A Phase 1/2 Study of TAS3351 in Patients With Advanced Non-Small Cell Lung Cancer and EGFR Mutations
Phase: PHASE1
Conditions: Non-Small Cell Lung Cancer
Sponsor: Taiho Oncology, Inc.

Official Title:
 
A Phase 1/2 Study of TAS3351 in Patients with Advanced Non-Small Cell Lung
Cancer and EGFR Mutations
NCT ID:
 
NCT05765734
Document Date:
 
Protocol Amendment 2:
 
08 July 2023

Clinical Study Protocol
A Phase 1/2 Study of TAS3351 in Patients with Advanced 
Non-Small Cell Lung Cancer and EGFR Mutations
Study Number: 10073010
Amendment 2 
Date: 07 July 2023
US IND Number: 162166
ClinicalTrials.gov identifier: NCT05765734
EUCT: 2022-502595-23
jRCT: jRCT2031220742
DOCUMENT HISTORY
Amendment 1  05 January 2023
Original  10 November 2022
SPONSORS
Taiho Pharmaceutical Co., Ltd.
1-27 Kandanishiki-cho,
Chiyoda-ku, Tokyo, 101-8444, Japan
Taiho Oncology, Inc.
101 Carnegie Center, Suite 101
Princeton, NJ 08540, USA
This clinical study will be conducted in accordance with the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), Good 
Clinical Practice (GCP) Guidelines and applicable regulatory requirements.
CONFIDENTIAL
The information contained in this document is the property of Taiho Pharmaceutical Co., Ltd. 
(TPC) and Taiho Oncology, Inc. (TOI). This document contains strictly confidential 
information and no part of this document may be published or disclosed without the prior 
written approval of TPC and TOI, except by request from competent authorities.
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SUMMARY OF CHANGES
The purpose of this amendment was to address the EMA’s comments and clarify existing 
information. All changes have been incorporated into the study synopsis as appropriate; the 
Table of Contents has also been updated.
In addition to these substantive changes, minor administrative alterations were made as 
necessary throughout the protocol, including formatting adjustments and correction of 
typographical errors. These editorial changes do not affect the rationale or planned conduct of 
the study or analyses, and therefore are not summarized in the table below.
Section #
Section Name
Description of Change
Synopsis
Replaced detailed inclusion/exclusion criteria with a high level summary of 
patient population by study part.
Section 1.3
Schedule of Events
Table 1: Schedule of 
Events for Phase1 (Parts A 
and B)
Table 2: Schedule of 
Events for Phase 2 (Part C)
Table 3: Schedule of 
Events – Study Extension 
Phase
Added direction to physical examination assessment that skin examination 
should be performed at each timepoint (Table 1, Table 2 and Table 3).
Clarified pre-dose collection window timing for hematology, chemistry, 
coagulation, and urinalysis assessments in alignment with Section 7.1.4 (Table 
1 and Table 2).
Added MUGA to echocardiography assessment (Table 1) to align with Table 
12.
Clarified timing of PK assessments in the PK Lead-in period (Table 1).
Clarified timing of ECG assessments (Table 1 and Table 2) and timing of 
triplicate ECGs.
Clarified timing of optional tumor tissue biopsy samples (Table 1 and Table 2)
Section 2.1.1
Disease Background and 
Study Population
Clarified existing information sourced from literature.
Added summary of post-osimertinib response in patients with C797S mutation
Section 2.2.3
Overall Benefit/Risk Ratio 
Evaluation
Corrected references.
Section 3
Objectives and Endpoints
Restructured section to include subheadings for each study part and removed 
use of Table caption.
Section 3.3
Phase 2 – Part C
Corrected version of PRO assessment to be used.
Section 4.1
Overview of Study Design
Removed study schema and added cross-reference to Section 1.2.
Section 4.2.1
Phase 1 Dose Escalation 
(Part A)
Clarified that TAS3351 will be administered to patients who harbor any EGFR 
mutation in Part A1.
Added description of safety and efficacy signals to be used in selection of Part 
A2 dose levels.
Section 4.2.4
Study Stopping Criteria
Modified to include additional stopping criteria.
Section 4.3
Scientific Rationale for 
Study Design
Added to include more detailed rationale for Phase 1/2 study design.
Section 4.10
Patient Enrollment
Removed requirement regarding timing of first dose.
Updated definition of enrolled patient.
Section 4.11
Randomization and 
Blinding
Added text regarding randomization in Parts A and C, and for no blinding in 
study.
Clarified Part B randomization language.
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Section #
Section Name
Description of Change
Section 4.12
Data Monitoring 
Committee
Added section.
Section 5.1
Inclusion Criteria
Reformatted inclusion criteria #4 and #5 to convert bulleted content to 
alphabetical list.
Modified inclusion criterion #4a to remove acceptability of patient declining 
standard of care prior to study entry.
Separated Part A2 from Part B and C in inclusion criteria #4 b and c; criteria 
remain the same for both parts.
Section 5.2
Exclusion Criteria
Reformatted exclusion criterion #2c and #2d to converted bulleted content to 
numerical list.
Reformatted exclusion criterion #5 to convert bulleted content to alphabetical 
list.
Modified exclusion criterion #5 to allow patients with leptomeningeal disease 
in Parts A2, B, and C under specified circumstances.
Modified exclusion criterion #7b to clarify that screening for HBV, HCV and 
HIV is not required for consistency with Section 7.1
Section 6.1
Study Drug Administration
Added explanation of dosing in PK Lead-in period.
Section 6.1.1 
Part 1: Dose Escalation
Clarified column header in Table 6.
Added waiting period for dosing after first patient in dose levels following the 
first dosing group.
Section 6.1.2
Dose-limiting Toxicity
Added Sponsor/Investigator DLT communication plan.
Section 6.2.1
Dose Reduction, 
Interruption, and 
Resumption
Clarified dose reduction from 50 mg BID.
Section 6.2.1.2 
Dose Modifications for 
Non-hematologic 
Toxicities
Modified Grade 3 QT prolongation management recommendation to include 
cardiologist evaluation and clarified that resumption of study drug should be at 
the next lower dose level.
Section 6.4.4.2
Gastrointestinal Toxicities
Clarified antiemetic guidance language.
Section 6.4.4.4
Amylase or Lipase 
Elevations
Added section.
Section 6.5.2
Sun Protection
Clarified sun protection language. 
Section 7.1
Study Assessments and 
Procedures
Added race/ethnicity to demographics/medical history assessment.
Added direction to physical examination assessment that skin examination 
should be performed at each timepoint.
Added guidance regarding consistency in Echocardiography/MUGA modality 
used throughout study.
Updated serum chemistry assessment to include lipase and amylase.
Removed urobilinogen from urinalysis assessment and specified preference for 
a 24-hour quantitative measurement of proteinuria.
Removed viral tests assessment.
Section 7.1.2
12-Lead Electrocardiogram
Clarified timing and need for triplicate ECG assessments.
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Section #
Section Name
Description of Change
Section 7.1.6
PRO Measurements
Corrected version of PRO assessment to be used.
Section 8.1
Sample Collection
Clarified timing of ECGs with respect to PK sampling on same day.
Added ECG timepoints to Table 13 and Table 14 for consistency with Table 1.
Clarified timing, use of central vs local, and need for triplicate ECG 
assessments (Table 13 and Table 14)
Clarified timing and conduct of PK sampling.
Section 9.1
Efficacy Criteria
Removed reference to content in Appendix C.
Section 10.1.4.3
Causal Relationship with 
Study Drug
Clarified criterion #2.
Section 10.2
Laboratory Assessments
Added urine to list of assessments for which normal reference ranges must be 
provided.
Section 10.3.3
Reporting of Deaths 
(within 24 hours)
Clarified that all deaths must be recorded on the eCRF death page.
Section 10.4.1
Pregnancy
Added section heading.
Clarified existing language.
Section 10.5
Communication of New 
Information Affecting the 
Conduct of the Study
Section added.
Section 11
Analysis of Biomarkers
Clarified biomarker sample collection, patient eligibility, and sample storage 
and disposal language.
Section 12
Statistical Considerations
Added confirmation that SAP will be finalized prior to database lock.
Section 12.3
Estimation of Sample Size
Corrected term “historical ORR” to “the current standard of care ORR” and 
added reference to supporting literature.
Section 12.5
Analysis Populations
Added All Consenting Population to Table 17.
Clarified PK Analysis and Pharmacodynamic/Biomarker Analysis Populations 
definitions.
Section 12.7.5
Other Analyses
Corrected version of PRO assessment to be used.
Section 13.12
Post-study Provisions
Section removed due to redundancy.
Section 15.3
Institutional Review Board/ 
Independent Ethics 
Committee
Updated section heading to include Independent Ethics Committee.
Section 17
Signatures of Sponsor and 
Investigator
Section removed to align with updated corporate policies.
Section 17
References
Section numbering updated due to removal described above.
Added Oken et al, Yin et al, Wages et al, and Yang et al 2021 to reference list.
Removed Hesketh et al and Takeda et al. from list.
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Section #
Section Name
Description of Change
Appendix A
Examples of Clinical 
Substrates, Inhibitors, and 
Inducers of CYP Enzymes 
and Transporters
Added edoxaban to P-gp and BCRP substrates table to align with current 
version of listed source.
Appendix B
Eastern Cooperative 
Oncology Group (ECOG) 
Performance Status
Appendix removed to align with updated corporate policies.
Appendix C
Tumor Definitions and 
RECIST v1.1 Response 
Criteria
Appendix removed to align with updated corporate policies.
Appendix D
Supplemental 
Requirements for Japan
Appendix relocated to a Japan-specific addendum.
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1.
PROTOCOL SUMMARY
1.1.
SYNOPSIS
Name of Sponsor:
Taiho Pharmaceutical Co., Ltd. and Taiho Oncology, Inc.
Name of Investigational Product:
TAS3351
Title of the Study: 
A Phase 1/2 Study of TAS3351 in Patients with Advanced Non-Small Cell Lung Cancer and 
EGFR Mutations
Brief Title: Phase 1/2 of TAS3351 in EGFRmt NSCLC 
Phase of Development: Phase 1/2
Study Rationale: 
About 10%–15% of Caucasian patients with non-squamous non-small cell lung cancer (NSCLC) and 
up to 50% of East-Asian patients with NSCLC have tumors harboring epidermal growth factor 
receptor (EGFR) activating mutations (eg, L858R or exon 19 deletion mutations).1 The current 
standard of care for patients with locally advanced or metastatic NSCLC is treatment with an EGFR 
tyrosine kinase inhibitor (TKI). Several Phase 3 clinical trials have established the role of first-
generation (gefitinib and erlotinib) and second-generation (afatinib and dacomitinib) EGFR TKIs as 
first-line treatment with similar median response rates of 70%-75% and progression-free survival 
(PFS) ranging from 10-14 months as first-line treatment, which was a significant improvement 
compared to platinum-based chemotherapy.2 The most frequent resistance mechanism to first-and 
second-generation EGFR TKIs is the emergence of T790M EGFR kinase domain mutations. More 
recently, the third-generation EGFR TKI osimertinib active against T790M EGFRmt showed superior 
efficacy in first-line EGFRmt NSCLC patients when compared against erlotinib, with improved PFS 
(18.9 versus 10.2 months) and overall survival (OS) (38.6 versus 31.8 months).3,4 
Despite third-generation EGFR TKIs being highly effective in advanced EGFRmt NSCLC, resistance 
to EGFR TKIs inevitably occurs leading to disease progression. The current treatment options for 
EGFRmt NSCLC patients progressing on treatment with third-generation EGFR TKIs are limited. 
Platinum-based chemotherapy combinations with pemetrexed is currently considered standard of 
care.5 However, the reported clinical outcome is poor with approximately 25% ORR and median PFS 
of approximately 4-5 months post osimertinib.6,7,8,9 One of the prevalent resistance mechanisms to 
third-generation EGFR TKIs is an acquired C797S EGFR mutation which is observed in 10%-25% of 
NSCLC patients progressing on osimertinib.10,11,12,13
TAS3351 is a novel fourth-generation EGFR TKI designed to potently inhibit triple-mutant EGFR in 
NSCLC patients. In addition to its activity against EGFR sensitizing mutations (eg, L858R or exon 19 
deletion mutations) and the acquired T790M resistance EGFRmt, TAS3351 also inhibits C797S 
EGFRmt observed in patients progressing on third-generation EGFR TKIs, while sparing EGFR wild-
type. In nonclinical studies, TAS3351 demonstrated dose-dependent activity in vitro and in vivo in 
NSCLC models with co-occurrence of sensitizing EGFRmt and T790M/C797S EGFRmt (data on 
file). Furthermore, TAS3351 has been shown to be brain penetrant in nonclinical models. 
Approximately 25%-40% of patients with NSCLC develop brain metastases and, due to limited 
treatment options, the prognosis of patients with brain metastases remains poor. Thus, TAS3351 
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might also provide a new treatment option for patients with EGFR deregulated NSCLC who have 
brain metastases.  
Based on these results, TAS3351 is expected to have antitumor activity in NSCLC patients with 
tumors harboring an acquired C797S EGFRmt, a population with an unmet medical need.
Objectives and Endpoints: 
Objectives
Endpoints
Phase 1 Dose Escalation
Primary
•
To investigate safety and determine the 
recommended Phase 2 dose (RP2D) and 
dosing schedule of TAS3351
•
Safety, including (but not limited to) 
AEs graded by CTCAE v5.0, and 
incidence of dose limiting toxicities 
(DLTs). As supplementary data, 
preliminary antitumor activity and 
PK/PD results will be considered. 
Secondary 
•
To evaluate the antitumor activity of 
TAS3351
•
Objective response rate (ORR) per 
Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 by Investigator
•
Duration of response (DoR), disease 
control rate (DCR), and time on 
treatment
•
Progression free survival (PFS) and 
Overall Survival (OS) (Patients in part 
A2 only)
•
To characterize the pharmacokinetics 
(PK) of TAS3351 and its active 
metabolite (TAS-05-14317) in plasma 
•
PK parameters including but not limited 
to maximum plasma concentration 
(Cmax), time to maximum plasma 
concentration (Tmax), area under the 
plasma concentration-time curve (AUC), 
and terminal elimination half-life (T½)
Exploratory
•
To explore the relationship between 
exposures of TAS3351 and its active 
metabolite (TAS-05-14317) in plasma 
and QT prolongation
•
Time matched plasma exposures of 
TAS3351 and its active metabolite 
(TAS-05-14317) and changes from 
baseline in QTcF 
•
To explore biomarkers for TAS3351 
including their potential association with 
antitumor activity
•
Biomarkers from tumor tissue and blood 
samples, including (but not limited to) 
DNA/RNA, protein, and cfDNA 
analysis 
•
To explore metabolites of TAS3351 in 
plasma
•
Metabolites of TAS3351 in plasma will 
be characterized
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Objectives
Endpoints
Phase 1 Dose Expansion
Primary
•
To explore the efficacy of TAS3351
•
ORR per RECIST v1.1 by independent 
central review (ICR)
Secondary
•
To confirm the safety and tolerability of 
TAS3351 at the RP2D and dosing 
schedule 
•
AEs, including SAEs, clinical laboratory 
tests, vital signs, and 12-lead ECGs 
graded according to CTCAE v5.0
•
To further explore the antitumor efficacy 
of TAS3351
•
DoR, PFS, and DCR by ICR
•
ORR, DoR, PFS, and DCR by 
Investigator assessment
•
Intracranial ORR (icORR) and DoR 
(icDoR) by ICR and Investigator 
assessment
•
Overall survival (OS)
Exploratory
•
To explore biomarkers for TAS3351 
including their potential association with 
efficacy
•
Biomarkers from tumor tissue and blood 
samples, including (but not limited to) 
DNA/RNA, protein, and cfDNA 
analysis 
•
To explore the potential exposure-
response associations for efficacy and 
safety
•
Exposures estimated by Population PK 
model and selected efficacy and safety 
measures
Objectives
Endpoints
Phase 2
Primary
•
To assess the efficacy of TAS3351
•
ORR per RECIST v1.1 by ICR
Secondary
•
To further assess the efficacy of 
TAS3351
•
DoR, PFS, and DCR by ICR
•
ORR, DoR, PFS, and DCR by 
Investigator assessment
•
Intracranial ORR (icORR) and DoR 
(icDOR) by ICR and Investigator 
assessment
•
Overall survival (OS)
•
To evaluate the safety and tolerability of 
TAS3351
•
AEs, including SAEs, clinical laboratory 
tests, vital signs, and 12-lead ECGs 
graded according to CTCAE v5.0
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Objectives
Endpoints
•
To evaluate patient reported outcomes 
(PROs)
•
EORTC QLQ-C30 and EQ-5D-5L
Exploratory
•
To investigate biomarkers of response to 
TAS3351 and determine their potential 
association with efficacy
•
Biomarkers from tumor tissue and blood 
samples, including (but not limited to) 
DNA/RNA, protein, and cfDNA 
analysis 
•
To explore the potential exposure-
response associations for efficacy and 
safety
•
Exposures estimated by Population PK 
model and selected efficacy and safety 
measures 
Study Design:
Study 10073010 is a first-in-human (FIH) Phase 1/2 study designed to determine the 
recommended Phase 2 dose (RP2D) and efficacy of TAS3351 in patients with locally 
advanced or metastatic non-small cell lung cancer (NSCLC) harboring an acquired C797S 
epidermal growth factor receptor (EGFR) mutation.
The study will consist of 3 parts:
• Part A: Phase 1 Dose Escalation part to determine the RP2D and dosing schedule of 
TAS3351 in advanced NSCLC patients. Part A of study 10073010 will consist of a Dose 
Escalation part (Part A1) and a part for “Backfill” patients (Part A2)
o Part A1: Dose Escalation
TAS3351 will be administered once daily (QD) on a 21-day cycle at a starting dose of 
50 mg QD to patients who harbor any EGFR mutations. The study is designed to 
escalate TAS3351 up to 700 mg QD based on safety and tolerability, with lower 
increments considered if clinically relevant toxicities are observed (see Section 6.1.1). 
The study will use a Bayesian Optimal Interval (BOIN) design 
.15 A 
PK lead-in period will be utilized to assess the terminal elimination phase of 
TAS3351 and active metabolite TAS-05-14317 in plasma. If PK, pharmacodynamics, 
and/or safety data indicate, twice daily (BID) dosing of TAS3351 may be explored.
o Part A2: Backfill Patients
When a dose level has been determined to be safe in Part A1 and either preliminary 
antitumor activity has been observed or the TAS3351 exposure level is associated 
with antitumor activity in nonclinical models, up to 10 additional patients may be 
enrolled at each of such dose levels (“backfill” patients, see also Section 4.2.1). 
“Backfill” patients enrolled are required to have a tumor harboring a C797S EGFRmt. 
The additional information from these “backfill” patient cohorts will broaden the 
amount of safety and preliminary antitumor activity data for TAS3351 at potential 
active dose levels in Part A to inform the selection of the RP2D of TAS3351.
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• Part B: Phase 1 Dose Expansion part to explore the efficacy of TAS3351 in patients with 
C797S EGFRmt NSCLC.
The Phase 1 Dose Expansion part of the study will be initiated after an RP2D and dosing 
scheme have been identified in Part A. Patients with C797S EGFRmt NSCLC will be 
enrolled to explore the efficacy and confirm the safety of TAS3351 at the RP2D in a 
larger patient population. Moreover, a second dose level of TAS3351 might be evaluated 
in an additional cohort of patients in Part B if promising antitumor activity is observed at 
another lower TAS3351 dose level during the Phase 1 Dose Escalation. In such case, 
patients will be randomized between the two dose levels. The results from the Phase 1 
Dose Expansion will confirm the RP2D of TAS3351 and are expected to provide, in 
combination with the “Backfill” patients, the proof of concept for the efficacy of 
TAS3351 in patients with C797S EGFRmt NSCLC. Based on these results, the Phase 2 
part of this study will be initiated.
• Part C: Single arm Phase 2 part to assess efficacy of TAS3351 in patients with C797S 
EGFRmt NSCLC.
The Phase 2 part of the study will be an open-label, single-arm Phase 2 study to assess 
the efficacy of TAS3351 in advanced NSCLC patients with a C797S EGFRmt who 
progressed on a prior treatment with another EGFR inhibitor. Patients will receive 
TAS3351 at the RP2D and dosing scheme and be evaluated for ORR based on RECIST 
1.1 by independent central review (ICR) as the primary endpoint of the Phase 2. A key 
secondary endpoint of this part of the study will be duration of response by ICR.
Number of Patients (planned):
Approximately 200 patients with NSCLC will be enrolled in this study. The total number of 
patients will depend upon the number of dose levels evaluated and potential patient 
replacements including: 
-
Part A (Phase 1): Up to 60 NSCLC patients 
o Part A1: Dose escalation in up to 40 patients with any EGFRmt status
o Part A2: “Backfill” cohorts with approximately 20 patients with C797S EGFRmt 
-
Part B (Phase 1 Dose Expansion): Up to 40 patients with C797S EGFRmt NSCLC
-
Part C (Phase 2): 100 patients with C797S EGFRmt NSCLC.
Study Population:
Part A1
The study population for Part A1 includes adult patients with histologically or cytologically 
confirmed, locally advanced, nonresectable or metastatic NSCLC with any EGFRmt. Patients 
who have received standard of care and no more than 2 lines of prior cytotoxic chemotherapy 
for locally advanced or metastatic disease are eligible.
Part A2 
The study population for Part A2 includes adult patients with histologically or cytologically 
confirmed, locally advanced, nonresectable or metastatic NSCLC with any sensitizing 
EGFRmt and a confirmed C797S EGFRmt. Patients who have progressed on any third-
generation EGFR TKI and are not eligible for platinum-based chemotherapies or other 
targeted therapies (in case of off-target alterations), and have received no more than 2 lines of 
prior cytotoxic chemotherapy for locally advanced or metastatic disease are eligible.
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Parts B and C
The study population for Parts B and C includes adult patients with histologically or 
cytologically confirmed, locally advanced, nonresectable or metastatic NSCLC with any 
sensitizing EGFRmt and a confirmed C797S EGFRmt. Patients who have progressed on any 
third-generation EGFR TKI and have received no more than 2 lines of prior cytotoxic 
chemotherapy for locally advanced or metastatic disease are eligible.
Investigational Product:
TAS3351 is supplied as 25, 100, and 200 mg tablets. TAS3351 will be administered orally 
once daily (QD) on a 21-day cycle. If PK, pharmacodynamic, and/or safety data indicate that 
splitting the TAS3351 dose into 2 daily doses might be preferable, twice daily (BID) dosing 
of TAS3351 may be explored.
Reference and/or Control Therapy, Dosage, and Mode of Administration:
Not applicable.
Duration of Treatment:
Patients will receive TAS3351 study medication until documentation of progressive disease 
(PD), unacceptable toxicity, or any other discontinuation or withdrawal criterion is met.
Criteria for Evaluation:
Efficacy:
Efficacy will be evaluated based on tumor assessments (including CT]/magnetic resonance 
imaging [MRI) performed by Investigator/local radiologist according to RECIST v1.1 
guideline.
Safety:
Safety and tolerability will be assessed based on the incidence of treatment-emergent adverse 
events (TEAEs, including serious adverse events [SAEs] and DLTs), dose modifications, 
clinical laboratory parameters, 12-lead electrocardiograms (ECGs), measurement of ejection 
fraction, ophthalmologic abnormalities, and vital signs. Grading of TEAEs will be performed 
based on CTCAE, Version 5.0.PK matched central ECG will be performed as triplicates for 
patients enrolled in Part A1. 
Pharmacokinetics
The plasma concentrations of TAS3351 as well as its active metabolite, TAS-05-14317, will 
be measured by a validated LC/MS/MS method. The PK data obtained in the Dose Escalation 
phase will be analyzed by non-compartmental analysis to derive key PK parameters including 
but not limited to Cmax, Tmax, AUC, and T1/2. The concentration data by time and study day 
obtained in the Expansion phase and/or Phase 2 will be summarized descriptively.
Biomarkers
For patient eligibility, the EGFRmt status has to be determined by a CLIA certified (US), 
locally certified (outside of the US), or the study central laboratory based on tumor tissue or 
plasma cfDNA. For patients enrolled based on local results, EGFRmt status will be 
confirmed at the Sponsor’s designated study central laboratory post-enrollment. 
For exploratory biomarker analysis, changes in circulating free tumor DNA (cfDNA) from 
blood samples collected at baseline and on-treatment may be assessed retrospectively for any 
change of genomic variants following TAS3351 treatment and any association with clinical 
outcomes. Changes in biomarkers from optional tumor samples (eg, pEGFR) collected 
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on-treatment may be analyzed relative to baseline expression, if paired tumor samples are 
available.
Patient Reported Outcome
Patients’ health-related quality of life, symptoms, functioning, and general well-being will be 
captured using the EORTC QLQ-C30 and EQ-5D-5L questionnaires.
Statistical Methods:
Sample Size Calculation:
•
Part A: Phase 1 Dose Escalation
There will be up to 40 evaluable patients enrolled using the BOIN design, 
 
