-testing will be 
disclosed to the subject or Investigators, as they affect the treatment selection.  As the value of 
additional future biomarker assessments is currently unknown, 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 
PGx testing as part of the main study ICF.  For subjects who give informed consent for PGx 
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 PGx analysis will be collected from each subject who has 
provided informed consent, according to the Schedule of Events (Table 6.1 and 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 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 PGx research cannot be known at this time, any results 
obtained from research involving PGx samples will not be disclosed to the subject or 
Investigators now or in the future. 


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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 PGx analysis has been completed 
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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 last dose of study drug), whether observed 
by the Investigator or reported by the subject, will be recorded on the AE 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 events of special interest 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.  Adverse events 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 
Informed Consent Form) 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. 
Any serious, untoward event that may occur subsequent to the reporting period that the 
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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 AEs of special interest (AESIs) should be reported to the Sponsor by the 
Investigator 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 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 ≥Grade 2 (average QTc 481 ms to 500 ms) should be 
reported as an 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), 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 osimertinib (see current prescribing information).  If a subject is 
suspected or diagnosed as having ILD, the Investigator should consult with a 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 


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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, October 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, October 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. 
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 Informed Consent Form) procedures or treatments 
requiring hospitalizations for pre-existing conditions that do not worsen in severity 
are not SAEs. 


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An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important.  All occurrences of overdose must be 
reported as an SAE. 
9.4.3. 
Adverse Event Severity 
The severity of AEs will be graded using the NCI-CTCAE version 5.0.  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 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. 


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 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 
9.4.6. 
Other Action Taken for Event 
 None:  No treatment was required 
 Medication required:  Prescription and/or 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 
9.5. 
Serious Adverse Events Reporting Procedure For Investigators 
All AEs, AESIs, and SAEs will be reported in the eCRF. 
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: 
 SAEs (see Section 9.4.2 for definition) 


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 Hepatic events (both serious and non-serious, and clinical laboratory results) meeting 
the potential Hy’s Law criteria defined as an elevated ALT or AST ≥3 × ULN with 
simultaneously elevated total bilirubin ≥2 × ULN should be reported as an AESI (see 
Section 9.3.1 for additional details), regardless of whether these hepatic events are 
symptomatic, lead to study drug discontinuation/dose reduction, require corrective 
treatment, constitute an AE in the Investigator’s clinical judgement, 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 should 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. 
In the event that an eCRF is unavailable, report SAEs by faxing the paper 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. 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Institutional Ethics Committee 
The Sponsor and/or CRO will inform Investigators, Institutional Review Boards/Institutional 
Ethics Committees (IRBs/IECs), and regulatory authorities of any Suspected Unexpected Serious 
Adverse Reactions (SUSARs) occurring in other 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 the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the study 
drug, unless delegated to the Sponsor, it is the Investigator’s responsibility to inform the IRB per 
Sponsor’s instruction. 
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. 
In the European Economic Area (EEA) states, it is the Sponsor’s responsibility to report 
SUSARs to all ECs. 


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9.7. 
Exposure In Utero During Clinical Studies 
The Sponsor must be notified of any subject who becomes pregnant while receiving, or within 
4 months of discontinuing, the study drug.  Daiichi Sankyo, Inc. must be notified of any male 
subject whose female partner becomes pregnant while the subject is receiving, or within 
4 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, hemoglobin, hematocrit, platelet count, white blood cell 
count, and differential white blood cell count (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils) 
Chemistry 
Total protein, albumin, ALP, ALT, AST, TBL, BUN or urea, calcium, chloride, 
creatine kinase, serum creatinine, LDH, lipase, magnesium, potassium, sodium, 
FSH (if indicated), estradiol (if indicated), T3,a,b T4,a,b TSH,a and triglycerides 
Coagulation  
Prothrombin time or PT-INR, and partial thromboplastin time (PTT/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; T4 = thyroxine; TBL = total bilirubin; TSH = thyroid 
stimulating hormone 
a Thyroid function tests (ie, T3, T4, and TSH) will be performed as described in the Schedule of Events (Table 6.1, 
Table 6.2, Table 6.3).  More frequent examinations may be performed at the discretion of the Investigator and if 
indicated. 
b Triiodothyronine (T3) may be measured as total T3 or free T3 and thyroxine (T4) as total T4 or free T4. 
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, a SAVER form should be 
submitted, and other relevant procedures must be followed (see Section 9.4.2).  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 heart rate, 
respiratory rate, and body temperature.  Additionally, SpO2 will be performed as outlined in the 
Schedule of Events (Table 6.1, Table 6.2, and Table 6.3). 
Blood pressure and heart rate will be measured after the subject has rested supine for at least 
5 minutes. 
9.10. 
Electrocardiograms 
9.10.1. 
Safety ECGs 
The QTcF will be used for clinical assessments and should be calculated as follows: 
 