. Up to approximately 20 
patients may be added for backfill cohorts as needed in the Phase 1 Dose Escalation (up 
to 60 patients total). 
•
Part B: Phase 1 Dose Expansion
Approximately 40 patients in 2 cohorts may be enrolled in the Phase 1 dose expansion in 
Part B of this study. Beside the RP2D, an additional lower dose level may be evaluated 
in the Phase 1 expansion. Sample size considerations for each cohort were based on 
estimating the proportion of responders with certain precision. If there are 9 responders, 
a sample size of 20 patients per cohort would allow to exclude the current standard of 
care ORR of 25% (90% CI: 27.4%, 68.0%).
•
Part C: Phase 2
Approximately 100 patients will be enrolled in the Phase 2 part of this study. Sample 
size considerations were based on estimating the proportion of responders with certain 
precision. The 95% exact CI for ORR would exclude the current standard of care ORR 
of 25% if the overall ORR is 35% or higher. With 100 patients, if there are 35 responses, 
the 95% exact CI is (25.7 to 45.2%) to exclude the current standard of care ORR of 25%.
Efficacy Analysis
Descriptive statistics and summaries will be presented. Two-sided 95% CI will be estimated 
using the Clopper–Pearson method. For time to event endpoints, the Kaplan-Meier method 
will be used to estimate the median and percentile with the 2-sided 95% CI calculated using 
the Brookmeyer and Crowley method.
Safety Analysis
Safety data will be summarized descriptively.
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1.2.
STUDY DIAGRAM 
Abbreviations: 2L=second line; EGFRmt=epidermal growth factor receptor mutation; ICR=independent central review; NSCLC=non-small cell lung cancer; ORR= overall 
response rate; pts=patients; TKI=tyrosine kinase inhibitor
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1.3.
SCHEDULE OF EVENTS
Table 1:
Schedule of Events for Phase 1 (Parts A and B)
Treatment Period
Follow-up Period
Notes
PK 
Lead-
ina
Cycle 1
 (21 days)
Cycle 2
 (21 days)
Cycles 
≥3
 (21 
days)
Safety 
Follow-upb
Survival 
Follow-up
Procedure
Screening
Period
Within 28 
Days prior to 
first dose
Day
-3 
Day 
1
Day 
8 
(±1 
day)
Day 
15 
(±3 
days)
Day 1
(±3 
days)
Day 8
(±3 
days)
Day 1 
(±3 
days)
30 (+3) days 
after last dose 
EGFR C797S status
(pre-screening 
informed consent)
See Notes
Only if central pre-screening done. Can be 
done any time prior to screening.
Written informed 
consent (main study) 
X
To be obtained prior to any study related 
procedures.
Review inclusion / 
exclusion criteria 
X
All patients in Part A2 and B must have 
documented C797S EGFRmt. See Section 4.1 
and Section 4.2 
Demographics/
Medical history 
X
Including prior antitumor treatment
Physical examination 
X
X
X
X
X
X
X
Within 24 hours prior to dosing. May be 
symptom directed during treatment period. 
Examination of skin should be performed at 
each timepoint. See Section 7.1 
Ophthalmological 
examination
X
As clinically indicated
X
See Section 7.1.5 
Height and weight 
X
X
X
X
X
X
Height at screening only  
Vital signs 
X
X
X
X
X
X
X
X
X
Heart rate, blood pressure, and body 
temperature. See Section 7.1
Hematology 
X
X
X
X
X
X
X
X
X
Assessment prior to first day of dosing may 
be done up to 72 hours prior to dosing 
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(Section 7.1.4)
All other assessments may be done within 24 
hours prior to dosing
See Section 7.1 
Chemistry
X
X
X
X
X
X
X
X
X
Assessment prior to first day of dosing may 
be done up to 72 hours prior to dosing 
(Section 7.1.4)
All other assessments may be done within 24 
hours prior to dosing
See Section 7.1 
Coagulation
X
X
X
X
X
X
Assessment prior to first day of dosing may 
be done up to 72 hours prior to dosing 
(Section 7.1.4)
All other assessments may be done within 24 
hours prior to dosing 
See Section 7.1 
Urinalysis
X
X
X
X
X
X
Assessment prior to first day of dosing may 
be done up to 72 hours prior to dosing 
(Section 7.1.4)
All other assessments may be done within 24 
hours prior to dosing. See Section 7.1 
Pregnancy test
X
X
(X)
X
X
For WOCBP only: Serum pregnancy test 
required at screening only. See Section 7.1 
(X) not required for patients in Part A1
Adverse events
X
X
X
X
(X)
From signing ICF through 30-day safety 
follow-up or until start of new anticancer 
therapy, whichever is earlier. See 
Section 10.1 
(X) only related SAE Investigator becomes 
aware of 
Concomitant 
medications
X
X
X
X
From signing ICF through 30-day safety 
follow-up or until start of new anticancer 
therapy, whichever is earlier.  See Section 6.4 
ECOG Performance 
Status
X
X
X
X
X
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a PK lead-in period applies to Part A1 only: During PK lead-in period, patients will receive a single dose of TAS3351 3 days prior to the start of multiple TAS3351 dosing in Cycle 1 with 
subsequent PK blood collection. The PK blood sample collection times during the PK lead-in period may be found in Table 13. For these patients, 72-hour post-dose assessments occur on 
C1D1, prior to C1D1 dosing. 
b The 30-day Safety Follow-up visit should be performed 30 days (+3 days) following the last dose of study therapy. If the patient starts new anticancer therapy within 30 days of the last dose 
of study medication, the 30-day Safety Follow-up visit should be performed before the start of new anticancer therapy. Only if the patient is unable to return to the study site, a follow-up 
phone call can be made by the study site to collect any new safety information that occurred during the Safety Follow-up period.
c ECG assessment for C1D1, and D1 of C2 and beyond should be conducted pre-dose (up to 30 minutes prior to dosing). ECG should be performed on D1 of every cycle. All ECGs should be 
performed in triplicate on Day 1 of Cycles 1 to 3 for all patients. After C3D1, ECGs are not required to be performed in triplicate unless clinically indicated.
PK sampling
See Table 13 / Table 14
Table 13 for QD dosing /Table 14 for BID
Central ECG
See Table 13 / Table 14
To be performed as triplicates. For patients in 
Part A1 only. See Section 7.1.2 
Local ECGc
X
X
X
X
X
12-lead ECG. Not needed if central ECG 
done the same day. Additional ECG 
monitoring as clinically indicated. See 
Section 7.1.2 
Echocardiography/ 
MUGA
X
X
From Cycle 4 onwards, every 4 cycles or as 
clinically indicated. See Section 7.1.3
cfDNA blood samples
X
X
X
X
From Cycle 3 onwards, every other cycle. 
After 12 months, every 3 cycles.  
Tumor tissue samples
X
(X)
(X)
Baseline sample optional for patients in Part 
A1. See Section 11.2 
(X) On-treatment biopsy optional; can be 
done at one of these timepoints
Radiologic tumor 
assessment 
X
X
(X)
(X)
Every 6 weeks (±7 days) from C1D1 
irrespective of cycle. After 12 months, every 
9 weeks (±7 days).
(X) Patients who discontinue study treatment 
without radiographic PD will continue every 
9 weeks (±7 days) until radiographic PD. See 
Section 7.1 
Survival status
X
Every 3 months (±2 weeks); collect also 
further anticancer therapies. See Section 7.1. 
For patients in Part A2 and B only 
Administration of 
TAS3351
X
X
Continuous dosing
See Section 6.1
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Abbreviations: AE=adverse event; C=cycle; cfDNA=cell-free DNA; D=day; DLT=dose-limiting toxicity; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end of 
therapy; ICF=informed consent form; MUGA=multi-gated acquisition scan; PD=progressive disease; PK=pharmacokinetics; QD=once daily; RECIST=Response Evaluation Criteria in Solid 
Tumors; SAE=serious adverse event; WOCBP=women of childbearing potential
Note: (X) = See notes for details. 
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Table 2:
Schedule of Events for Phase 2 (Part C)
Treatment Period
Follow-up Period
Cycle 1
 (21 days)
Cycle ≥2
(21 days)
Safety 
Follow-upa
Survival 
Follow-up
Notes
Procedure
Screening
Period
 
Within 28 
Days prior 
to first dose
Day 1
Day 8 
(±1 day)
Day 1
(±3 days)
30 (+3) days 
after last 
dose
EGFR C797S status
(pre-screening informed consent)
See Notes
Only if central pre-screening done. Can take place any 
time prior to screening
Written informed consent
(Main study)
X
To be obtained prior to any study related procedures. Can 
take place any time before Day 1
Review inclusion / exclusion criteria 
X
All patients must have documented C797S EGFRmt
Demographics/Medical history 
X
Including prior antitumor treatment
Physical examination 
X
X
X
X
Within 24 hours prior to dosing. May be symptom directed 
during treatment period. Examination of skin should be 
performed at each timepoint.
Ophthalmological examination
X
As clinically indicated
X
See Section 7.1.5
Height and weight 
X
X
X
X
Height at screening only  
Vital signs 
X
X
X
X
X
Heart rate, blood pressure, body temperature
Hematology 
X
X
X
X
X
Assessment prior to first day of dosing may be done up to 
72 hours prior to dosing (Section 7.1.4)
All other assessments may be done within 48 hours prior 
to dosing, See Section 7.1 
Chemistry
X
X
X
X
X
Assessment prior to first day of dosing may be done up to 
72 hours prior to dosing (Section 7.1.4)
All other assessments may be done within 48 hours prior 
to dosing. See Section 7.1 
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Treatment Period
Follow-up Period
Cycle 1
 (21 days)
Cycle ≥2
(21 days)
Safety 
Follow-upa
Survival 
Follow-up
Notes
Procedure
Screening
Period
 
Within 28 
Days prior 
to first dose
Day 1
Day 8 
(±1 day)
Day 1
(±3 days)
30 (+3) days 
after last 
dose
Coagulation
X
X
X
X
Assessment prior to first day of dosing may be done up to 
72 hours prior to dosing (Section 7.1.4)
All other assessments may be done within 48 hours prior 
to dosing. See Section 7.1 
Urinalysis 
X
X
X
X
Assessment prior to first day of dosing may be done up to 
72 hours prior to dosing (Section 7.1.4)
All other assessments may be done within 48 hours prior 
to dosing. See Section 7.1 
Pregnancy test 
X
X
X
For WOCBP only: Serum pregnancy test required at 
screening only. See Section 7.1 
Local ECGb 
X
X
X
X
12-lead ECG. Additional ECG monitoring as clinically 
indicated.  See Section 7.1
Adverse events
X
X
X
(X)
From signing ICF through 30-day safety follow-up. 
(X) only related SAE Investigator becomes aware of
Concomitant medications
X
X
X
X
X
From signing ICF through 30-day safety follow-up.
ECOG Performance Status
X
X
X
X
Patient reported outcomes
X
X
X
During treatment period, to be assessed as close as 
possible to the tumor assessments.
PK sampling
See Table 13
cfDNA blood samples 
X
X
X
From C3D1 onwards, every other cycle. After 12 months, 
every 3 cycles  
Tumor tissue samples
X
(X)
(X)
(X) On-treatment biopsy optional; can be done at one of 
these timepoints
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Treatment Period
Follow-up Period
Cycle 1
 (21 days)
Cycle ≥2
(21 days)
Safety 
Follow-upa
Survival 
Follow-up
Notes
Procedure
Screening
Period
 
Within 28 
Days prior 
to first dose
Day 1
Day 8 
(±1 day)
Day 1
(±3 days)
30 (+3) days 
after last 
dose
Radiologic tumor assessment 
X
X
(X)
(X)
Every 6 weeks (±7 days) from C1D1 irrespective of cycle. 
After 12 months, every 9 weeks (±7 days).
(X) Patients who discontinue study treatment without 
radiographic PD will continue every 9 weeks (±7 days) 
until radiographic PD. See Section 7.1 
Survival status
X
After discontinuation of treatment, survival follow-up 
should occur every 3 months (±2 weeks), collection of 
further anticancer therapies. See Section 7.1 
Administration of TAS3351
X
Continuous dosing. See Section 6.1
a The 30-day Safety Follow-up visit should be performed 30 days (+3 days) following the last dose of study therapy. If the patient starts new anticancer therapy within 30 days of the last dose 
of study medication, the 30-day Safety Follow-up visit should be performed before the start of new anticancer therapy. Only if the patient is unable to return to the study site, a follow-up 
phone call can be made by the study site to collect any new safety information that occurred during the Safety Follow-up period.
b ECG assessment for C1D1, and D1 of C2 and beyond should be conducted pre-dose (up to 30 minutes prior to dosing). ECG should be performed on D1 of every cycle. All ECGs should be 
performed in triplicate on Day 1 of Cycles 1 to 3 for all patients. After C3D1, ECGs are not required to be performed in triplicate unless clinically indicated.
Abbreviations: AE=adverse event; C=cycle; cfDNA=cell-free DNA; D=day; DLT=dose-limiting toxicity; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end of 
therapy; ICF=informed consent form; PD=progressive disease; PK=pharmacokinetics; QD=once daily; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; 
WOCBP=women of childbearing potential
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Table 3:
Schedule of Events – Study Extension Phase
Treatment Period
At Least Every 3 
Cyclesa
Safety Follow-up
30 (±7) Days After 
Last Dose
Notes
Physical examination
X
X
May be symptom directed during treatment period. Examination of skin should be 
performed at each timepoint.  
Vital signs
X
X
Heart rate, blood pressure, and body temperature
Local ECG
X
X
12-lead ECG
Weight
X
X
Hematology
X
X
See Section 7 
Chemistry 
X
X
See Section 7 
Pregnancy test
X
Serum or urine pregnancy test 
Concomitant medications, AE 
assessments
X
X
Collect from the time main informed consent is signed through 30 days after 
administration of the last dose of study therapy or until the start of new anticancer therapy, 
whichever is earlier. See Section 6.4.1 and Section 10.1 
Tumor assessments / scans
X
Tumor assessments may be performed as necessary to determine continued benefit from 
treatment, every 3 cycles (±14 days), or as clinically indicated, until clinical or 
radiographic PD.  See Section 7.1.1 
Administer TAS3351
X
Continuous dosing. See Section 6.1 
Abbreviations: AE=adverse event; ECG=electrocardiogram; PD=progressive disease
a More frequent visits/assessments may be performed as per local practice.
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TABLE OF CONTENTS
SUMMARY OF CHANGES ...................................................................................................2
1.
PROTOCOL SUMMARY....................................................................................6
1.1.
SYNOPSIS............................................................................................................6
1.2.
STUDY DIAGRAM ...........................................................................................13
1.3.
SCHEDULE OF EVENTS .................................................................................14
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................28
2.
INTRODUCTION...............................................................................................32
2.1.
Background and Study Rationale........................................................................32
2.1.1.
Disease Background and Study Population ........................................................32
2.1.2.
Overview of TAS3351 ........................................................................................32
2.1.2.1.
Nonclinical Experience .......................................................................................33
2.1.2.2.
Clinical Studies ...................................................................................................35
2.2.
Potential Risks and Benefits................................................................................35
2.2.1.
Possible Risks Based on Nonclinical Studies .....................................................36
2.2.1.1.
Gastrointestinal Toxicities ..................................................................................36
2.2.1.2.
Skin Disorders.....................................................................................................36
2.2.1.3.
Lung Disorders....................................................................................................36
2.2.1.4.
Liver Enzyme Elevation......................................................................................36
2.2.1.5.
Hematological Toxicities ....................................................................................36
2.2.1.6.
QT Prolongation..................................................................................................37
2.2.1.7.
Eye Disorders......................................................................................................37
2.2.1.8.
Granulomatous Inflammation .............................................................................37
2.2.1.9.
Phototoxicity .......................................................................................................37
2.2.1.10.
Effects on Reproductive Organs .........................................................................37
2.2.1.11.
Drug Class Safety Issues.....................................................................................37
2.2.1.12.
Reproductive and Developmental Risks .............................................................38
2.2.1.13.
Special Patient Populations.................................................................................38
2.2.2.
Possible Benefits .................................................................................................38
2.2.3.
Overall Benefit/Risk Ratio Evaluation................................................................38
3.
OBJECTIVES AND ENDPOINTS ....................................................................39
3.1.
Phase 1 Dose Escalation – Part A .......................................................................39
3.2.
Phase 1 Dose Expansion – Part B .......................................................................40
3.3.
Phase 2 – Part C ..................................................................................................41
4.
INVESTIGATIONAL PLAN .............................................................................42
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4.1.
Overview of Study Design..................................................................................42
4.2.
Study Design .......................................................................................................42
4.2.1.
Phase 1 Dose Escalation (Part A)........................................................................42
4.2.2.
Phase 1 Dose Expansion (Part B)........................................................................43
4.2.3.
Phase 2 (Part C)...................................................................................................43
4.2.4.
Study Stopping Criteria.......................................................................................44
4.3.
Scientific Rationale for Study Design.................................................................44
4.4.
Justification for Primary Endpoint and Key Secondary Endpoint......................45
4.5.
Justification for Starting Dose.............................................................................45
4.6.
Study Period........................................................................................................45
4.7.
Study Completion................................................................................................46
4.8.
Study Extension ..................................................................................................46
4.9.
End of Study........................................................................................................46
4.10.
Patient Enrollment...............................................................................................46
4.11.
Randomization and Blinding...............................................................................47
4.12.
Data Monitoring Committee ...............................................................................47
5.
SELECTION AND WITHDRAWAL OF PATIENTS ......................................48
5.1.
Inclusion Criteria.................................................................................................48
5.2.
Exclusion Criteria................................................................................................49
5.3.
Screen Failure......................................................................................................51
5.4.
Discontinuation of Treatment .............................................................................51
5.5.
Post-treatment Discontinuation Considerations..................................................52
5.6.
Withdrawal from the Study.................................................................................52
6.
STUDY TREATMENT ......................................................................................54
6.1.
Study Drug Administration.................................................................................54
6.1.1.
Dose Escalation...................................................................................................54
6.1.2.
Dose-limiting Toxicity........................................................................................56
6.2.
Dose and Schedule Modifications.......................................................................57
6.2.1.
Dose Reduction, Interruption, and Resumption..................................................57
6.2.1.1.
Dose Modifications for Hematological Toxicities..............................................58
6.2.1.2.
Dose Modifications for Non-hematologic Toxicities .........................................59
6.3.
Treatment Compliance........................................................................................61
6.4.
Concomitant Medications and Therapies............................................................61
6.4.1.
Prohibited Concomitant Medications..................................................................61
6.4.2.
Concomitant Medications and Therapies Requiring Precautions .......................62
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6.4.3.
Permitted Concomitant Medications...................................................................63
6.4.4.
Supportive Care...................................................................................................63
6.4.4.1.
Hematologic Support ..........................................................................................63
6.4.4.2.
Gastrointestinal Toxicities ..................................................................................63
6.4.4.3.
Interstitial Lung disease (ILD) / Pneumonitis.....................................................63
6.4.4.4.
Amylase or Lipase Elevations.............................................................................64
6.5.
Lifestyle Considerations......................................................................................64
6.5.1.
Dietary.................................................................................................................64
6.5.2.
Sun Protection .....................................................................................................64
6.6.
Contraceptive Guidance......................................................................................64
6.7.
Study Drug Materials and Management .............................................................65
6.7.1.
Description of Study Drug ..................................................................................65
6.7.2.
Packaging and Labeling ......................................................................................65
6.7.3.
Accountability.....................................................................................................65
7.
STUDY ASSESSMENTS...................................................................................66
7.1.
Study Assessments and Procedures ....................................................................66
7.1.1.
Efficacy Assessments..........................................................................................68
7.1.2.
12-Lead Electrocardiogram.................................................................................68
7.1.3.
Cardiac Function Evaluation...............................................................................69
7.1.4.
Laboratory Assessments......................................................................................69
7.1.5.
Ophthalmological Assessments ..........................................................................69
7.1.6.
PRO Measurements.............................................................................................70
7.1.7.
COVID-19 Pandemic Considerations.................................................................70
8.
PHARMACOKINETICS....................................................................................72
8.1.
Sample Collection ...............................................................................................72
8.2.
Drug Concentration Measurements.....................................................................74
8.3.
Pharmacokinetics Analysis .................................................................................74
8.3.1.
Pharmacokinetic Parameters ...............................................................................74
8.3.2.
Dose-proportionality ...........................................................................................75
8.3.3.
Population PK Modeling and Exposure-response Analysis................................75
8.4.
Metabolite Profiling ............................................................................................75
9.
EFFICACY EVALUATIONS ............................................................................76
9.1.
Efficacy Criteria..................................................................................................76
9.2.
Efficacy Endpoints..............................................................................................76
10.
SAFETY EVALUATIONS ................................................................................77
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10.1.
Adverse Events....................................................................................................77
10.1.1.
Definition of Adverse Events..............................................................................77
10.1.2.
Events Meeting the Adverse Event Definition....................................................77
10.1.3.
Time Period for Collection of AE and SAE Information ...................................77
10.1.4.
Reporting of Adverse Events ..............................................................................78
10.1.4.1.
Terms of Reported Adverse Events ....................................................................78
10.1.4.2.
Severity of Adverse Events.................................................................................78
10.1.4.3.
Causal Relationship with Study Drug.................................................................78
10.1.4.4.
Outcome of Adverse Events................................................................................79
10.1.4.5.
Follow-up of Adverse Events..............................................................................79
10.2.
Laboratory Assessments......................................................................................79
10.2.1.
Reporting and Evaluation of Laboratory Test Results........................................79
10.2.2.
Repeat Testing.....................................................................................................80
10.3.
Serious Adverse Events.......................................................................................80
10.3.1.
Definitions of Serious Adverse Events ...............................................................80
10.3.2.
Reporting of Serious Adverse Events (within 24 hours) ....................................80
10.3.3.
Reporting of Deaths (within 24 hours)................................................................81
10.3.4.
Follow-up of Serious Adverse Events.................................................................81
10.4.
Other Safety Information ....................................................................................82
10.4.1.
Pregnancy............................................................................................................82
10.4.2.
Overdose .............................................................................................................82
10.5.
Communication of New Information Affecting the Conduct of the Study.........82
11.
ANALYSES OF BIOMARKERS.......................................................................84
11.1.
Biomarker Sample Collection.............................................................................84
11.2.
Biomarkers for Patient Eligibility .......................................................................84
11.3.
Exploratory Biomarkers......................................................................................84
11.4.
Sample Storage and Disposal..............................................................................85
11.5.
Analytical Procedures .........................................................................................85
12.
STATISTICAL CONSIDERATIONS................................................................86
12.1.
Timing of Analyses.............................................................................................86
12.2.
Statistical Hypothesis..........................................................................................86
12.3.
Estimation of Sample Size ..................................................................................86
12.4.
Planned Interim Analyses ...................................................................................87
12.5.
Analysis Populations...........................................................................................87
12.6.
Criteria for Handling of Patient Data..................................................................87
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12.7.
Statistical Analyses .............................................................................................88
12.7.1.
Demographic and Baseline Characteristics.........................................................88
12.7.2.
Study Drug Administration.................................................................................88
12.7.3.
Efficacy Analyses................................................................................................88
12.7.3.1.
Primary Endpoint Analyses.................................................................................88
12.7.3.2.
Secondary Endpoint Analyses.............................................................................88
12.7.4.
Safety Analyses...................................................................................................89
12.7.4.1.
Primary Endpoint Part A1 Dose Escalation........................................................89
12.7.4.2.
Safety Analysis for All Parts...............................................................................89
12.7.5.
Other Analyses....................................................................................................90
13.
ADMINISTRATIVE CONSIDERATIONS.......................................................91
13.1.
Protocol Compliance...........................................................................................91
13.2.
Protocol Deviations.............................................................................................91
13.3.
Protocol Amendments.........................................................................................91
13.4.
Study Termination...............................................................................................91
13.5.
Case Report Forms..............................................................................................91
13.6.
Access to Source Data/Documents .....................................................................91
13.6.1.
Source Data/Documents......................................................................................91
13.6.2.
Access to Source Data.........................................................................................92
13.7.
Data Handling .....................................................................................................92
13.8.
Responsibilities of Recordkeeping......................................................................92
13.8.1.
Investigator and Study Site .................................................................................92
13.8.2.
Sponsor................................................................................................................92
13.9.
Monitoring...........................................................................................................93
13.10.
Financial Disclosure............................................................................................93
13.11.
Compensation for Health Injury..........................................................................93
13.12.
Study Administrative Structure...........................................................................93
14.
QUALITY CONTROL AND QUALITY ASSURANCE..................................94
14.1.
Quality Control....................................................................................................94
14.2.
Quality Assurance ...............................................................................................94
15.
ETHICS...............................................................................................................95
15.1.
Ethical Conduct of the Study ..............................................................................95
15.2.
Written Informed Consent...................................................................................95
15.3.
Institutional Review Board/Independent Ethics Committee...............................95
16.
PUBLICATION POLICY...................................................................................96
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16.1.
Publication Policy ...............................................................................................96
16.2.
Secondary Use of Data........................................................................................96
17.
REFERENCES....................................................................................................97
APPENDIX A.
EXAMPLES OF CLINICAL SUBSTRATES, INHIBITORS, AND 
INDUCERS OF CYP ENZYMES AND TRANSPORTERS...........................100
LIST OF TABLES
Table 1:
Schedule of Events for Phase 1 (Parts A and B).................................................14
Table 2:
Schedule of Events for Phase 2 (Part C) .............................................................18
Table 3:
Schedule of Events – Study Extension Phase .....................................................21
Table 4:
Definition of Study Periods.................................................................................46
Table 5:
TAS3351 Dose Levels ........................................................................................54
Table 6:
Dose Escalation and De-Escalation Rules ..........................................................55
Table 7:
Definition of Dose Limiting Toxicity .................................................................56
Table 8:
Dose Reduction ...................................................................................................58
Table 9:
Recommendations for Management of Hematologic Toxicities ........................58
Table 10:
Recommendations for Managing Non-Hematologic Toxicities .........................59
Table 11:
Description of TAS3351 .....................................................................................65
Table 12:
Study Assessments..............................................................................................66
Table 13:
Schedule for PK and ECG Sampling (QD Dosing) ............................................72
Table 14:
Schedule for PK and ECG Sampling (BID Dosing) ...........................................73
Table 15:
Efficacy Endpoint Definitions.............................................................................76
Table 16:
ORR 95%CI for Sample Size of 100 Patients.....................................................87
Table 17:
Definitions of Analysis Populations....................................................................87
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
APTT
Activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-24
Area under the plasma concentration-time curve from 0 to 24 hours
AUCinf 
Area under the plasma concentration-time curve to infinity
AUClast
Area under the plasma concentration-time curve up to the last observable 
concentration
BCRP
Breast cancer resistance protein
BID
Twice daily (or 2 times a day)
BOIN
Bayesian optimal interval design
BUN
Blood urea nitrogen
cfDNA
Circulating free DNA
CHF
Congestive Heart Failure
CI
Confidence interval
CLIA
Clinical laboratory improvement amendments
CL/F
Apparent clearance of drug from plasma after extravascular administration
Cmax
Maximum plasma concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CR
Complete response
CrCl
Creatinine clearance
CRP
C reactive protein
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DCR
Disease control response
DLT
Dose-limiting toxicity
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
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Abbreviation
Definition
DoR
Duration of response
DRESS
drug rash with eosinophilia and systemic symptoms
EC50
50% effective concentration
ECG
Electrocardiogram
ECHO
Echocardiography
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EGFRmt
Epidermal growth factor receptor mutation
eGFR
Estimated glomerular filtration rate
Emax
Maximum induction ratio
EORTC 
European Organization for Research and Treatment of Cancer
FIH
First-in-human
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
HBs
Hepatitis B surface
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HED
Human equivalent dose
hERG
Human ether-a-go-go related gene
HIV
Human immunodeficiency virus
HNSTD
highest non-severely toxic dose
HRCT
High-resolution computed tomography
HSA
Human serum albumin
IC50
Half maximal inhibitory concentration
icDOR
Intracranial duration response
ICF
Informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
icORR
Intracranial overall response rate
ICR
Independent central review
IEC
Independent ethics committee
ILD
Interstitial lung disease
IRB
Institutional review board
IXRS
Interactive voice/web response system
Kp, brain
Brain to plasma concentration ratio
Kinact
Inactivation rate constant
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Abbreviation
Definition
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MRT
Mean residence time
MTD
Maximum tolerated dose
MUGA
Multi-gated acquisition scan
NSCLC
Non-small cell lung cancer
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PFS
Progressive free survival
P-gp
P-glycoprotein
PGx
Pharmacogenomics
PK
Pharmacokinetics
PO
Oral
PRO
Patient reported outcomes
PT-INR
Prothrombin time - international normalized ratio
QD
Once daily
QTc
QT interval corrected
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RBC
Red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Stable disease
SOC
Standard of care
SOP
Standard operating procedure
SPE
Sun protection factor 
STD10
Severely toxic dose in 10%
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Terminal elimination half-life
TEAE
Treatment-emergent adverse event
TKI
Tyrosine-kinase inhibitor
tmax
Time to maximum plasma concentration
ULN
Upper limit of normal
US or USA
United States or United States of America
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Abbreviation
Definition
Vz/F
Apparent volume of distribution during the terminal (z) phase
WBC
White blood cell
WOCBP
Women of childbearing potential
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2.
INTRODUCTION
2.1.
Background and Study Rationale
2.1.1.
Disease Background and Study Population
About 10%-15% of Caucasian patients with non-small cell lung cancer (NSCLC) and up to 
50% of East-Asian patients with NSCLC have tumors harboring an epidermal growth factor 
receptor (EGFR) activating mutation (ie, L858R or exon 19 deletion mutations).1 The current 
standard of care for these patients with locally advanced or metastatic NSCLC is treatment 
with an EGFR tyrosine kinase inhibitor (TKI). Several Phase 3 clinical trials have established 
the role of first-generation (gefitinib and erlotinib) and second-generation (afatinib and 
dacomitinib) EGFR TKIs as first-line treatment with a similar median response rate of 70%-
75% and progression-free survival (PFS) ranging from 10-14 months, which was a significant 
improvement compared to platinum-based chemotherapy.2 The most frequent resistance 
mechanism to first-and second-generation EGFR TKIs is the emergence of T790M EGFR 
kinase domain mutations. More recently, the third-generation EGFR TKI osimertinib active 
against T790M EGFRmt showed superior efficacy when compared against erlotinib, with 
improved PFS (18.9 versus 10.2 months) and overall survival (OS) (38.6 versus 31.8 
months).3,4 
Despite third-generation EGFR TKIs being highly effective in treatment of advanced 
EGFRmt NSCLC, resistance to EGFR TKIs inevitably occurs leading to disease progression. 
The current treatment options for patients with EGFRmt NSCLC progressing on treatment 
with third-generation EGFR TKIs are limited. Platinum-based chemotherapy combinations 
with pemetrexed are currently considered standard of care.5 However, the reported clinical 
outcome is poor with approximately 25% ORR (range: 20.7% to 34.1%) and median PFS of 
approximately 4-5 months post osimertinib.6,7,8,9 One of the prevalent resistance mechanisms 
to third-generation EGFR TKIs is an acquired C797S EGFR mutation which is observed in 
10%-25% of patients with NSCLC progressing on osimertinib.10,11,12,13 A study of patients 
with C797S mutations after treatment with osimertinib showed 1 tumor response out of 23 
patients (4%) treated with chemotherapy.14
2.1.2.
Overview of TAS3351
TAS3351 is a novel fourth-generation EGFR TKI designed to potently inhibit triple-mutant 
EGFR in patients with NSCLC. In addition to its activity against EGFR sensitizing mutations 
(ie, L858R or exon 19 deletion mutations) and acquired T790M resistance EGFRmt, 
TAS3351 also inhibits C797S EGFRmt while sparing wild-type EGFR. In nonclinical 
studies, TAS3351 demonstrated dose-dependent activity in in vitro and in vivo models with 
co-occurrence of a sensitizing EGFRmt and T790M/C797S EGFRmt (data on file). 
Furthermore, TAS3351 has been shown to be brain penetrant in nonclinical models. 
Approximately 25%-40% of patients with NSCLC develop brain metastases and, due to 
limited treatment options, the prognosis of patients with brain metastases remains poor.15 
Thus, TAS3351 might also provide a new treatment option for patients with EGFR 
deregulated NSCLC who have brain metastases.
Based on these results, TAS3351, is expected to have antitumor activity in patients with 
NSCLC harboring an acquired C797S EGFRmt, a population with an unmet medical need.
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2.1.2.1.
Nonclinical Experience
2.1.2.1.1. Pharmacology
TAS3351 is a novel and highly potent and selective inhibitor of EGFRmt. In biochemical 
assays, TAS3351 and its active metabolite TAS-05-14317 inhibited EGFR enzymes 
harboring T790M and/or C797S mutation in addition to exon 19 deletion (ex19del) or L858R 
point mutation with mean half-maximal inhibitory concentration (IC50) values ranging from 
0.28 to 1.1 nmol/L, while sparing WT EGFR enzyme (mean IC50: 3.9 nmol/L). 
In cellular assays, TAS3351 inhibited autophosphorylation of EGFR in EGFRmt cell lines 
with mean IC50 values ranging from 12 to 465 nmol/L and showed potent inhibition of cell 
viability with mean IC50 values ranging from 2.84 to 241 nmol/L regardless of the presence 
of co-occurring EGFR T790M and/or C797S resistance mutations, while sparing 
autophosphorylation of WT EGFR. The cell viability mean IC50 values ranged from 6.55 to 
241 nM in cell lines with C797S mutation. Similar results were observed for TAS3351 active 
metabolite TAS-05-14317 in cellular assays.
In vivo, TAS3351 demonstrated antitumor activity in models with sensitizing EGFRmt and 
co-occurring EGFR resistance mutations following oral administration at doses from 10 to 
80 mg/kg/day. In xenograft tumor models harboring L858R and T790M EGFR mutations, 
TAS3351 inhibited phosphorylation of downstream proteins AKT and ERK, in addition to 
EGFR in a dose-dependent manner. Furthermore, TAS3351 treatment led to potent tumor 
growth inhibition and/or tumor regression in the NIH/3T3-EGFR (ex19del/T790M/C797S) 
allograft model and the HCC827 and NCI-H1975 xenograft models, both of which express 
EGFR with ex19del or L858R/T790M mutation, respectively. In addition to these 
subcutaneously transplanted tumor mouse models, TAS3351 also demonstrated antitumor 
activity in an intracranially transplanted EGFRmt (ex19del/T790M/C797S) allograft model 
and improved survival time compared to the control group.
Secondary pharmacology studies for TAS3351 showed an IC50 value of 860 nmol/L for 
human ether-a-go-go related gene (hERG) channel inhibition. The dog telemetry study of 
TAS3351 revealed a corrected QT (QTc)-prolongation at 10 mg/kg or higher at 4 hours 
post-dose only (up to +9% relative to the pre-dose value at the highest dose level, 40 mg/kg). 
There were no TAS3351-related effects on blood pressure, heart rate, or other 
electrocardiogram parameters at any dose level up to 40 mg/kg. In the rat functional 
observational battery for CNS effects, there were no relevant findings, except a 1.3% 
decrease in the rectal temperature was detected at 120 mg/kg TAS3351. No effect on body 
temperature was noted in the dog cardiovascular study in conscious dogs up to 40 mg/kg. For 
the respiratory system, no effects were observed in rats up to 120 mg/kg TAS3351.
2.1.2.1.2. Absorption, Distribution, Metabolism, and Excretion
Absorption
Plasma concentration profiles and pharmacokinetic (PK) parameters of TAS3351 and TAS-
05-14317 (active metabolite of TAS3351) were determined following a single dose of 
TAS3351 in mice and repeated dosing of TAS3351-10 (succinate co-crystal) in rats and dogs. 
After a single oral administration of TAS3351 to male nude mice (20, 40, and 80 mg/kg), the 
maximum plasma concentration (Cmax) and area under the plasma concentration-time curve 
from 0 to 24 hours (AUC0-24) values of TAS3351 and TAS-05-14317 increased in a dose-
dependent manner, and the metabolic ratios of TAS-05-14317 to TAS3351 ranged from 
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0.192 to 0.253. In mice, the observed total (TAS3351 and TAS-05-14317) AUC0-24 was 
approximately 86 µM*hr for 20 mg/kg and approximately 473 µM*hr for 80 mg/kg. 
Following 3-week repeated oral administrations of TAS3351-10 to female rats (75 and 
150 mg/kg), the Cmax and AUC0-24 values of TAS3351 and TAS-05-14317 tended to increase 
with repeated dosing (up to 2-fold increase for TAS-05-14317 at dose of 150 mg/kg). The 
metabolic ratios of TAS-05-14317 to TAS3351 ranged from 0.13 to 0.16 and showed no 
difference at either dose level on Day 1 and Day 21.
Following 3-week repeated oral administrations of TAS3351-10 to male and female dogs 
(40 and 80 mg/kg), there was no apparent change in any PK parameter by repeated dosing 
and no apparent sex-related differences in any PK parameter. The metabolic ratios of TAS-
05-14317 to TAS3351 ranged from 0.66 to 1.32 and showed no difference at either dose 
level.
Distribution
Plasma protein binding ratios of TAS3351 and TAS-05-14317 were >99% in all animal 
species (mice, rats, rabbits, dogs, monkeys, and humans) and almost constant regardless of 
their concentrations. TAS3351 and TAS-05-14317 were bound to α1-acid glycoprotein (AGP) 
and human serum albumin (HSA).
Protein binding ratios in mouse brain homogenates (2 to 200 nmol/g) were >99.6% for both 
TAS3351 and TAS-05-14317.
TAS3351 and TAS-05-14317 demonstrated high brain penetrability after a single oral 
administration with brain to plasma concentration ratio (Kp, brain) values of 0.319 to 0.691 (20 
to 80 mg/kg) for TAS3351, and 0.0558 to 0.150 (20 to 80 mg/kg) for TAS-05-14317. 
Metabolism
Cytochrome P450 (CYP3) A4/5 were the major isoforms involved in the metabolism of 
TAS3351 among CYP isoforms in human liver microsomes.
The major metabolites observed in human liver microsomes were a mono-oxidized product 
(M18, TAS-05-14317) and a mono-oxidized and hydrated product (M11). These metabolites 
were also observed in rat and dog liver microsomes. M18 is a biologically active metabolite 
and has been evaluated in nonclinical studies. In human hepatocytes, a glutathione conjugate 
of hydrogenated product (M4) was observed as the major metabolite. M4 is a biologically 
non-active metabolite and was also observed in rat and dog hepatocytes. One metabolite 
(M2), a cysteinylglycine conjugate of the hydrogenated product, was observed in human 
hepatocytes but not observed in other animal species. 
Based on these in vitro results, oxidation, hydration, and glutathione conjugations were 
estimated to be the main metabolic pathways.
Elimination
No excretion studies have been conducted with TAS3351.
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Drug-Drug Interactions
In human liver microsomes, TAS3351 showed potential to reversibly inhibit CYP2C8, 
CYP2C9, and CYP2C19 with IC50 values of 2.6, 1.2, and 2.1 µmol/L, respectively. TAS3351 
inhibited CYP3A (testosterone 6β-hydroxylation) in a time-dependent manner with the 
maximal inactivation rate constant (kinact) value of 0.0114 min-1 and the concentration causing 
half maximal inactivation (KI) of 6.97 µmol/L. For CYP3A (midazolam 1'-hydroxylation), 
the kinact and KI values were not calculable since the time-dependent inhibitory effect was 
weak. 
In primary human hepatocytes, TAS3351 showed CYP1A2 induction potency with maximum 
fold induction (Emax) of 1.89-fold and 50% effective concentration (EC50) of 1.09 µmol/L. No 
induction was observed for CYP2B6, CYP3A4, CYP2C8, CYP2C9, or CYP2C19 enzymes.
In vitro, TAS3351 was not a substrate for P-glycoprotein (P-gp) or breast cancer resistance 
protein (BCRP). TAS3351 showed an in vitro potential to inhibit P-gp and BCRP with IC50 
values of 0.161 and 0.181 µmol/L in Caco-2 cells, respectively.
2.1.2.1.3. Toxicology
The main toxicological findings for TAS3351 were overall consistent with previous reports 
for other EGFR TKIs.16 
Repeated dose studies with and without a recovery period were performed in rats and dogs. 
Findings included abnormal stools, atrophy of epithelial tissues (eg, tongue, cornea, and 
skin), and regressive and atrophic changes in the gastrointestinal tract. In addition, 
granulomatous inflammation in various organs (eg, liver, lung) were observed, including 
arteritis and granulomatous vasculitis. In the 4-week repeated dose toxicity studies in rats and 
dogs, all toxicities showed reversibility during the 4-week recovery period. 
The severely toxic dose in 10% of the animals (STD10) was determined to be 120 mg/kg/day 
in rats and the highest non-severely toxic dose (HNSTD) in dogs was determined to be 
10 mg/kg/day in dogs.
TAS3351 demonstrated negative mutagenicity and clastogenicity in the Ames test and in 
vitro chromosomal aberration study, respectively.
TAS3351 was considered to have a potential for phototoxic effects based on the results of the 
in vitro phototoxicity study. 
For further nonclinical information about TAS3351 please refer to the current version of the 
IB.
2.1.2.2.
Clinical Studies
This will be the first in human study of TAS3351; therefore, no clinical experience is 
available.
2.2.
Potential Risks and Benefits
There is no human experience with TAS3351. Potential risks are based on nonclinical 
toxicity study results.
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2.2.1.
Possible Risks Based on Nonclinical Studies
2.2.1.1.
Gastrointestinal Toxicities
In nonclinical studies with TAS3351, abnormal stool (watery, mucinous, and/or bloody stool) 
and vomiting were observed. Histopathological findings included erosion/ulcer and atrophy 
of the squamous epithelium in the tongue, erosion/ulcer in the duodenum, villous atrophy, 
granulomatous inflammation and infiltration of foamy macrophages in in the ileum, 
inflammation, hemorrhage of the mucosa, and dilation of the crypts in the intestines. 
Potential side effects and risks anticipated in human are mucositis, nausea, vomiting, diarrhea 
(and possibly dehydration and electrolyte imbalance in severe cases), bloody stool, and 
abdominal pain. Monitoring of patients for gastrointestinal AEs will rely mainly on careful 
clinical evaluation (physical examination and medical history, sign, symptoms) and on 
laboratory evaluation. Patients should be treated promptly for gastrointestinal AEs.
2.2.1.2.
Skin Disorders 
In nonclinical studies, inflammatory changes, atrophy of the squamous epithelium and 
adnexa was observed in the skin. In addition, skin toxicities are common toxicities of EGFR 
TKIs. 
Potential side effects and risks anticipated are dry skin, pruritus, and rash. Monitoring of 
patients for skin toxicities will be included during routine physical examination.
2.2.1.3.
Lung Disorders
In nonclinical studies, pathological findings included hemorrhage, perivascular edema, 
macrophage/inflammatory cell infiltration in the alveoli, and perivascular/peribronchiolar 
eosinophil infiltration. In addition, lung toxicities are a known class effect of EGFR TKIs. 
Potential side effects and risks anticipated are hemoptysis (alveolar hemorrhage), lung 
infiltration, and interstitial lung disease. Monitoring of patients for lung disorders will include 
routine physical examination and medical history as well as adequate exploration/testing in 
case of respiratory symptom identification.
2.2.1.4.
Liver Enzyme Elevation
In nonclinical studies, elevation of liver enzymes was observed. Histopathological changes 
included periportal inflammation, multifocal granuloma, and single cell necrosis of 
hepatocytes.
Potential side effects and risks anticipated are liver function test abnormalities. Monitoring of 
patients for liver toxicities will include routine laboratory testing. 
2.2.1.5.
Hematological Toxicities
In nonclinical studies, decrease in erythrocytic parameters was observed. 
Potential side effects and risks anticipated are anemia and hematologic test abnormalities. 
Monitoring of patients for hematological toxicities will include routine laboratory testing and 
physical examination.
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2.2.1.6.
QT Prolongation 
Human ether-a-go-go related gene (hERG) current inhibition was detected with an IC50 value 
of 860 nmol/L TAS3351, and a dog telemetry study revealed a non-dose proportional 
QT-prolongation at 10-40 mg/kg at a single time point. Therefore, TAS3351 has a potential 
to induce QT prolongation.
Patients with pre-existing increased QTc interval, cardiac comorbidity(ies), and any other 
risks associated with QT prolongation will be excluded per study protocol. Patients will have 
an ECG assessment at baseline and during treatment. Electrolytes will be monitored, and 
imbalance should be corrected.
2.2.1.7.
Eye Disorders 
In nonclinical studies, atrophy of corneal epithelium was observed.  
Potential side effects and risks anticipated are keratitis, corneal erosion, corneal ulcer, vision 
blurred, corneal opacity, and eye pain. Monitoring of patients for eye disorders will be 
conducted by ophthalmological examinations at baseline and any time during study treatment 
if clinically indicated. Patients should be advised to contact their study physician if 
experiencing any change in vision. 
2.2.1.8.
Granulomatous Inflammation
In nonclinical studies, mild to moderate granulomatous inflammation in various organs (eg, 
liver, lung) were observed, including arteritis and granulomatous vasculitis.
Potential side effects and risks anticipated are vasculitis and thrombosis. Monitoring of 
patients for granulomatous inflammation will rely on clinical evaluation of signs, symptoms, 
and laboratory parameters indicative for vasculitis, thrombosis, or other manifestations of 
granulomatous inflammation. 
2.2.1.9.
Phototoxicity
A phototoxicity risk for TAS3351 was identified based on in vitro neutral red uptake 
phototoxicity test using BALB/3T3 clone A31 cells.
Potential side effects and risks anticipated are photosensitivity and sunburn. Patients should 
be advised to use sun protection measures (eg, sunglasses, broad spectrum sunscreen) and 
limit direct sunlight/artificial sunlight exposure.
2.2.1.10.
Effects on Reproductive Organs 
In nonclinical studies, pathological findings were atrophic changes in female reproductive 
organs and testicular germ cell degeneration.
Potential side effects and risks anticipated are possible decreases in reproductive potential. 
2.2.1.11.
Drug Class Safety Issues
Safety findings reported for other EGFR TKIs such as erlotinib, afatinib, gefitinib, and 
osimertinib typically include gastrointestinal, dermatologic, and ocular toxicities. Cutaneous 
toxicities including rash, acne, pruritus, and dry skin were the most frequently observed 
toxicities. Interstitial lung disease has also been reported.
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2.2.1.12.
Reproductive and Developmental Risks
No reproductive and developmental studies have been conducted with TAS3351. Pregnant 
women and breastfeeding women should not be included in studies with TAS3351. Both 
males and females of reproductive potential must agree to use effective birth control during 
the study prior to the first dose and for 6 months after the last dose of study treatment for 
females, and 3 months after the last dose of study treatment for males, (or longer) based on 
local requirements.
2.2.1.13.
Special Patient Populations
No clinical studies of TAS3351 have been conducted to date and there is no information on 
use in special patient populations.
2.2.2.
Possible Benefits
As this is a FIH study, the clinical benefit of TAS3351 is still unknown. TAS3351 is an 
EGFR inhibitor and may provide therapeutic benefit to patients with advanced cancer with 
EGFR aberrations. Patients to be enrolled in this study must have a documented EGFRmt 
status, progressed or were intolerant to available standard therapy for their disease, and have 
exhausted standard treatment options. 
Given the disease stage, available treatment options, and potentially manageable expected 
toxicities, the risk/benefit assessment supports conduct of the study, with the potential for 
patients to benefit from TAS3351.
The planned study is designed to ensure the safety of participants. Patients will be enrolled at 
the Investigator’s discretion, considering patient’s individual benefit and risk and the 
availability of staff in the trial sites. The Sponsor performs a risk assessment of the study on 
an ongoing basis and prioritizes patient safety. 
2.2.3.
Overall Benefit/Risk Ratio Evaluation
The Sponsor considers that the overall benefit will outweigh the risks for patients with 
serious and life-threatening disease to be enrolled in Study 10073010.
This positive benefit/risk ratio justifies the initiation of Study 10073010 even in the context 
of the currently ongoing coronavirus disease 2019 (COVID-19) pandemic, as the clinical 
benefit/risk ratio for patients with serious and life-threatening tumor disease remain 
unchanged. The study procedures in this trial are designed to ensure the safety of participants 
during and after the COVID-19 pandemic, and appropriate measures (eg, remote visits, 
protocol-required laboratory safety and efficacy assessments performed at a local qualified 
facility) will be implemented in accordance with guidelines from regulatory authorities.17,18
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3.
OBJECTIVES AND ENDPOINTS
The primary, secondary and exploratory objectives and endpoints of this study are shown 
below.
3.1.
Phase 1 Dose Escalation – Part A
Objectives
Endpoints
Phase 1 Dose Escalation
Primary
•
To investigate the safety and determine 
the recommended Phase 2 dose (RP2D) 
and dosing schedule of TAS3351
•
Safety, including (but not limited to) 
AEs graded by CTCAE v5.0, and 
incidence of dose limiting toxicities 
(DLTs). As supplementary data, 
preliminary antitumor activity and 
PK/PD results will be considered. 
Secondary 
•
To evaluate the antitumor activity of 
TAS3351
•
Objective response rate (ORR) per 
Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 by Investigator
•
Duration of response (DoR), disease 
control rate (DCR), and time on 
treatment
•
Progression free survival and OS 
(Patients in part A2 only)
•
To characterize the pharmacokinetics 
(PK) of TAS3351 and its active 
metabolite (TAS-05-14317) in plasma 
•
PK parameters including but not limited 
to maximum plasma concentration 
(Cmax), time to maximum plasma 
concentration (Tmax), area under the 
plasma concentration-time curve (AUC), 
and terminal elimination half-life (T½)
Exploratory
•
To explore the relationship between 
exposures of TAS3351 and its active 
metabolite (TAS-05-14317) in plasma 
and QT prolongation
•
Time matched plasma exposures of 
TAS3351 and its active metabolite 
(TAS-05-14317) and changes from 
baseline in QTcF
•
To explore biomarkers for TAS3351 
including their potential association with 
antitumor activity
•
Biomarkers from tumor tissue and blood 
samples, including (but not limited to) 
DNA/RNA, protein, and cfDNA 
analysis 
•
To explore metabolites of TAS3351 in 
plasma
•
Metabolites of TAS3351 in plasma will 
be characterized
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3.2.
Phase 1 Dose Expansion – Part B
Objectives
Endpoints
Phase 1 Dose Expansion
Primary
•
To explore the efficacy of TAS3351
•
ORR per RECIST v1.1 by independent 
central review (ICR)
Secondary
•
To confirm the safety and tolerability of 
TAS3351 at the RP2D and dosing 
schedule 
•
AEs, including SAEs, clinical laboratory 
tests, vital signs, and 12-lead ECGs 
graded according to CTCAE v5.0
•
To further explore the anti-tumor 
efficacy of TAS3351
•
DoR, PFS, and DCR by ICR
•
ORR, DoR, PFS, and DCR by 
Investigator assessment
•
Intracranial ORR (icORR) and DoR 
(icDOR) by ICR and Investigator 
assessment
•
Overall survival (OS)
Exploratory
•
To explore biomarkers for TAS3351 
including their potential association with 
efficacy
•
Biomarkers from tumor tissue and blood 
samples, including (but not limited to) 
DNA/RNA, protein, and cfDNA 
analysis 
•
To explore the potential exposure-
response associations for efficacy and 
safety
•
Exposures estimated by Population PK 
model and selected efficacy and safety 
measures
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3.3.
Phase 2 – Part C
Objectives
Endpoints
Phase 2
Primary
•
To assess the efficacy of TAS3351
•
ORR per RECIST v1.1 by ICR
Secondary
•
To further assess the efficacy of 
TAS3351
•
DoR, PFS, and DCR by ICR
•
ORR, DoR, PFS, and DCR by 
Investigator assessment
•
Intracranial ORR (icORR) and DoR 
(icDoR) by ICR and Investigator 
assessment
•
Overall survival (OS)
•
To evaluate the safety and tolerability of 
TAS3351
•
AEs, including SAEs, clinical laboratory 
tests, vital signs, and 12-lead ECGs 
graded according to CTCAE v5.0
•
To evaluate patient reported outcomes 
(PROs)
•
EORTC QLQ-C30 and EQ-5D-5L
Exploratory
•
To investigate biomarkers of response to 
TAS3351 and determine their potential 
association with efficacy
•
Biomarkers from tumor tissue and blood 
samples, including (but not limited to) 
DNA/RNA, protein, and cfDNA 
analysis 
•
To explore the potential exposure-
response associations for efficacy and 
safety
•
Exposures estimated by Population PK 
model and selected efficacy and safety 
measures 
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4.
INVESTIGATIONAL PLAN
4.1.
Overview of Study Design
Study 10073010 is a first-in-human (FIH) Phase 1/2 study designed to determine the RP2D 
and efficacy of TAS3351 in patients with locally advanced or metastatic non-small cell lung 
cancer (NSCLC) harboring an acquired C797S EGFR mutation.
The study will consist of 3 parts:
•
Part A: Phase 1 Dose Escalation part to determine the RP2D and dosing schedule 
of TAS3351 in patients with advanced NSCLC 