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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. 
QTc prolongation ≥Grade 2 (average QTc 481 ms to 500 ms) should be reported as an AESI.  If 
a subject experiences QTc prolongation of Grade 4 (torsades de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of serious arrhythmia), 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 the New York Heart Association (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 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. 


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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 TSH reported.38  Although an association with osimertinib has yet to 
be established, thyroid function tests (ie, T3, T4, 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.  Triiodothyronine (T3) may be measured as total T3 or free T3 and 
thyroxine (T4) as total T4 or free T4. 


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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 cohort 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 C0D 1 
measurements for all ECG. 
Safety analyses will be performed based on the safety 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 sets.  Data from Dose Escalation 
will be summarized by dose group 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. 
 Full Analysis Set will include all subjects in the Enrolled Analysis Set who received 
at least 1 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 
1 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 1 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 osimertinib. 


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 Concentration-QTc Analysis Set will include all subjects who are in the Safety 
Analysis Set with at least 1 pair of post-dose plasma concentration data and 
time-matched QTc data from the same timepoint.  The PK/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, 
Full Analysis Set, 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 
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 
full analysis set by dose group for Dose Escalation and Dose Expansion.  For the final analysis, 
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 phase and the dose expansion phase.  
Subjects with unknown or missing response will be treated as non-responders.  Response rate 
will be summarized by treatment group with the 95% CI using the Clopper-Pearson method. 
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. 
DCR will be reported as a summary statistic by dose cohort.  Point estimates and 2-sided 95% 
exact binomial confidence intervals will be provided. 


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Time-to-event variables including PFS, TTR, and OS will be summarized with median event 
times with 2-sided 95% confidence interval (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.  Evaluation of dose proportionality may also be performed using power analysis. 
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 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 cohort. 
11.6.1. 
Adverse Event Analyses 
A TEAE is defined as an AE that emerges during the treatment period (from first dose date until 
follow-up call 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 osimertinib. 
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. 
Deaths, other SAEs, and other significant AEs, including those leading to permanent 
discontinuation from study treatment, will be listed. 
AEs of special interest (AESI) will be added as needed.  The details will be described in the SAP. 


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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 QTcF 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, 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 version 5.0, 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 Grade 4 
will be listed. 
11.6.4. 
Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements by scheduled time of 
evaluation and by treatment group 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 Adjudication Committee (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 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.  This additional data collection will cover a more 
in-depth, relevant medical history (eg, smoking, radiation, chronic obstructive pulmonary disease 
and other chronic lung conditions, etc.), diagnostic evaluation, treatment, and outcome of the 
event.  This data collection will be triggered for any safety event reported using a Medical 
Dictionary for Regulatory Activities (MedDRA) PT from the current ILD SMQ.  The ILD AC 


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will adjudicate ILD cases (including potential ILDs) on an ongoing basis.  Adjudication of ILD 
cases will be based on evaluation of eCRFs and source documents, including, but not limited to, 
high-resolution CT of the chest, arterial blood gases, pulmonary function testing, and the 
diffusing capacity of the lung for carbon monoxide.  The ILD AC will review ongoing cases of 
ILD to make the final determination of ILD diagnoses to guide Daiichi Sankyo decisions 
regarding trial suspension or trial discontinuation and to provide assessment of ILD prevalence at 
the end of the study.  The findings of the ILD AC along with its recommendations will be 
provided to Daiichi Sankyo. 
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 
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. 
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 
CCI