Part A1: Dose escalation in patients with any EGFRmt

Part A2: Backfill patients with C797S EGFRmt
•
Part B: Phase 1 Dose Expansion part to explore the efficacy of TAS3351 in 
patients with C797S EGFRmt NSCLC
•
Part C: Single-arm Phase 2 study to evaluate efficacy of TAS3351 in patients 
with C797S EGFRmt NSCLC
The study design is summarized graphically in Section 1.2.
4.2.
Study Design
4.2.1.
Phase 1 Dose Escalation (Part A)
The primary objective of Part A is to determine the recommended Phase 2 dose (RP2D) of 
TAS3351 based on observed DLTs, safety, antitumor activity, PK, and pharmacodynamics. 
Part A of Study 10073010 will consist of a Dose Escalation part (Part A1) and a part for 
“Backfill” patients (Part A2)
Part A1: Dose Escalation
The Phase 1 Dose Escalation is designed to evaluate 6 dose levels of TAS3351 from 50 to 
700 mg/day (Table 5) using a Bayesian Optimal Interval (BOIN) design. 
 
 
 
 
 
 
 
. 
TAS3351 will be administered once daily (QD) on a 21-day cycle at a starting dose of 50 mg 
QD and escalated based on tolerability (see Section 6.1.1) to patients who harbor any EGFR 
mutation, with consideration of lower increments than planned if clinically relevant toxicities 
are observed (intermediate dose levels). In the event of unacceptable toxicities at Dose Level 
1, lower dose levels may be explored (eg, Dose Level -1). If PK, pharmacodynamic, and/or 
safety data indicate, twice daily (BID) dosing of TAS3351 may be explored. In order to 
appropriately characterize the PK profile of TAS3351, there will be a PK lead-in with a 
single administration of TAS3351 followed by PK sampling 3 days prior to the start of 
continuous daily dosing of TAS3351 for patients enrolled in the Dose Escalation Part A1 
only.
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Part A2: Backfill Patients
When a dose level has been determined to be safe in Part A1 and preliminary antitumor 
activity has been observed, up to 10 further patients may be enrolled in that dose level (for a 
total of up to 20 backfill patients). A dose is deemed to be safe in Part A1 if there is an 
acceptable DLT rate in that dose level as per the BOIN design. Antitumor activity is defined 
as evidence of tumor shrinkage in at least one of the patients at that dose level.  
If no preliminary antitumor activity is observed in Part A1, the totality of nonclinical in vitro 
and in vivo data as well as clinical PK data may be used to inform selection of dose level(s) 
for “backfill” patients. This will include IC50 values from various in vitro assays and/or the 
total exposure of TAS3351 and its active metabolite associated with tumor shrinkage in 
preclinical xenograft mouse models to be used as thresholds for targeted efficacious Cmin 
and/or AUC, respectively. The exposure linked with nonclinical activity is a total TAS3351 
and TAS-05-14317 Cmin of 40.3 nM. Clinical PK simulation will be applied to project dosing 
regimen(s) which may achieve the targeted threshold(s). The doses explored in the A2 part of 
the trial will be chosen in consultation between the investigators and the Sponsor based on 
the above safety and efficacy criteria as well as a review of the PK data. “Backfill” patients 
enrolled are required to have a tumor harboring a C797S EGFRmt. The additional 
information from these “backfill” patient cohorts will broaden the amount of safety and 
preliminary antitumor activity data for TAS3351 at potential active dose levels to inform the 
selection of the RP2D of TAS3351.
4.2.2.
Phase 1 Dose Expansion (Part B)
The Phase 1 Dose Expansion part of the study will be initiated after an RP2D and a dosing 
scheme has been identified in Part A. NSCLC patients with C797S EGFRmt will be enrolled 
to explore the efficacy and confirm the safety of TAS3351 at the RP2D in a larger patient 
population. Moreover, a second dose level of TAS3351 may be evaluated in an additional 
cohort of patients in Part B if promising antitumor activity is observed at another lower 
TAS3351 dose level during Part A. In this case, patients enrolled in Part B will be 
randomized at a 1:1 ratio between the two treatment arms to evaluate the optimal RP2D of 
TAS3351 based on a comparative analysis considering the totality of efficacy and safety data 
observed. 
The results from Part B will confirm the RP2D of TAS3351 and are expected to provide, in 
combination with the “Backfill” patients from Part A2, the proof of concept for the efficacy 
of TAS3351 in NSCLC patients with the C797S EGFRmt. Based on these results, the Phase 2 
part of this study will be initiated.
In addition, further cohorts may be added by an amendment to explore the activity of 
TAS3351 in further subgroup(s) of patients based on activity observed in the Part A dose 
escalation and/or emerging scientific data. This may include an additional cohort for 
EGFRmt NSCLC patients with brain metastases to explore the efficacy of TAS3351 against 
CNS metastases or against other type of EGFRmt, if promising results are observed during 
Part A of this study. 
4.2.3.
Phase 2 (Part C)
The Phase 2 part of the study will be an open-label, single-arm, Phase 2 study to assess the 
safety and efficacy of TAS3351 in advanced NSCLC patients with C797S EGFRmt who 
progressed on a prior treatment with another EGFR inhibitor. Patients will receive TAS3351 
at the RP2D and dosing scheme confirmed in Part B and be evaluated for ORR based on 
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RECIST v1.1 by Independent Central Review (ICR) as the primary endpoint. A key 
secondary endpoint of this part of the study will be duration of response (DoR) by ICR.
4.2.4.
Study Stopping Criteria
The study will be stopped in the event of unacceptable toxicities. If the following toxicities 
are observed in at least 1 patient, dosing of new patients will be suspended until further 
review of safety to determine if dosing can resume. These toxicities will include, but are not 
limited to, the following: 
•
Any death other than disease progression in any patient in which the cause of 
death is judged to be at least possibly related to the study treatment by the 
investigator.
•
Liver function test increase that is considered to be a Hy’s Law case 
•
≥Grade 4 severe cutaneous adverse reactions (Steven-Johnson syndrome, toxic 
epidermal necrolysis, erythema multiforme, acute generalized exanthematous 
pustulosis, drug rash with eosinophilia and systemic symptoms (DRESS) 
syndrome) 
In Part A1, dosing of patients in a dose level will stop if there is an unacceptable DLT rate as 
per the BOIN design. 
For the patients participating in Part A2 (“back-fill”) and Part B (dose expansion), if adverse 
events meeting the DLT definition surpass 30% during Cycle 1 in a particular cohort, 
enrollment will be stopped for that cohort. Patients in other cohorts without such safety issues 
may continue dosing.
After approximately 25% of patients are enrolled in Part C, the data will be reviewed to 
determine if there are safety concerns that justify modification to or termination of the trial. 
Timing of subsequent reviews will depend on the rate of recruitment in this part of the study.
The Sponsor’s medical monitor, in consultation with the study investigators, will decide 
following review whether suspension of patient accrual may be lifted and if any adjustments 
of the protocol are required prior to reopening enrollment. Prior to the start of Phase 2, a Data 
Monitoring Committee (DMC), including members external to the Sponsor, will be 
established (Section 4.12). The DMC will review all safety data after dose expansion before 
proceeding to Part C (Phase 2). The trial may be terminated by the Sponsor, if after 
discussion with the investigators or DMC, the benefit risk ratio is no longer favorable for 
patients. 
4.3.
Scientific Rationale for Study Design
The study design of this Phase 1/2 study will allow efficient assessment of the safety and 
efficacy of TAS3351 in the target population of patients with advanced NSCLC with tumors 
harboring an acquired C797S EGFRmt. The Phase 1 Dose Escalation will use the BOIN 
design, a simple and well-performing design for Phase 1 oncology trials15 followed by a Dose 
Expansion part to confirm the RP2D and explore efficacy. In order to appropriately 
characterize the PK profile of TAS3351, there will be a PK lead-in for patients enrolled in the 
Dose Escalation part with a single administration of TAS3351 3 days prior to the start of 
daily dosing of TAS3351 with subsequent PK sampling.
The Phase 2 part of this study will be a single-arm study of TAS3351 monotherapy in the 
absence of any approved or well-established standard of care treatment options for these 
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patients on a potential control arm, highlighting the unmet medical need in this patient 
population.
In trials of molecularly targeted agents, minimal toxicity may arise over all doses under 
consideration and higher doses may not result in a greater response.19 The Phase 1/2 study 
design employed here could facilitate selection of a dose/regimen with acceptable toxicity 
that maximizes efficacious response. It allows for faster adaptation and refinement of 
subsequent parts of the study based on emerging data. It could enhance monitoring of 
cumulative safety data over time. If Phase 1 data show a favorable benefit/risk profile, the 
Phase 2 can start to enroll patients right away, which would speed up the drug development 
in an area of high unmet medical need.20 
4.4.
Justification for Primary Endpoint and Key Secondary Endpoint
The primary endpoint of the Phase 1 Dose Escalation part of this study is to identify the 
RP2D based on safety and preliminary antitumor activity observed as standard for Phase 1 
first in human studies.
The primary endpoint of the Phase 1 Dose Expansion and the Phase 2 part is ORR assessed 
by ICR according to RECIST v1.1. ORR is a clinically meaningful and accepted endpoint by 
regulatory agencies for studies in later-line EGFRmt NSCLC patients.21 ORR will be 
assessed by ICR to avoid any potential Investigator bias and to increase the validity of the 
ORR results observed. 
As a key secondary objective, this study will include DoR as assessed by ICR to evaluate the 
durability of responses. Durability of responses are considered a key factor to determine 
whether an observed ORR is clinically meaningful.22
4.5.
Justification for Starting Dose
The starting dose is based on toxicology studies in dogs, where the HNSTD was 5 mg/kg 
BID (10 mg/kg/day), and intolerable toxicities were observed at doses ≥10 mg/kg BID 
(20 mg/kg/day) (see Section 2.1.2.1). The starting dose was adjusted to 1.67 mg/kg/day (1/6 
of HNSTD) which translates to a human equivalent dose (HED) of 33.4 mg/m2 based on 
normalization of dose to body surface area as described in the International Conference on 
Harmonization of technical requirements for registration of pharmaceuticals for human use 
(ICH) S9 guideline on using animal data for FIH dose selection. Using the STD10 from 
rodent studies resulted in a HED of 72 mg/m2 based on allometric scaling; therefore, the 
lower dose of 33.4 mg/m2 observed for dogs was chosen for calculating the starting dose for 
human studies. Based on an average human body surface area of 1.62 m2, the starting dose of 
TAS3351 was calculated to be 54.1 mg in humans.
Based on the availability of 25 mg, 100 mg, or 200 mg tablet sizes, 50 mg QD was selected 
as the FIH starting dose.
4.6.
Study Period
The study periods for each patient are defined in Table 4.
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Table 4:
Definition of Study Periods
Period
Definition
Study Period
From the day of the first ICF signature to the last day of Survival 
Follow-up Period
Screening Period
From the day of main ICF signature to the day before the first dose
Treatment Period
From the first day of dosing to the last day of dosing
Safety Follow-up Period
30 (+3) days after the last day of dosing
Survival Follow-up 
Period
From the last day of Safety Follow-up period to death, or study 
completion, whichever happens first
4.7.
Study Completion
The study will be considered completed (that is, the scientific evaluation will be finished) 
when it has been determined by the Sponsor that the scientific evaluation of this study is 
sufficient and complete.
Investigators will continue to follow the Schedule of Events (Table 1, Table 2, and Table 3) 
for all patients until notified by the Sponsor that study completion has occurred.
4.8.
Study Extension
Following study completion (Section 4.7), all patients who are still receiving TAS3351 and 
deriving clinical benefit with no undue risk may continue to receive study treatment in a 
study extension phase. During study extension, patients may receive treatment until any of 
the study treatment discontinuation criteria (Section 5.4) are met.
During study extension, assessments are to be conducted according to the Schedule of Events 
shown in Table 3.
Investigators will perform any other standard procedures and tests needed to treat and 
evaluate patients; however, the choice and timing of the tests will be at the Investigator’s 
discretion. The Sponsor will not routinely collect the results of these assessments.
In the event that an SAE occurs, the Sponsor may request additional information (such as 
local laboratory results, concomitant medications, and hospitalizations) in order to evaluate 
the reported SAE.
4.9.
End of Study
The end of the study is defined as the date of the last visit of the last patient in the study 
including the last scheduled procedure shown in the Schedule of Events (Table 1, Table 2, or 
Table 3 in case of study extension).
4.10.
Patient Enrollment
Eligibility must be verified prior to patient enrollment. Upon eligibility verification, patient 
information will be entered into an Interactive Web Response System (IXRS). Patients are 
considered enrolled in the study when consented, screened, and determined to be eligible. 
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4.11.
Randomization and Blinding
No blinding of treatment assignments is required as this study is open-label.
No randomization is planned in Part A and Part C, and is only planned in Part B if 2 dose 
levels of TAS3351 are evaluated in Part B (see Section 4.2.2). Should 2 dose levels be 
evaluated, a total of 40 patients with C797S EGFRmt will be enrolled in Part B and will be 
randomized at a 1:1 ratio between the two treatment arms (ie, TAS3351 dose levels).
4.12.
Data Monitoring Committee
A data monitoring committee (DMC), including members external to the Sponsor, will be 
established prior to the transition from the Phase 1 study part to the Phase 2 part to monitor 
data on an ongoing basis to ensure the continuing safety of the patients enrolled in this study. 
The committee will meet periodically to review interim data. After the review, the DMC will 
make recommendations regarding the continuation of the study. The details will be provided 
in a separate DMC charter.
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5.
SELECTION AND WITHDRAWAL OF PATIENTS
Eligibility must be verified prior to patient enrollment. Prospective approval of protocol 
deviations to eligibility criteria (also known as protocol waivers or exemptions) is not 
permitted. 
5.1.
Inclusion Criteria
A patient must meet all of the following inclusion criteria to be eligible for participation in 
this study:
1. Provide written informed consent
2. ≥18 years of age (or meets the country’s regulatory definition for legal adult age, 
whichever is greater)
3. Histologically or cytologically confirmed, locally advanced, non-resectable or 
metastatic NSCLC
4. Has received the following prior treatment and no more than 2 lines of prior cytotoxic 
chemotherapy for locally advanced or metastatic disease setting:
a.
Part A1 (Phase 1 Dose Escalation): Standard of care (SOC) that is available to the 
patient, unless contraindicated, or intolerable to the patient 
b. Part A2: Progression on third-generation EGFR TKI (eg, osimertinib, lazertinib)
c.
Parts B and C: Progression on third-generation EGFR TKI (eg, osimertinib, 
lazertinib) 
5. Has the following EGFRmt status as determined by a CLIA certified (US), locally 
certified (outside of the US), or the study central laboratory based on tumor tissue or 
plasma cfDNA:
a.
Part A1 (Phase 1 Dose Escalation): Any EGFRmt 
b. Parts A2, B, and C: Any sensitizing EGFRmt and a confirmed C797S EGFRmt
(Note: no T790M EGFRmt required) 
6. Has tumor tissue available collected after progression on the most recent systemic 
EGFR TKI treatment in a quantity sufficient to allow for analysis of EGFRmt status 
by the Sponsor’s central laboratory (optional for Part A1 only). Please refer to the 
Laboratory Manual for details.  
7. Has measurable disease per RECIST v1.1 (optional for patients in Part A1)
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
9. Adequate organ function as defined by the following criteria:
a.
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
b. Platelet count ≥ 100,000/mm3 (≥ 100 × 109/L); last transfusion of blood products 
must be ≥2 weeks prior to start of study treatment.
c.
Hemoglobin ≥ 9.0 g/dL
d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × 
upper limit of normal (ULN); if liver function abnormalities are due to underlying 
liver metastasis, AST and ALT ≤ 5.0 × ULN
e.
Total bilirubin ≤ 1.5 × ULN, or ≤ 3.0 × ULN for patients with Gilbert’s syndrome
f.
Creatinine clearance (CrCl) (calculated or measured value): ≥50 mL/min. For 
calculated CrCl, use the Cockcroft-Gault formula
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g. Potassium blood levels ≥3.0 mmol/L
10. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy 
test prior to administration of the first dose of study treatment. Female patients are not 
considered to be of child-bearing potential if they are post-menopausal (no menses for 
12 months without an alternative medical cause) or permanently sterile 
(hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
11. Both males and females of reproductive potential must agree to use highly effective 
birth control throughout the study and at least for: 

6 months after the last dose of study treatment for females

3 months after the last dose of study treatment for males
or longer, based on local requirements.
5.2.
Exclusion Criteria
A patient must not meet any of the following exclusion criteria to be eligible for participation 
in this study:
1. Currently receiving an investigational drug in a clinical trial or participating in any 
other type of medical research judged not to be scientifically or medically compatible 
with this study
2. Has received prior treatment with any of the following within the specific time frame 
prior to the first dose of study treatment:
a.
Major surgery/surgical therapy for any cause within 4 weeks; the patient must 
have recovered adequately from the toxicity and/or complications of the 
intervention prior to starting study treatment
b. Chemotherapy, biologic therapy, targeted therapy, immunotherapy, or 
investigational agents within 5 half-lives or within 4 weeks (whichever is shorter) 
prior to the first dose of study treatment. Patient must have recovered from 
toxicities of the prior therapy based on the Investigator’s judgement prior to 
starting study treatment
c.
No prior treatment with: 
(i). Part A1 (Phase 1 Dose Escalation): Systemic immunotherapy (eg, PD-
1/PD-L1 antibody)
(ii). Parts A2, B, and C: Any EGFR C797S mutation-targeting agent (eg, 
BLU-945) 
d. Radiotherapy prior to the start of study treatment within: 
(i). 2 weeks for radiation therapy of non-thoracic regions (7 days for palliative 
radiation of single lesions)
(ii). 3 months for radiation therapy including thoracic region. 
Patients must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis.
3. Have any unresolved clinically relevant toxicity of Grade ≥2 from previous 
anti-cancer treatment, except for alopecia, skin pigmentation, and Grade 2 prior 
platinum-therapy related neuropathy. Patients with chronic, but stable Grade 2 
toxicities may be allowed to enroll if the Investigator and Sponsor agree.
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4. Any strong and moderate inhibitors/inducers of cytochrome P450 (CYP) 3A two 
weeks prior to start of therapy. If a patient is receiving strong inhibitors/inducers of 
CYP3A (see Appendix A), these medications and substances must be discontinued ≥2 
weeks prior to the first dose of study treatment. 
5. Has the following CNS metastases disease status:
a.
Part A1 (Phase 1 Dose Escalation): Known untreated central nervous system 
(CNS) metastases, or history of uncontrolled seizures, or leptomeningeal disease. 
Patients with treated brain metastases are eligible if there is no evidence of 
progression for at least 4 weeks after CNS-directed treatment, as ascertained by 
clinical examination and brain imaging (MRI or CT scan) during the screening 
period, and they are on a stable or decreasing dose of corticosteroids for at least 2 
weeks prior to the first dose of study treatment. 
b. Parts A2, B, and C: Spinal cord compression, symptomatic and unstable CNS 
metastases, requiring steroids over the last 4 weeks prior to enrollment 
(asymptomatic and symptomatic brain metastases stable for at least 4 weeks and 
off steroids are allowed). Patients with leptomeningeal disease are allowed if it is 
determined that immediate CNS treatment is unlikely to be required.
6. Impaired cardiac function or clinically significant cardiac disease, including any of 
the following: 
a.
Baseline QT interval > 470 msec corrected for heart rate using Fridericia’s 
formula (QTcF, verified on repeat measurements)
b. History of QTc prolongation or predisposition for QTc prolongation (clinically 
relevant electrolyte abnormalities, cardiac disorder, bradycardia, etc.), or family 
history of sudden cardiac death or QT prolongation (long QT syndrome)
c.
Regular use of medications known to prolong QTc interval or to be 
arrhythmogenic (such as ondansetron, erythromycin, droperidol) within 2 weeks 
of the first dose of TAS3351. A list of these medications can be found at: 
http://crediblemeds.org.
d. History or presence of clinically important abnormalities in rhythm or conduction 
in resting ECG (eg, sinus arrest, second- or third-degree atrioventricular block 
(first degree atrioventricular block not excluded), serious uncontrolled ventricular 
arrhythmias), or severe myocardial infarction within 6 months of screening.
7. General health condition of the patient is not suitable for the study including: 
a.
Disease or condition that significantly affects gastrointestinal absorption of the 
study treatment 
b. Clinically relevant active infection (ie, known HBV, HCV, HIV – screening not 
required) or other uncontrolled medical condition
c.
History of interstitial lung disease/pneumonitis, drug-induced lung 
disease/pneumonitis 
d. Known additional malignancy that is progressing or requires active treatment, 
with the exception of patients with a prior or concurrent malignancy whose natural 
history or treatment does not have the potential to interfere with the safety or 
antitumor assessment of the investigational regimen. Exceptions must be 
discussed with the Sponsor prior to patient enrollment
8. Known hypersensitivity to the ingredients of TAS3351
9. Unable to swallow whole tablets
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10. Pregnant female or breastfeeding female
11. Any other clinically significant acute or chronic medical or psychiatric condition that 
may increase the risk associated with study drug administration, or may interfere with 
the interpretation of study results based on Investigator discretion 
5.3.
Screen Failure
Screen failures are defined as patients who consent to participate in the clinical study but are 
not subsequently enrolled in the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure patients to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE after completion of the ICF. 
Patients who do not meet the criteria for participation in this study (ie, screen failures) may 
be rescreened twice or after discussion with the Medical Monitor. Previously completed 
study assessments remaining within the protocol-defined window will be accepted for 
rescreening. 
If the Sponsor or the Investigator identifies a patient who did not meet the eligibility criteria 
and was inadvertently enrolled, a decision on whether or not the patient may remain on study 
will be made between the Investigator and the Sponsor. If both agree that it is medically 
appropriate, the patient may continue on study following written approval by the Sponsor. 
5.4.
Discontinuation of Treatment
Discontinuation of study treatment does not represent a withdrawal from the study.
A patient must be discontinued from study treatment for any of the following reasons, but 
will continue to be monitored in the study:
1. Documentation of radiographic disease progression assessed by Investigator per 
RECIST v1.1* criteria.
2. Clinical progression. 
3. Unacceptable AEs or change in an underlying condition such that the patient can no 
longer tolerate therapy, for instance any Grade ≥3 toxicity that does not resolve to 
Grade 1 or baseline (or to Grade 2 for toxicities that are manageable with supportive 
care) within 21 days should result in permanent discontinuation.
4. Physician’s decision, including the need for other anticancer therapy not specified in 
the protocol or surgery or radiotherapy to the only site(s) of the disease being 
followed in the study.
5. Pregnancy or intent to become pregnant.
6. Termination of the study by the Sponsor.
7. At the patient’s request at any time irrespective of the reason (including withdrawal of 
consent from further treatment with the study drug or follow-up).
8. Noncompliance with the study protocol that, in the opinion of the Investigator or the 
Sponsor, warrants withdrawal from treatment with the study drug.
Patients who withdraw consent for further study treatment may choose to remain on study 
and should continue with all study evaluations as outlined in this protocol. If the patient 
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withdraws consent to all follow-up assessments, the patient is considered to have 
discontinued the study.
* Note: If a patient demonstrates radiographic disease progression but continues to have 
clinical benefit (including stable performance status and absence of symptoms and signs 
indicating clinically significant progression of the disease), the continuation of TAS3351 may 
be considered in exceptional cases following consultation with the Sponsor and in accordance 
with the following criteria: 
•
Absence of unacceptable toxicity
•
Absence of clinical symptoms or signs indicating clinically significant disease 
progression
•
No decline in ECOG performance status
•
Absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (eg, CNS metastasis, respiratory failure due to tumor 
compression, spinal cord compression) requiring urgent alternative medical 
intervention.
Written informed consent will need to be obtained prior to continuation of study treatment 
beyond radiologic disease progression and after discussion of alternative treatment options, 
including any available approved therapies and participation on alternative clinical trials.
5.5.
Post-treatment Discontinuation Considerations
The Investigator remains responsible for following the patient through an appropriate health 
care option for AEs that are considered related to the study or caused the patient to 
discontinue the study and have not been resolved at the 30-day Safety Follow-up visit. The 
patient should be followed up until the events are resolved or explained. Frequency of follow-
up is left to the discretion of the Investigator.
Investigators are not obligated to actively seek any new AEs after the 30-day Follow-up 
period. However, if the Investigator learns of any SAE at any time after a participant has been 
discontinued from the study and the Investigator considers the event to be reasonably related 
to the study treatment or participation, the Investigator must promptly notify the Sponsor.
5.6.
Withdrawal from the Study
A patient will be withdrawn from all study interventions and assessments (ie, discontinued 
from the study without follow-up) for any of the following reasons:
1. Death
2. Patient withdrawal of consent to further follow-up assessments, irrespective of the 
reason.
3. Lost to follow-up
•
A patient will be considered lost to follow-up if he/she repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site.
•
The following actions must be taken if a patient fails to return to the clinic for 
a required study visit:
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•
The site must attempt to contact the patient and reschedule the missed visit 
as soon as possible, counsel the patient on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the patient wishes to and/or 
should continue in the study.
•
Before a patient is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the patient (when possible, 3 telephone 
calls, and [if necessary] a certified letter to the patient’s last known mailing 
address, or local equivalent methods). These contact attempts should be 
documented in the patient’s medical records.
•
Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
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6.
STUDY TREATMENT
6.1.
Study Drug Administration
TAS3351 will be administered orally once daily (QD) on Days 1 to 21 of a 21-day cycle. 
Patients enrolled in Part A1 will also be administered a single dose of TAS3351 on Cycle 1 
Day -3 during the PK Lead-in Period. If PK, pharmacodynamic, and/or safety data indicate, 
twice daily (BID) dosing of TAS3351 may also be explored. 
•
TAS3351 should be taken at approximately the same time every day on an empty 
stomach and should be taken with water. Patients should not consume food 2 
hours before and ending 1 hour after taking TAS3351 but will be allowed to drink 
water during this period. Patients should be instructed to swallow the tablets 
whole and not to chew or crush them.
•
In the event of a dosing delay up to 12 hours (6 hours for BID dosing) after the 
scheduled dosing time, the patient should still take that day’s dose. If the dosing 
delay is >12 hours (6 hours for BID dosing) or if the patient vomits after a dose, 
the patient should skip that dose and continue with the planned subsequent dose 
(skipped or missed doses should not be made up).
On PK sampling days, TAS3351 should be administered on-site after the pre-dose PK sample 
collection (Table 13). Actual dosing time will be recorded.
Patients will receive TAS3351 until disease progression, unacceptable toxicity, or any other 
discontinuation criterion or withdrawal criterion is met (Section 5.4, Section 5.6). 
6.1.1.
Dose Escalation
The starting dose of TAS3351 will be 50 mg QD (Table 5). The study is designed to escalate 
TAS3351 up to a dose of 700 mg daily based on safety and tolerability observed, with lower 
increments considered, if clinically relevant toxicities are observed. The upper end of 700 mg 
TAS3351 total daily dose levels are based on more conservative assumptions for PK 
predictions and non-clinical efficacy data observed. In case of toxicity, other dose levels, 
such as intermediate or dose levels lower than Dose Level 1, may be explored following 
discussion and agreement between the Sponsor and the Investigators. 
Table 5:
TAS3351 Dose Levels
Dose Level
Total Daily Dose (mg/d)
Absolute and % Change 
from Previous Total Daily 
Dose
-1
25
-25 mg / -50%
1 (Starting dose)
50
-
2
100
50 mg / 100%
3
200
100 mg / 100%
4
350 
150 mg / 75%
5
500
150 mg / 43%
6
700
200 mg / 40%
Note: If no DLTs observed at 700 mg QD, any further dose escalation will not exceed 33% increments. 
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In addition, if PK, pharmacodynamic, and/or safety data indicate that splitting the dose of 
TAS3351 in two daily doses might be preferable (eg, due to short half-life, saturation of 
exposure), then twice daily (BID) dosing of TAS3351 may be explored following discussion 
and agreement between the Investigators and the Sponsor. In such case, the dose of the 
highest QD dose shown previously to be safe and tolerable will be divided into two equal 
doses to be taken in the morning and evening approximately 12 hours apart. Dose escalation 
for twice daily dosing will follow total daily doses shown in Table 5 (ie, total daily dose 
divided by 2 for BID dosing). 
The planned dose escalation will follow a BOIN design, 
 
. For further information about statistical 
considerations, please see Section 12. 
The Dose Escalation part (Part A1) will enroll approximately 40 evaluable patients. After 
treatment of the first patient in the study, a waiting period of 2 weeks will be implemented to 
evaluate safety before treatment of subsequent patients at the first dose level. For subsequent 
dose levels, additional patients will not be allowed to initiate study drug until the first patient 
at each dose level has been evaluated for safety 48 hours after initiating treatment. 
Subsequent patients may be enrolled in parallel in absence of toxicities meeting DLT criteria. 
With the maximum sample size of 15 patients per dose level, the boundary guiding the 
number of patients treated at the current dose is displayed in Table 6. This table provides the 
dose-finding decisions given the numbers of patients treated at the current dose level, and the 
observed numbers of patients experiencing toxicity.
Table 6:
Dose Escalation and De-Escalation Rules
Number of patients treated at the current dose level
Actionsa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Escalate if patients with 
DLT ≤
0
0
0
0
1
1
1
1
2
2
2
2
3
3
3
De-escalate if patients 
with DLT ≥
1
1
2
2
2
3
3
3
4
4
4
5
5
6
6
Eliminate if # of DLT ≥
NA
NA
3
3
4
4
5
5
5
6
6
7
7
8
8
a If no actions (ie, escalate, de-escalate, eliminate) are triggered, stay at the current dose for treating the next cohort of 
patients. 
Abbreviations: DLT=dose-limiting toxicity; NA=not applicable
Note: # of DLT = number of patients with at least 1 DLT; NA = this dose cannot be eliminated before treating 3 patients.
A minimum of 3 patients at each dose level are required. The general stopping rules are as 
follows:
•
Escalation stops if 40 evaluable patients have already been dosed
•
Escalation stops if there are 15 patients already dosed on next dose level
For the purpose of overdose control, a dose level will be eliminated if at least 3 patients have 
been treated and the probability of overdose is greater than 95%.
For patients in Part A1 who have completed the DLT assessment period, intra-patient dose 
escalation (IPDE) of TAS3351 to dose levels demonstrated to be safe and tolerable (eg, only 
Grade ≤2 toxicities were observed during previous treatment cycles including the DLT 
assessment period) may be allowed to minimize patient exposure at subtherapeutic doses 
following discussion between the Investigator and the Sponsor’s medical monitor and written 
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approval by the Sponsor. The decision to allow for IPDE should be made after considering 
the potential safety profile of the investigational drug including cumulative drug toxicity.
6.1.2.
Dose-limiting Toxicity
Dose-limiting toxicity (DLT) will be assessed during the first cycle (including the PK lead-in 
period for patients in Part A1). The occurrence of any toxicity outlined in Table 7 that is 
clinically significant will be considered a DLT, excluding toxicities clearly related to disease 
progression or intercurrent illness. The investigator must report all DLTs to the Sponsor 
promptly during the dose escalation part and well in advance of the dose escalation call. In 
addition, meetings between the Sponsor and investigators will be held on a regular basis to 
review safety data and in the event of emerging safety issues.
Table 7:
Definition of Dose Limiting Toxicity
Toxicity
DLT Definition
Hematologic
•
Grade 4 neutropenia lasting >7 consecutive days
•
Grade 4 thrombocytopenia
•
Grade 3 thrombocytopenia associated with clinically significant bleeding requiring 
intervention
•
Febrile neutropenia (ANC <1000/mm3 with a single body temperature of >38.3°C 
[101 °F] or a sustained temperature of ≥38°C [100.4°F] for more than 1 hour)
•
Grade ≥3 total bilirubin elevation 
•
Grade ≥3 AST and/or ALT elevation 
•
For patients with liver metastases, AST or ALT >8 × ULN regardless of duration or 
AST or ALT >5 × ULN but ≤8 × ULN lasting ≥7 consecutive days
Hepatic
•
Hy’s Law criteria concurrent observation of the following, with no other reason 
found to explain the findings (such as viral hepatitis A, B, or C; pre-existing or acute 
liver disease; or another drug capable of causing the observed liver injury):
-
Elevated aminotransferase enzymes >3 × ULN
-
Associated with an increase in bilirubin >2 × ULN
-
Absence of initial findings of cholestasis (elevated ALP)
Renal
•
Calculated CrCl ˂30 mL/min for >3 days despite optimal supportive care
Skin
•
Grade ≥3 skin toxicity uncontrolled by adequate skin therapy, including topical 
steroid and/or systemic corticosteroid therapy that does not return to Grade ≤2 within 
7 days
Other 
Nonhematologic
•
Any other Grade ≥3 toxicities with the following exceptions:

Grade 3 nausea, vomiting, and diarrhea lasting <72 hours despite optimal 
supportive care. Grade 4 vomiting or diarrhea will be considered a DLT.

Fatigue lasting <7 days 

Asymptomatic Grade 3 electrolyte abnormality with a duration of ≤72 hours that 
can be substituted or treated and are clinically uncomplicated (eg, not requiring 
hospitalization). 