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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.  Consequently, 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 maximum tolerated dose (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: 
Parameters 
Means 
Standard Deviations 
Correlation 
log(α), log(β) 
(-1.0741, -0.3292) 
(2.094, 1.3662) 
-0.2101 
11.11.3. 
Escalation with Overdose Control Principle 
Dose recommendation for the next cohort of subjects will be based on summaries of the posterior 
probability of DLT rate for provisional doses.39  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] 


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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 and CRO monitor and regulatory authority inspectors are responsible for contacting 
and visiting the Investigator for the purposes 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”. 


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The eCRF 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 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 according to specifications given to 
Chiltern International, Inc.  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. 
Serious adverse events in the clinical database will be reconciled with the safety database. 
All AEs will be coded using the latest version of 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. 
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, Investigator’s Brochure, 
copies of relevant essential documents required prior to commencing a clinical study, 
and all correspondence to and from the IRB and Sponsor 
 Records related to the investigational product(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. 
These records will be retained in a secure file for the period required by the institution or study 
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. 
12.5. 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, 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. 


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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 Daiichi Sankyo.  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 
Daiichi Sankyo, Inc. is committed to meeting the highest standards of publication and public 
disclosure of information arising from clinical trials sponsored by the company.  We 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.  We follow 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 we are 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. 
Ethics and Study Administrative Information 
15.2. 
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 and/or 
 Other applicable local regulations 
15.3. 
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 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. 
15.4. 
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. 
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 


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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. 
15.5. 
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, 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 


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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. 
15.6. 
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. 
15.7. 
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 information.  The Investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised ICF. 
15.8. 
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 


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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 the Summary of Changes. 
15.9. 
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). 
15.10. 
Data and Safety Monitoring Board 
Not applicable. 
15.11. 
Address List 
A full list of contacts will be provided in the study site binder and/or operations manual. 
A list of key study personnel (including personnel at the Sponsor, CRO, laboratories, and other 
vendors) and their contact information (address, telephone, fax, email) is kept on file and 
updated as necessary. 


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Residue of Epidermal Growth Factor Receptor. Drug Metab Dispos. 2016;44(8):1201-12. 
35. Tornøe CW, Garnett CE, Wang Y, et al. Creation of a knowledge management system for 
QT analyses. J Clin Pharmacol. 2011;51(7):1035-42. 
36. Cleveland WS. Robust Locally Weighted Regression and Smoothing Scatterplots. 
Journal of the American Statistical Association. 1979;74(368):829-36. 
37. Hurvich CM, Simonoff JS, Tsai C-L. Smoothing Parameter Selection in Nonparametric 
Regression Using an Improved Akaike Information Criterion. Journal of the Royal 
Statistical Society Series B (Statistical Methodology). 1998;60(2):271-93. 
38. 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. 
39. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Stat Med. 2008;27(13):2420-39. 
40. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41. 
41. 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. 
42. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. ed. Boston: Little, 
Brown & Co. 


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43. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
44. National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0. Available from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50. 
45. Woosley RL, Heise CW, Romero KA. QTdrugs List Available from: 
http://www.CredibleMeds.org. 
46. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table2007. 
Available from: http://medicine.iupui.edu/clinpharm/ddis/clinical-table/. 


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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 equation40 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 1.1.41  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. 


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 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. 
 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. 
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 30 days 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. 


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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 
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. 


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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 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 


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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). 
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 


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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. 
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 is 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 progressive 
disease.  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. 


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17.2.2.4.3. Best Overall Response:  All Time Points 
Best response determination in trials where confirmation of complete or partial response 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.  
Complete or partial responses 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. 
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 


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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 
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. 


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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 14 Mar 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 
Assessment42 
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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17.5. 
National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.044 
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 version 5.0 is accessible online at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50