Grade 3 amylase or lipase elevation not associated with symptoms or clinical 
manifestations of pancreatitis
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Toxicity
DLT Definition
Other
•
Prolonged dose interruption (>2 weeks) in initiating Cycle 2 due to study drug-
related toxicity)
•
Any study drug related AE(s) leading to treatment discontinuation during Cycle 1 
despite optimal supportive treatment
•
Any death not clearly due to the underlying disease or extraneous causes.
•
Any other toxicity deemed a DLT and agreed upon between Sponsor and 
Investigator
Abbreviations: AE=adverse event; ALP=alkaline phosphatase; ALT=alanine aminotransferase; ANC=absolute neutrophil 
count; AST=aspartate aminotransferase; DLT=dose-limiting toxicity; ULN=upper limit of normal
A patient evaluable for DLT is defined as a patient who either experienced a DLT during the 
first cycle (including the PK Lead-in period for patients in Part A1), or who completed the 
first cycle without experiencing a DLT and with at least 80% of study treatment 
administered. Patients who are not evaluable for DLTs may be replaced. Trends for toxicities 
observed after the DLT period will be considered when selecting the RP2D.
6.2.
Dose and Schedule Modifications
The following general dose modification guidelines for patients receiving TAS3351 should 
be followed:
•
Supportive treatment for any AE should be optimized before any modification is 
considered.
•
If the symptoms of AE promptly resolve with supportive care, consideration 
should be given to continuing study drug along with appropriate continuing 
supportive care.
Recommended dose modifications are based on the occurrence of treatment-related AEs and 
are provided for hematological toxicities (Section 6.2.1.1) and non-hematological toxicities 
(Section 6.2.1.2). If an Investigator suspends treatment or reduces doses without one of the 
dose reduction, interruption and resumption criteria being met, this is acceptable and would 
not be considered a protocol deviation. 
6.2.1.
Dose Reduction, Interruption, and Resumption 
Dose reductions for TAS3351 should be made according to Table 8. No more than 3 dose 
reductions are allowed. If dose reductions fail to result in achieving the minimum criteria to 
resume treatment or if toxicities occur that would necessitate reducing TAS3351 dosing 
below 25 mg QD (or BID), the patient should be discontinued from TAS3351 treatment.
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Table 8:
Dose Reduction
TAS3351 Total Daily Dose
Current Dose (mg/d) a
Reduce to (mg/d)a
50
25
100
50
200
100
350
175
500
300
700 
500
 a In case of BID dosing, total daily dose to be divided in two equal doses to be administered 12 h apart. For a 
current dose of 50 mg, dose would be reduced to 25 mg QD.
Abbreviations: BID=twice daily; d=day; h=hour; mg=milligram
Patients with dose reduction of TAS3351 may be re-escalated up to the starting dose, if the 
toxicity leading to dose reduction has been resolved and the benefit/risk assessment favors 
re-escalation of TAS3351. A discussion between Investigator and the Sponsor’s medical 
monitor is required prior to the TAS3351 dose re-escalation. 
If dosing of TAS3351 needs to be interrupted, the 21-day cycle will be maintained. There 
will be no delay in the start of a new cycle except the start of Cycle 1 for patients with a PK 
Lead-in period in Part A1, if clinically indicated.
6.2.1.1.
Dose Modifications for Hematological Toxicities
Recommendations for dose modification due to study drug-related hematologic toxicities are 
presented in Table 9.
Table 9:
Recommendations for Management of Hematologic Toxicities
Grade by CTCAE 
v5.0
Management Recommendation
Grade 1 and 2
No dose modifications required 
Anemia and Thrombocytopenia
Grade 3 
Suspend TAS3351 until resolved to Grade ≤2 or baseline, then: 
• If resolved ≤14 days, resume at the same dose level
• If resolved >14 days or re-occurrence, resume at next lower dose level
Grade 4
Suspend until resolved to Grade ≤2 or baseline, then resume at next 
lower dose level
Neutropenia (ANC)
Grade 3 lasting ≤3 
days
No dose modifications required
Grade 3 lasting >3 
days
or Grade 4
Suspend TAS33551 until resolved to Grade ≤2 or baseline, then 
• If resolved ≤7 days, resume at the same dose level
• If resolved >7 days or re-occurrence, resume at next lower dose level
Febrile neutropenia 
Suspend TAS3351 until resolved, then resume at next lower dose level
Abbreviations: ANC=absolute neutrophil count; CTCAE=Common Toxicity Criteria for Adverse Events
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6.2.1.2.
Dose Modifications for Non-hematologic Toxicities
Recommendations for dose modification due to study drug-related diarrhea, hepatic events, 
skin rash, QT prolongation, interstitial lung diseases (ILD), and other non-hematologic 
toxicities are presented in Table 10.
Table 10:
Recommendations for Managing Non-Hematologic Toxicities
Grade by CTCAE v5.0
Management Recommendation
Diarrhea (see also Section 6.4.4.2)
Grade 1 and 2
No dose modifications required, initiate supportive therapy (see 
Section 6.4.4.2)
If persistent / recurrent Grade 2 that does not resolve with maximal 
supportive measures, reduce to next lower dose level
Grade 3
Suspend dose until resolved to ≤Grade 2, then: 
• If resolved ≤14 days, resume at the same dose level and consider anti-
diarrheal prophylaxis
• If resolved >14 days or re-occurrence, resume at next lower dose level
Grade 4
Suspend dose until resolved to ≤Grade 1 or baseline, then resume at next 
lower dose level.  
Hepatic events
Bilirubin increased
Grade 1 and 2
No dose modifications required 
Note: Assess AST and ALT for ≥ Grade 2 bilirubin (see Hy’s law below)
Grade 3 
Suspend dose until resolved to ≤ Grade 1 or baseline, then:
• If resolved ≤14 days, resume at the same dose level
• If resolved >14 days or re-occurrence, resume at the next lower dose 
level
Grade 4 
Discontinue study drug
AST or ALT increase
Grade 1 and 2
No dose modifications required 
NOTE: Assess bilirubin for ≥ Grade 2 AST/ALT (see Hy’s law below)
Grade 3 
Suspend dose until resolved to ≤Grade 1 (≤ Grade 2 in the presence of 
liver metastasis) or baseline, then: 
• If resolved ≤14 days, resume at the same dose level
• If resolved >14 days, resume at the next lower dose level
Grade 4
Discontinue study drug
Hy’s law
AST or ALT 
>3.0 × ULN 
with 
bilirubin >2.0 × ULN
Discontinue study drug, except: 
• Other reason found to explain the findings (such as viral hepatitis A, B, 
or C, pre-existing or acute liver disease, or another drug capable of 
causing the observed liver injury) or
• Initial findings of cholestasis (elevated serum ALP)
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Grade by CTCAE v5.0
Management Recommendation
Skin Rash
Grade 1 and 2
No dose modifications required 
Topical steroid (eg, hydrocortisone 2.5%) and clindamycin cream BID, as 
needed, and consider oral antibiotic (eg, doxycycline 100 mg BID) for 2 
to 4 weeks  
Grade ≥ 3
Suspend dose until resolved to ≤Grade 2 and manage as shown above for 
Grade 1/2 considering additional oral steroids, then: 
• If resolved ≤14 days, resume at the same dose level and consider 
prophylactic management of skin rash
• If resolved >14 days or re-occurrence, resume at next lower dose level
QT prolongation
Grade 1
• Repeat ECG (triplicates, 2-3 minutes apart)
• If QTcF is still on average >450 ms, check electrolytes and replace to 
maintain K ≥ 4.0 mmol/L, Mg ≥1.8 mg/dL (0.9 mmol/L) and Ca >8.0 
mg/dL (2.0 mmol/L) and repeat ECG 
• No dose modifications required
Grade 2 
For first occurrence: 
• Repeat ECG (triplicates, 2-3 minutes apart)
• Check electrolytes and replace to maintain K ≥ 4.0 mmol/L, 
Mg ≥1.8 mg/dL (0.9 mmol/L) and Ca >8.0 mg/dL (2.0 mmol/L) and 
repeat ECG 
• If QTcF is still on average >481 ms, suspend drug until resolved to 
≤ Grade 1, and then resume at the same dose level
If re-occurrence:
-
Suspend drug until resolved to ≤ Grade 1 and then resume at the next 
lower dose level 
Grade 3 
• Repeat ECG (triplicates, 2-3 minutes apart)
• Check electrolytes and replace to maintain K ≥ 4.0 mmol/L, 
Mg ≥1.8 mg/dL (0.9 mmol/L) and Ca >8.0 mg/dL (2.0 mmol/L) and 
repeat ECG 
• If QTcF is still >500 ms and/or >60 ms change from baseline, suspend 
drug until resolved to ≤Grade 1 and obtain an evaluation by a 
cardiologist. If study drug can be resumed, it should be at the next lower 
dose level 
• If re-occurrence, consider discontinuing the study drug
Grade 4 
Discontinue study drug
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Grade by CTCAE v5.0
Management Recommendation
Interstitial Lung Disease (ILD) / Pneumonitis (see also Section 6.4.4.3)
Grade 1 
No dose modifications required, consider follow-up at regular intervals as 
per institutional standards
Grade 2
Suspend dose until resolved to ≤Grade 1, then: 
• If resolved ≤14 days, maintain dose level 
• If resolved >14 days, resume at the next lower dose level
If clinical symptoms persist/worsen despite treatment, consider 
discontinuing study drug
Grade 3 and 4
Discontinue study drug
Corneal ulceration
Grade ≥ 3
Discontinue study drug
Other Non-hematologic Toxicities
Grade 1 and Grade 2
No dose modifications required, administer supportive therapy as 
indicated
Grade 3 
Suspend dose until resolved to ≤Grade 1 or baseline (≤Grade 2 for 
toxicities that are manageable by supportive therapy, such as 
asymptomatic electrolyte changes, dyspepsia, hypertension), then: 
• If resolved ≤14 days, resume at the same dose level
• If resolved >14 days or re-occurrence, resume at next lower dose level
Grade 4
Suspend dose until resolved to ≤ Grade 1 or baseline, then resume at next 
lower dose level. 
Discontinue study drug if re-occurrence or occurrence of an irreversible 
treatment related clinically significant event. 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BID=twice daily; CTCAE=Common Terminology Criteria for Adverse Events; ECG=electrocardiogram; 
QD=once daily; QTc=corrected QT interval; QTcF=Fridericia's Correction Formula for corrected QT interval; 
T-bil=total bilirubin; ULN=upper limit of normal.
6.3.
Treatment Compliance
The patient will be instructed to comply with the dosage and dosing regimen of study 
treatment. The Investigator or designated study-site personnel will maintain a log of all study 
drug dispensed and returned. Compliance to all study drug administration should be 
documented in the patients’ source documents. Additionally, noncompliance can also be 
considered in the event a patient intentionally takes more study drug than prescribed. In the 
event a patient is noncompliant with study treatment, discontinuation of the patient may be 
considered after discussion between the Sponsor and Investigator.
6.4.
Concomitant Medications and Therapies
6.4.1.
Prohibited Concomitant Medications
Patients are not permitted to receive any other investigational or anticancer therapy, including 
chemotherapy, immunotherapy, biological response modifiers, or antineoplastic endocrine 
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therapy during the study treatment period (with the exception of permitted tumor therapies 
listed in Section 6.4.4).
Acid-reducing agents may have the potential to reduce TAS3351 plasma concentration and 
potentially the activity of TAS3351. The use of proton pump inhibitors (PPI) is prohibited for 
patients receiving TAS3351. For other acid reducing agents (ARAs), see Section 6.4.2.
6.4.2.
Concomitant Medications and Therapies Requiring Precautions
Drug interaction studies have not been conducted in humans. The following information is 
based on results from in vitro studies. Caution is advised if these drugs (examples provided in 
Appendix A) are given concomitantly:
Potential effects of TAS3351 on other drugs:
•
CYP2C8, CYP2C9, and CYP2C19 substrates: TAS3351 is a potential 
reversible inhibitor of CYP2C8, CYP2C9, and CYP2C19. Depending on 
achievable steady-state plasma TAS3351 concentrations, TAS3351 may increase 
the concentration and activity of CYP2C8, CYP2C9, and CYP2C19 substrates. 
•
CYP3A substrates: TAS3351 has the potential to time-dependently inhibit 
CYP3A. Depending on achievable steady-state plasma TAS3351 concentrations 
and doses, TAS3351 may increase the concentration and activity of CYP3A 
substrates.
•
CYP1A2 substrates: TAS3351 is a potential inducer of CYP1A2. Depending on 
achievable steady-state plasma TAS3351 concentrations, TAS3351 may reduce 
the concentration and activity of CYP1A2 substrates.
•
P-gp and BCRP substrates: TAS3351 is a potential inhibitor of P-gp and BCRP. 
Depending on achievable steady-state plasma TAS3351 concentrations and dose, 
TAS3351 may increase the concentration and activity of P-gp and BCRP 
substrates.
Potential effects of other drugs on TAS3351:
•
Strong and moderate inhibitors/inducers of CYP3A: TAS3351 is a potential 
substrate of CYP3A metabolism. CYP3A inhibitors/inducers (see Appendix A) 
may increase/reduce the concentration and activity of TAS3351.
Strong or moderate CYP3A inhibitors inducers and medications known to prolong QTc 
interval or to be arrhythmogenic (such as ondansetron, erythromycin, droperidol; see also: 
http://crediblemeds.org) should be avoided or substituted with other concomitant therapies 
while receiving TAS3351, if possible. However, if concomitant use cannot be avoided, 
patients should be closely monitored for any potential AEs and TAS3351 dose modifications 
should be performed accordingly as outlined in Section 6.2. The Investigator may also 
consider a TAS3351 dose reduction while concomitant treatment with a strong or moderate 
CYP3A inhibitor is being administered (eg, ciprofloxacin for an infection).
Acid-reducing agents (ARAs) may have the potential to reduce TAS3351 plasma 
concentration and potentially the activity of TAS3351. As mentioned in Section 6.4.1, the use 
of proton pump inhibitors (PPI) is prohibited for patients receiving TAS3351. Concomitant 
use of other ARAs should be avoided whenever possible. If concomitant use of ARAs is 
unavoidable, staggered dosing of histamine H2 receptor antagonists (H2 blockers) (TAS3351 
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administered at least 2 hours before or at least 12 hours after administration of H2 blockers) 
or antacids (TAS3351 administered at least 2 hours before or at least 2 hours after antacids) is 
recommended. Caution is advised with concomitant administration of ARAs with TAS3351.
6.4.3.
Permitted Concomitant Medications 
Local or regional palliative cryotherapy or radiation, such as for bone pain or palliative 
surgery (non-antineoplastic intent), are permitted (provided the target lesion is not a site of 
measurable disease and is not indicative of disease progression). If extended field radiation 
therapy or palliative radiation to a focal site of measurable disease is deemed to be in the best 
interest of the patient following discussion between the Investigator and the Sponsor, the 
patient will be censored for the primary analysis of efficacy. Study therapy should be ceased 
a minimum of 2 days prior to administration of palliative treatment and may be resumed 7 
days after the procedure or when the patient has recovered from the side effects of the 
procedure. Moreover, endocrine therapy for controlled prostate or breast cancer is permitted, 
if approved by the treating physician. Patients are allowed to receive COVID-19 vaccination 
while being on study.
6.4.4.
Supportive Care 
Supportive treatment should be provided based on available institutional or local guidelines. 
6.4.4.1.
Hematologic Support
Hematologic support (blood transfusions, granulocyte colony-stimulating factor [G-CSF], 
erythropoietin-stimulating agents) may be administered as medically indicated, according to 
the institutional site standards or American Society of Clinical Oncology (ASCO) 
guidelines.23,24,25
6.4.4.2.
Gastrointestinal Toxicities 
Prophylactic treatment for diarrhea (such as loperamide) is permitted during the study if 
clinically indicated according to the institutional or published guidelines.26
In the event of diarrhea, antidiarrheal therapy should be initiated as early as possible if not 
already receiving such therapy (eg loperamide). Patients should also be encouraged to drink 
fluids (for example, 8 to 10 glasses of clear liquids per day). Dehydration and any associated 
electrolyte disturbances should be prevented or corrected at the onset. 
For the management of nausea/vomiting, antiemetics may be administered as clinically 
indicated. Antiemetics which have the potential to prolong QTc, such as 5-HT3 receptor 
antagonists (eg, ondansetron) should be avoided when possible. Suggested antiemetics for the 
treatment of nausea include diphenhydramine, prochlorperazine, lorazepam, and/or steroids. 
If nausea is not controlled by these agents, and if antiemetics such as metoclopromide need to 
be used, then there should be additional ECG monitoring per Investigator discretion. In 
addition, dehydration and any associated electrolyte disturbances should be prevented or 
corrected at onset of symptoms.
6.4.4.3.
Interstitial Lung disease (ILD) / Pneumonitis
If new or worsening pulmonary symptoms (eg, dyspnea) occur or radiological abnormalities 
suggestive of interstitial lung disease is observed, a full diagnostic workup (including 
high-resolution CT (HRCT), blood and sputum culture, and hematological parameters) 
should be performed. It is strongly recommended to perform a full diagnostic workup in 
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order to exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, 
cardiogenic edema, or pulmonary hemorrhage. In the presence of confirmatory HRCT scans 
where other causes of respiratory symptoms have been excluded, a diagnosis of interstitial 
lung disease should be considered. Consult lung disease specialists as indicated and consider 
corticosteroid administration. 
6.4.4.4.
Amylase or Lipase Elevations
If amylase or lipase are >3×ULN, radiological imaging should be performed to evaluate the 
presence/absence of pancreatitis or other etiologies.
6.5.
Lifestyle Considerations
6.5.1.
Dietary
Patients will be prohibited from consuming herbal supplements and/or ingestion of foods and 
beverages known to be strong inducers or strong inhibitors of CYP3A. Furthermore, the 
consumption of grapefruit juice, grapefruit hybrids, pomegranates, starfruit, pomelos, Seville 
oranges, or juice products is prohibited during the study. 
6.5.2.
Sun Protection
A preclinical toxicity study using TAS3351 indicated a potential risk for phototoxicity. For 
this reason, it is recommended to advise patients to avoid prolonged exposure to natural 
sunlight, avoid artificial sunlight (eg, suntan bed), wear protective clothing, lip balm, and use 
broad-spectrum sunscreen with a high sun protection factor (SPF) ≥30 when outdoors.
6.6.
Contraceptive Guidance
To participate in the study, patients of childbearing potential must adhere to the contraception 
requirements from the day of study medication initiation, throughout the study, and up to 
6 months after the last dose of study treatment. 
For WOCBP (for definition see Section 5.1), including female study patients and partners of 
male patients, highly effective contraception is required during the study, and for 6 months 
after the last dose of study medication. 
Highly effective contraception is defined as follows:
•
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation with an oral, intravaginal or transdermal 
form
•
Progestogen-only hormonal contraception associated with inhibition of ovulation 
with an oral, injectable, or implantable form 
•
Intrauterine device
•
Intrauterine hormone-releasing system
•
Bilateral tubal occlusion 
•
Vasectomized partner with documentation of the success of the vasectomy 
•
Complete abstinence from heterosexual intercourse (periodic abstinence is not a 
safe method) 
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Male patients, unless sterile (vasectomy with post-procedure semen analysis), with partners 
who are WOCBP should use a male condom in combination with at least one of the effective 
contraception methods during the study and for 3 months after the last dose of study drug. 
Donation of sperm or ova is not allowed during the study and for 6 months after the last dose 
of TAS3351.
6.7.
Study Drug Materials and Management
TAS3351 will be supplied by the Sponsor.
Detailed information such as the requirements for accountability and disposal of study drug 
can be found in the Pharmacy Manual, which will be provided separately.
6.7.1.
Description of Study Drug
A description of the study drug and the recommended storage condition are provided in 
Table 11.
Table 11:
Description of TAS3351
Generic name
Not assigned
Dosage form
25, 100, and 200 mg tablets
Appearance
Pale yellow to grey solid
Formulation
TAS3351 tablets (25, 100, and 200 mg) contain 25, 100, and 200 mg 
of TAS3351 drug substance free base, respectively. In addition, these 
tablets contain the following inactive ingredients:
Microcrystalline cellulose 
Lactose monohydrate 
Croscarmellose sodium 
Hydroxypropyl methyl cellulose 
Colloidal silicone dioxide 
Sodium stearyl fumarate
Magnesium stearate
HPCM-based color coating
Storage condition
Store TAS3351 tablets according to the label.
6.7.2.
Packaging and Labeling
TAS3351 will be packaged and labeled according to local laws and regulations.
6.7.3.
Accountability
The Investigator is responsible for ensuring that all study drug received at the site is 
inventoried and accounted for throughout the study. All study drugs will be stored and 
disposed of according to the Sponsor's instructions. The dispensing of study drug to the 
patient and the return of study drug from the patient must be documented. Patients must be 
instructed to return all original containers, whether they are empty or still containing the 
study drug. 
Refer to the Pharmacy Manual for more details.
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7.
STUDY ASSESSMENTS
7.1.
Study Assessments and Procedures
The Schedule of Events (Section 1.3) summarizes the frequency and timing of all study 
assessments applicable to this study.
Descriptions of the study assessments required are presented in Table 12.
Table 12:
Study Assessments
Assessment
Details
General Study Assessments
Written informed 
consent/consent for study 
continuation
Date when written informed consent was obtained.
Review of 
inclusion/exclusion 
criteria
Eligibility must be assessed during the screening period and should be 
confirmed prior to the first dose of study drug as clinically indicated. 
See Sections 5.1 and 5.2.
Demographics/medical 
history
Sex, age, race/ethnicity, clinical diagnosis, date of diagnosis, method 
of diagnosis, prior cancer therapy, and relevant medical history (past 
and concurrent).
Baseline signs and 
symptoms
Signs and symptoms which occurred after signing of ICF but before 
administration of first dose of TAS3351.
Concomitant 
medication/concomitant 
therapy
Medication/therapy with period and the reason of concomitant use 
(including blood and blood products). Include all 
medications/therapies administered from the time ICF is signed 
through 30 days after administration of the last dose of TAS3351 or 
until the start of new anticancer therapy.
Compliance
Drug accountability of investigational drug.
See Section 6.3 and Section 6.7.3.
Safety 
Physical examination
Physical examinations at screening include assessments of general 
appearance, skin, head and neck (including ears, eyes, nose and 
throat), respiratory, cardiovascular, abdomen, lymph nodes, thyroid, 
musculoskeletal (including spine and extremities), and neurological 
systems. Targeted symptom directed physical examinations may be 
utilized on the basis of clinical observations at subsequent visits. 
Examination of skin should be performed at each timepoint indicated 
in the Schedule of Events.
AE monitoring
See Section 10.
Local and central ECGs
Resting, semi-recumbent 12-lead ECGs; triplicates at baseline, Cycles 
1-3, and as clinically indicated (eg, for QT prolongation, see dose 
modifications in Section 6.2.1.2); RR interval (heart rate), QT interval, 
QTcF interval and abnormal finding by 12-lead ECG. See 
Section 7.1.2. 
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Assessment
Details
Vital signs, height and 
body weight
Systolic and diastolic blood pressure, pulse rate, body temperature, 
height (for body mass index calculations, recorded at baseline only) 
and body weight.
Echocardiography/MUGA
Baseline echocardiography/MUGA (multi-gated acquisition scan) is 
required. Left ventricular ejection fraction (LVEF) monitoring is 
needed every 4 cycles during TAS3351 treatment, and as clinically 
indicated.
LVEF can be assessed by ECHO or MUGA; same modality should be 
used for a patient at screening and after dosing. See Section 7.1.3.
Hematology
Red blood cell (RBC) count, hemoglobin, hematocrit, platelets, white 
blood cell (WBC) count with differential: neutrophils (ANC), 
lymphocytes, monocytes, eosinophils, basophils. See Section 7.1.4. 
Serum chemistry
AST, ALT, ALP, total bilirubin, direct bilirubin, albumin, LDH, 
triglyceride, total cholesterol, creatinine, BUN, Na, K, Cl, Ca 
(corrected value), Mg, blood glucose, C reactive protein (CRP), lipase, 
amylase, creatinine clearance (if there is a measured value, use the 
measured value) or eGFR. See Section 7.1.4.
For a calculated CrCl value, use the Cockcroft-Gault formula: 
Male:
CrCl =  (140 ― [insert age in years] × [insert weight in kg]
72 × [insert serum creatinine in mg/dL]
Female:
CrCl =  (140 ― [insert age in years] × [insert weight in kg]
72 × [insert serum creatinine in mg/dL]
 × 0.85
Coagulation
PT-INR, APTT, and fibrinogen. See Section 7.1.4 . 
Urinalysis
Urine protein (qualitative), sediment, occult blood by dipstick or 
laboratory. If urine protein is 2+, add urinary β2-microglobulin and 
quantitative measurement of proteinuria (24-hour urine collection for 
protein preferred). See Section 7.1.4. 
Pregnancy test
For all female patients of childbearing potential:
Serum or urine human chorionic gonadotrophin (human chorionic 
stimulating hormone) test (see the local regulation and/or CTFG 
recommendations). For screening, serum test required.
ECOG performance status
 See Oken et al. for details.27
Efficacy and other 
Efficacy assessments
Efficacy assessment by tumor imaging. See Section 7.1.1.
Survival follow-up
Patient or family should be contacted for survival follow-up until 
withdrawal of consent, death, or loss to follow-up, until study 
completion. This should also include further anti-cancer treatments 
administered. 
PK blood sampling
See Section 8.1 and Laboratory Manual.
Pharmacodynamic 
biomarker sampling
See Section 11. 
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7.1.1.
Efficacy Assessments
Efficacy assessments (including CT scan/MRI) will be performed by Investigator/local 
radiologist according to RECIST v1.1 guidelines at the timepoints outlined in the Schedule of 
Events (Section 1.3). 
Radiological assessment must include MRI/CT of the chest, abdomen (and pelvis, if 
clinically indicated or obtained at baseline) at each time point, as well as assessment of all 
other known sites of disease. MRI of the brain should be performed if signs or symptoms 
suggestive of CNS metastases are present. The same method of assessment and the same 
technique must be used to characterize each identified and reported lesion at screening, 
throughout the study including the follow-up period. Contrast-enhanced CT scans or MRIs 
are the preferred methods for tumor assessments. If a contrast agent is contraindicated in a 
patient, obtain a non-contrast chest CT and enhanced MRI of the abdomen (and pelvis if 
clinically indicated). A CT should be performed using a ≤5 mm contiguous reconstruction 
algorithm. 
For Part B and C of this study, all radiological imaging will be performed as indicated in the 
Site Imaging Manual provided by the central imaging core laboratory. Scans will be 
submitted to a Sponsor designated central imaging core laboratory for response assessment 
including RECIST v1.1, and/or exploratory analysis (eg, volumetric and viable tumor 
measurements). Detailed information regarding submission of images to the central imaging 
core laboratory is found in the Site Imaging Manual. 
Note that complete response and partial response (PR) require confirmatory CT or MRI 
repeat assessment at least 4 weeks after the first detection of response. PET may be used to 
upgrade a response to a CR in a manner similar to a biopsy in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring.28 
Patients who discontinue without documented radiographic disease progression per RECIST 
1.1 should continue to undergo tumor assessments/scans according to the Schedule of Events 
until radiographic PD per RECIST v1.1 is documented, the study is completed, or consent is 
withdrawn.
7.1.2.
12-Lead Electrocardiogram
Electrocardiograms (ECGs) will be collected using a 12-lead tracing. Patients should be in 
supine position in a rested and calm state for at least 10 minutes before ECG assessment is 
conducted. If the patient is unable to be in the supine position, the patient should be in most 
recumbent position as possible. ECGs should be performed on D1 of every cycle and more 
frequently for patients in Part A1 during the PK lead in period (for PK lead in, see Table 13). 
For ECGs during Extension, see Table 3. 
All ECGs should be performed in triplicate on Day 1 of Cycles 1 to 3 for all patients in Parts 
A1, A2, B and C. Patients in Part A1 will have additional triplicate ECGs performed during 
selected time points of the PK Lead-in period. After C3D1, ECGs are not required to be 
performed in triplicate unless clinically indicated. ECGs should be run consecutively, prior to 
blood draws or other invasive procedures. An ECG machine with the capacity to calculate 
standard intervals automatically should be used. If an abnormal ECG finding at screening or 
baseline is considered to be clinically significant by the Investigator, it should be reported as 
a concurrent medical history condition. If there is a clinically significant abnormal ECG 
finding during the treatment period, this should be recorded on the AE eCRF, according to 
standard AE collection and reporting processes.
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For Parts A2, B, and C, all ECGs will be performed using local ECG machines. Patients in 
Part A1 will have both local and central ECGs (see Table 13).
For central ECGs in Part A1 (see Schedule of Events; Table 1), the Investigator or delegate 
will review all ECGs for any on treatment decisions. Once signed, the original ECG tracing 
will be retained with the patient's source documents. All digital ECG data will be transferred 
electronically for central analysis of heart rate, PR, R-R, and QT intervals by an external 
cardiologist. 
7.1.3.
Cardiac Function Evaluation 
The commonly available imaging modalities (ECHO 2D, MUGA) will be used for the 
evaluation of LVEF evolvement during therapy with TAS3351 to detect presence of 
cardiotoxicity defined by the European Society of Cardiology as a decrease in LVEF of 
>10% points to a value below 50%.29 Imaging will be performed by the cardiologist or 
qualified delegate per the Schedule of Activities (Table 1). Additional on-study evaluation 
may be performed as needed based on physician judgment and/or symptoms or signs of LV 
dysfunction. Each evaluation will encompass:
•
LVEF assessment using MUGA, conventional 2DE biplane Simpson method or 
3DE, if available
•
Clinical symptoms of Congestive Heart Failure (CHF) will be noted and graded 
according to NYHA
Signs of CHF will be detected by routine clinical examination, including auscultation to 
detect S3 gallop, tachycardia, or both.
7.1.4.
Laboratory Assessments
The laboratory must provide normal reference ranges for all hematology, chemistry, 
coagulation tests, and urinalysis/urine parameters shown in Table 12. Laboratory results for 
hematology, serum chemistry, coagulation and urine assessments must be reviewed for 
clinically significant events. Any clinically significant events must be followed and reported 
as required by the protocol (see Section 10). Laboratory assessment prior to the first day of 
dosing may be done up to 72 hours prior to dosing.
7.1.5.
Ophthalmological Assessments
Ophthalmological examination will be performed by an ophthalmologist or qualified person 
at the time points described in Section 1.3. 
Ophthalmologic exam should be performed for each eye and should encompass: 
•
Best corrected visual acuity
•
External ocular examination
•
Routine slit lamp examinations, including the anterior and posterior chambers 
(Fluorescein or rose Bengal or other dyes used to evaluate the ocular surface can 
be used according to institutional guidelines and local clinical practice)
Any clinically significant findings must be reported as an AE. The type of examination used 
to identify any potential ocular adverse event AEs will be captured in the electronic case 
report form (eCRF).
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7.1.6.
PRO Measurements
For patients enrolled in Part C, patients’ health-related quality of life, symptoms, functioning, 
and general well-being will be captured using PRO measures and collected according to the 
Schedule of Events (Section 1.3). 
EORTC-QLQ-C30:
The EORTC-QLQ-C30 consists of 30 core items, with the 4-point Likert scales ranging from 
1: “Not at all” to 4: “Very much”. There are 2 items for global health status/quality of life. 
Functional scales include physical functioning (5 items), role functioning (2 items), 
emotional functioning (4 items), cognitive functioning (2 items), and social functioning (2 
items). Symptom scales/items include fatigue (3 items), nausea and vomiting (2 items), pain 
(2 items), dyspnea; insomnia; appetite loss; constipation; diarrhea; and financial impact (1 
item each).30,31 
EQ-5D-5L:
The EuroQol-5D (EQ-5D) is a standardized measure of the patient’s health-related quality of 
life. The 5-level version of the EQ-5D (EQ-5D-5L) consists of 2 pages: the EQ-5D 
descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-5L descriptive 
system comprises the following five dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The EQ VAS records 
the patient’s self-rated health on a vertical visual analogue scale where the endpoints are 
labelled ‘The best health you can imagine’ and ‘The worst health you can imagine’. The VAS 
can be used as a quantitative measure of health outcome that reflects the patient’s own 
judgement. See https://euroqol.org/eq-5d-instruments/.
7.1.7.
COVID-19 Pandemic Considerations
•
During the COVID-19 pandemic, the Sponsor will perform a risk assessment of 
the study on an ongoing basis to ensure:
•
The protection of patient safety, particularly if scheduled visits to the sites are 
postponed
•
The uninterrupted supply of drugs to patients for whom the drugs continue to 
benefit, while assuring patient safety (even if they are forced to remain at home)
•
The collection of key safety and efficacy data even if patients cannot keep their 
scheduled visits to the site due to the exceptional circumstances in relation to 
COVID-19
The following considerations may be applied in accordance with guidelines from regulatory 
authorities17,18 and individual site policies:
•
If a patient is unable to sign an informed consent for the study in person, the 
consent may be obtained electronically or remotely via a phone call or video 
conference.
•
If a patient is unable to attend a scheduled on-site visit and/or complete any 
protocol-required study assessments, the Sponsor should be contacted. Clinical 
assessments should be performed remotely via a phone call or video conference, 
assuring safety assessment and collection of new/follow-up AEs. 
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•
To ensure compliance with the protocol-required laboratory tests and assessments, 
the possibility for these tests to be performed at an external qualified laboratory or 
facility should be evaluated. The results of any tests or assessments performed by 
an external laboratory or facility must be communicated to the Investigator and 
documented in the patient’s source files. If it is not possible to have assessments 
performed at an external facility, the patient may be evaluated for safety via a 
phone call or video call, assuring the collection and follow-up of AEs are 
documented in the patient’s source file.
•
Tumor assessments should be performed (as much as the circumstances allow) 
as specified in the protocol. If a patient is unable to reach the site, an external 
qualified imaging facility can be used. Every effort should be made to ensure that 
the same imaging modality and image acquisition parameters (eg, anatomic 
coverage, imaging sequences, etc.) are used consistently for each patient 
throughout the study.
•
The results (including the images obtained from all radiographic procedures) 
should be sent to the Investigator. The imaging facility used, the time points, and 
the Investigator’s review of the images should be documented in the patient’s 
source files and the eCRF. 
•
If a patient becomes infected with severe acute respiratory syndrome coronavirus 
2 (SARS-CoV-2) and/or develops any symptoms suggesting COVID-19 infection, 
Investigators must follow local guidelines for the management of patients with 
COVID-19. Symptomatic COVID-19 cases should be reported as AEs or SAEs; 
however, asymptomatic COVID-19 cases do not have to be reported. The Sponsor 
needs to be contacted to discuss the continuation of the study treatment. However, 
the Investigator has the right to decide the continuation of treatment in COVID-19 
infected patients.
•
Considering the rarity of the disease (even after the COVID-19 pandemic 
settlement), the remote management options described above may apply to 
patients who are unable to frequently visit the sites for any other reasons (eg, 
extremely long distance to the sites) after discussion with the Sponsor.
•
All decisions and deviations due to COVID-19 must be documented in the 
patient’s source files and the eCRF.
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8.
PHARMACOKINETICS
8.1.
Sample Collection
Blood samples for PK analysis and ECG sampling will be collected at specific time points 
listed in Table 13 (Table 14 in case BID dosing will be explored) and used to evaluate PK of 
TAS3351 and its active metabolite (TAS-05-14317). ECGs should also be obtained prior to 
on-site TAS3351 administration. When a 12-lead ECG is obtained at the same timepoint as a 
PK blood draw, the 12-lead ECG should be obtained first.
Detailed information about collection procedures including blood sampling, collection, 
processing, and sample shipment will be provided in a separate Laboratory Manual. 
Table 13:
Schedule for PK and ECG Sampling (QD Dosing)
Phase 1 Dose Escalation (Part A1)
Day of Studya
Collection time relative to TAS3351 
administration (time windowb)
PK 
sample
ECGc
Pre-dose (up to -30 minutes)
X
0.5 hours (±10 minutes)
X
1 hour (±10 minutes)
X
X
2 hours (±15 minutes)
X
X
3 hours (±20 minutes)
X
4 hours (±25 minutes)
X
X
6 hours (±35 minutes)
X
8 hours (±45 minutesd)
X
X
24 hours (±2 hours)
X
X
48 hours (±2 hours)
X
PK Lead-in, 
Day -3 
72 hours (± 2 hourse)
X
X
Pre-dose (up to -30 minutes)
X
X
0.5 hours (±10 minutes)
X
1 hour (±10 minutes)
X
X
2 hours (±15 minutes)
X
X
3 hours (±20 minutes)
X
4 hours (±25 minutes)
X
X
6 hours (±35 minutes)
X
8 hours (±45 minutesd)
X
X
Cycle 1 Day 15
24 hours (±2 hourse)
X
X
Cycle 2 Day 1
Pre-dose (up to -30 minutes)
X
X (Local)
Cycle 3 Day 1
Pre-dose (up to -30 minutes)
X
X (Local)
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Phase 1 “Backfill” (Part A2), Dose Expansion (Part B), and Phase 2 (Part C)
Day of Studya
Collection time relative to TAS3351 
administration 
(time windowb)
PK 
sample
ECGc
Pre-dose (up to -30 minutes)
X
X (Local)
Cycle 1 Day 1
2 hours (±1 hour)
X
X (Local)
Pre-dose (up to -30 minutes)
X
X (Local)
Cycle 2 Day 1
2 hours (±1 hour)
X
X (Local)
Cycle 3 Day 1
Pre-dose (up to -30 minutes)
X
X (Local)
a For patients with TAS3351 dose interruptions, PK days might be postponed or waived upon discussion and 
written approval by the Sponsor. Additional optional PK samples may be collected if any safety concerns are 
identified. If no longer needed for PK evaluation, collection time points might be skipped upon written 
notification by the Sponsor. 
b Time window given for guidance; collection outside these windows will not be considered a protocol 
deviation as long as the exact time of dosing and sampling is documented. 
c ECG must be collected prior to PK sampling. All ECGs through C3 should be performed in triplicate. Central 
ECGs will be performed for all timepoints unless otherwise specified.
d This PK sample is mandatory for Dose Level 1. Following PK analysis for Dose Level 1, PK sampling at this 
timepoint at subsequent dose levels may be waived by the Sponsor, with this decision to be communicated to 
sites. 
e This PK sample must be collected prior to TAS3351 administration on this day. The ECG should be performed 
within 30 min prior to C1D1 dosing.
Table 14:
Schedule for PK and ECG Sampling (BID Dosing)
Phase 1 Dose Escalation (Part A1)
Day of Studya
Collection time relative to TAS3351 
administration (time windowb)
PK sample
ECGc
Pre-dose (up to -30 minutes)
X
0.5 hours (±10 minutes)
X
1 hour (±10 minutes)
X
X
2 hours (±15 minutes)
X
X
3 hours (±20 minutes)
X
4 hours (±25 minutes)
X
X
6 hours (±35 minutesd)
X
8 hours (±45 minutese)
X
X
Cycle 1 Day 1 
24 hours (±2 hoursf)
X
Pre-dose (up to -30 minutes)
X
X
0.5 hours (±10 minutes)
X
1 hour (±10 minutes)
X
X
2 hours (±15 minutes)
X
X
Cycle 1 Day 
15
3 hours (±20 minutes)
X
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Phase 1 Dose Escalation (Part A1)
4 hours (±25 minutes)
X
X
6 hours (±35 minutesd)
X
8 hours (±45 minutese)
X
X
24 hours (±2 hoursf)
X
Cycle 2 Day 
1
Pre-dose (up to -30 minutes)
X
X (Local)
Cycle 3 Day 
1
Pre-dose (up to -30 minutes)
X
X (Local)
a For patients with TAS3351 dose interruptions, PK days might be postponed or waived upon discussion and 
written approval by the Sponsor. Additional optional PK samples may be collected if any safety concerns are 
identified. If no longer needed for PK evaluation, collection time points might be skipped upon written 
notification by the Sponsor.
b Time window given for guidance; collection outside these windows will not be considered a protocol deviation 
as long as the exact time of dosing and sampling is documented.
c ECG must be collected prior to PK sampling. All ECGs through C3 should be performed in triplicate. Central 
ECGs will be performed for all timepoints unless otherwise specified.  
d Following PK analysis for Dose Level 1 (QD dosing), PK sampling at this timepoint may be waived by the 
Sponsor, with this communication to be communicated to sites. 
e This PK sample must be collected prior to administration of the second BID dose. 
f This PK sample must be collected prior to administration of the first BID dose on next study day.
Note: For patients enrolled in Phase 1 “Backfill” cohorts (Part A2), Dose Expansion (Part B), or Phase 2 (Part 
C), PK and ECG sample collection will follow the same schedule outlined in Table 13.
8.2.
Drug Concentration Measurements
PK samples will be analyzed by liquid chromatography/tandem mass spectrometry 
(LC-MS/MS) to determine plasma concentrations of TAS3351 and its active metabolite 
(TAS-05-14317) using validated bioanalytical methods. The detailed analytical plans will be 
described in a bioanalytical study protocol.
8.3.
Pharmacokinetics Analysis
Plasma concentration data by time and study day will be summarized descriptively.
8.3.1.
Pharmacokinetic Parameters
PK analyses for TAS3351 and its active metabolite (TAS-05-14317) in plasma following 
administration of TAS3351 in Part A1 on PK Lead-in (QD dosing) or Cycle 1 Day 1 (BID 
dosing) and Cycle 1 Day 15 (QD dosing and BID dosing) will be included in the calculation 
of the parameters listed below, whenever possible, according to the noncompartmental 
method.
•
Cmax, Tmax, AUCn, AUClast, and T1/2
The following PK parameters will be calculated only for PK Lead-in:
•
AUCinf, CL/F (only TAS3351), Vz/F (only TAS3351), and MRT (only TAS3351)
The following items will be calculated using PK parameters.
•
Accumulation ratio and metabolic ratio
Other PK parameters or items not listed above may be calculated if deemed appropriate.
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8.3.2.
Dose-proportionality
Dose-proportionality of PK parameters will be evaluated using statistical method in Part A1.
8.3.3.
Population PK Modeling and Exposure-response Analysis
A population PK analysis may be conducted as appropriate. In case such analysis is 
conducted, the concentration data obtained from Part A1, Part A2, Part B, and Part C of the 
study will be used to develop a Population PK model. Effects of intrinsic and/or extrinsic 
factors (eg, subject demographics, clinical laboratory values, disease characteristics) on PK of 
TAS3351 and TAS-05-14317 will be exploratorily evaluated by the population PK analysis 
as appropriate. PK data of TAS3351 and TAS-05-14317 obtained in other studies may be 
also combined with data from this study, if available. Individual exposures such as Cmax, Cmin, 
and AUC will be estimated by the Population PK analysis and used for the exploratory 
exposure-response analysis of safety and efficacy. Detailed procedures of Population PK and 
exposure-response analyses will be described in a separate statistical analysis plan (SAP), and 
the analysis results will be reported in the main CSR or a separate PK study report.
8.4.
Metabolite Profiling
Exploratory metabolite profiling will be performed using plasma samples collected in this 
clinical study. The concentration of major metabolites may be measured as appropriate.
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9.
EFFICACY EVALUATIONS
9.1.
Efficacy Criteria
Efficacy parameters will be evaluated by the investigator/local radiologist based on tumor 
imaging (including CT/MRI) according to RECIST v1.1 guidelines.28 Planned time points for 
all efficacy assessments are provided in the Schedule of Events (Table 1 and Table 2). 
Primary efficacy evaluation of TAS3351 will be based on independent central review (ICR) 
for patients enrolled in Part B and C of this study. In addition, efficacy will be assessed by the 
investigator/local radiologist for all patients. 
Determination of disease response for clinical management and discontinuation of study 
treatment of patients will be assessed at the clinical sites per RECIST v1.1. If the investigator 
determines that a patient has developed clinical disease progression manifested by 
symptomatic deterioration but not supported by radiographic evidence of progression, the 
patient may stop treatment. Symptoms of clinical disease progression must be documented in 
the patient’s source documents and must be reported as AEs. Every effort should be made to 
document objective radiographic disease progression even after discontinuation of treatment. 
For additional guidance, refer to RECIST v1.1 specification for standard anatomical 
radiological imaging.28
See Section 7.1.1 for additional efficacy assessment details.
9.2.
Efficacy Endpoints
Efficacy endpoints based on radiographic imaging will be assessed per RECIST 1.1; endpoint 
definitions are summarized in Table 15. 
Table 15:
Efficacy Endpoint Definitions
Endpoint
Definition
ORR
Proportion of patients experiencing a best overall response of PR or CR (per 
RECIST v1.1). Intracranial ORR be assessed based on ORR of CNS lesions only 
DoR
Time from the first documentation of response to the first documentation of 
objective tumor progression or death due to any cause, whichever occurs first. 
Intracranial DoR be assessed based on DoR of CNS lesions only
DCR
Percentage of patients who have achieved a CR, PR, or stable disease (SD)
PFS
Time from date of first dose to the date of documentation of disease progression, 
or date of death, whichever occurs first
OS
Measured from the date of first dose until the date of death due to any cause
Abbreviations: CNS=central nerve system; CR=complete response; DCR=disease control rate; DoR=duration 
of response; ICR=independent central review; ORR=objective response rate; OS=overall survival; 
PFS=progression-free survival; PR=partial response; RECIST=Response Evaluation Criteria in Solid Tumors; 
SD=stable disease
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10.
SAFETY EVALUATIONS
10.1.
Adverse Events
10.1.1.
Definition of Adverse Events
An AE is defined as any untoward medical occurrence in a clinical study patient and does not 
necessarily have a causal relationship with the study drug. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a study drug, whether or not related to the study drug.
Disease progression is not an acceptable AE term. In cases of nonfatal disease progression, 
the relevant signs, symptoms, and complications that led to the diagnosis of clinical disease 
progression should be reported as an AE. If the relevant signs, symptoms, and complications 
meet any of the serious criteria, they should be reported as SAEs. In both cases it should be 
indicated whether the signs, symptoms, and complications are related to clinical disease 
progression. Radiological progression without relevant signs, symptoms, and complications 
will not be reported as an AE or SAE.
10.1.2.
Events Meeting the Adverse Event Definition
•
Laboratory test results outside the normal range (hematology, clinical chemistry, 
or urinalysis) or other safety assessments (eg, ECG, diagnostic radiological scans, 
or vital signs measurements), including any that worsen in NCI CTCAE v5.0 
grade from baseline, which are considered clinically significant in the medical and 
scientific judgment of the Investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition resulting in an 
increase in NCI CTCAE grade.
•
Condition detected or diagnosed that is new in onset or increased in NCI CTCAE 
v5.0 grade from the baseline condition, except clinically nonsignificant changes in 
laboratory test results in the opinion of the Investigator.
•
Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study drug or a concomitant medication. An overdose or incorrect 
administration of study treatment is not itself an AE, but it may result in an 
AE.
10.1.3.
Time Period for Collection of AE and SAE Information
All AEs will be collected from the time the ICF is signed through 30 days after the last dose 
of study therapy (Safety Follow-up) or until the start of new antitumor therapy, whichever is 
earlier (see Section 10.2 regarding the assessment of AEs associated with laboratory results.)
The collection of AEs/SAEs after the 30-day follow-up period has ended has been described 
in Section 5.5.
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10.1.4.
Reporting of Adverse Events
10.1.4.1.
Terms of Reported Adverse Events
All AEs will be documented in the eCRF according to the eCRF Completion Guidelines. 
Documentation should include onset and resolution/stabilization dates, severity/grade, 
relationship to study drug, and outcome of the event. 
When a diagnosis for the reported signs or symptoms is known, the Investigator should report 
the diagnosis (not the symptoms) as the AE.
10.1.4.2.
Severity of Adverse Events
The Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 will be used to 
grade the severity of AEs.
10.1.4.3.
Causal Relationship with Study Drug
The causal relationship between an AE and the study drug will be assessed using the 
following 2-point scale, considering the patient’s condition, medical history, concomitant 
medications, and the temporal relationship between study drug administration and onset of 
the AE.
1. An AE is considered to be “Related” if the event follows a reasonable temporal 
sequence from administration of study drug and there is a reasonable possibility that 
at least one of the following conditions is true:
•
A positive dechallenge: This means that the event improves or resolves after the 
drug is stopped (temporarily or permanently).
•
A positive rechallenge: This means that the event reappears after the drug is 
restarted.
•
The event cannot be reasonably explained by the patient’s clinical state and/or 
other therapies administered.
•
A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, Stevens-Johnson syndrome).
2. An AE is considered to be “Not related” if at least one of the following conditions is 
true:
•
The event occurred prior to study drug administration.
•
There is no reasonable possibility that the study drug caused the event. (“No 
reasonable possibility” means there is no evidence to suggest a causal relationship 
between the study drug and the AE.)
•
The event does not follow a reasonable temporal sequence from administration of 
study drug and could have been produced by a documented pre-existing condition, 
concomitant medication, or patient’s clinical state.
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10.1.4.4.
Outcome of Adverse Events
Record the outcome of AEs as follows:
1. Recovered/resolved
2. Recovering/resolving
3. Not recovered/not resolved
4. Recovered/resolved with sequelae
5. Fatal
10.1.4.5.
Follow-up of Adverse Events
Any ongoing AEs should be followed until the earliest occurrence of one of the following:
•
AE has resolved 
•
Completion of Safety Follow-up visit
•
Start of new antitumor therapy
•
Patient’s refusal of follow-up
•
Death
•
Other (eg, transfer to another hospital)
10.2.
Laboratory Assessments
See Table 12 for the list of clinical laboratory assessments to be performed and the Schedule 
of Events (Table 1 and Table 2) for timing and frequency.
All laboratory assessments will be performed locally. The laboratory must provide normal 
reference ranges for hematology, chemistry, urine, and coagulation tests. If justified (eg, 
deterioration of the patient’s health conditions and/or distance from the clinical site) and 
permitted by the country and institution, laboratory tests performed by external laboratories 
may be used for the study. However, laboratory reference ranges and accreditation are 
required.
10.2.1.
Reporting and Evaluation of Laboratory Test Results
All laboratory test results (internal or external) except for those at screening (which are 
considered baseline) must be reviewed for clinical significance by the Investigator. 
Laboratory test results that are outside the normal range (hematology, clinical chemistry, or 
urinalysis) that worsen in NCI CTCAE v5.0 grade from baseline and are considered clinically 
significant in the medical and scientific judgment of the Investigator should be reported as 
AEs. A new laboratory abnormality that has a clinical impact on a patient (eg, resulting in 
study drug dose reduction, treatment delay, treatment discontinuation, and/or requirement of 
intervention) should be reported as an AE, unless it is considered part of clinical 
manifestations of a clinical diagnosis that is already reported as an AE. 
All laboratory values that are outside the normal range are to be evaluated for their clinical 
impact before exposing the patient to the next dose of TAS3351.
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10.2.2.
Repeat Testing
Evaluation of any clinically significant laboratory test will be repeated, as clinically 
indicated, until the value returns to the baseline level or clinically stabilizes, or until another 
treatment is given.
10.3.
Serious Adverse Events
10.3.1.
Definitions of Serious Adverse Events
An adverse event that results in one of the following is a serious adverse event (SAE):
•
Results in death
•
Is life-threatening
The term "life-threatening" in the definition of "serious" refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more severe.
•
Requires inpatient hospitalization or prolongation of existing hospitalization to 
treat the AE 
The following are not considered hospitalizations for the purposes of assessing 
seriousness (however, one of the other serious criteria may apply):

Emergency room visits <24 hours

Hospitalizations for preplanned procedures

Hospitalization for study-related treatment and procedures
•
Results in persistent or significant disability/incapacity, where disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions, 
either reported or defined as per clinical judgment.
•
Is a congenital anomaly/birth defect (if exposure to product just before conception 
or during pregnancy resulted in an adverse outcome in the child).
•
Is any other important medical event that based upon appropriate medical 
judgement may jeopardize the patient or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the definitions above 
(eg, may not result in death, be life-threatening, or require hospitalization). 
Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias, convulsions that do 
not result in inpatient hospitalization, or development of drug dependency or drug 
abuse.
10.3.2.
Reporting of Serious Adverse Events (within 24 hours)
All SAEs occurring from the time the ICF is signed through the Safety Follow-up period 
(30 days after the last dose of study treatment or discontinuation of the Safety Follow-up 
period, whichever is earlier) must be reported to Sponsor’s Pharmacovigilance group or its 
designee immediately and should not exceed 24 hours from the time the Investigator first 
becomes aware of the SAE. 
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Any untoward medical event that occurs after the Safety Follow-up Period is not considered 
an SAE, unless the Investigator considerers that the medical condition is related to the 
investigational drug.
Comprehensive information available at the time of initial reporting (including narrative 
description, medical history, and concomitant medications) needs to be provided with careful 
consideration regarding causality and serious criterion. The SAE reporting process and 
contact information are provided in supplemental guidelines.
After the initial SAE notification to the Sponsor’s Pharmacovigilance group or its designee, 
all follow-up SAE information will be submitted each time they become available (for 
example, clinical diagnosis, outcome, causality assessment, and results of specific 
investigations) on a follow-up SAE form. The Investigator also must submit further 
information if it is required by the Sponsor or the director of the study site or an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). Every SAE should be followed 
until it has resolved, stabilized, or returned to baseline.
10.3.3.
Reporting of Deaths (within 24 hours)
All deaths from the time the ICF is signed through the Safety Follow-up period (30 days after 
the last dose of study treatment or discontinuation, whichever is earlier) need to be recorded 
on the death page of the eCRF. Deaths, including death due to disease progression, if related 
to study drug, occurring from the time the ICF is signed through the Safety Follow-up period 
(30 days after the last dose of study treatment or discontinuation, whichever is earlier) must 
be reported immediately as SAEs and should not exceed 24 hours from the time the 
Investigator first becomes aware of the death. The primary cause of the death should be 
reported as the SAE term, if available, and entered on the death page of the eCRF.
When reporting a death, the Investigator will be required to identify which of the following 
best describes the category of death:
•
Toxicity caused by adverse event
•
Disease progression
•
Clinical disease progression
•
Other causes
Death is not an acceptable SAE term; death is an outcome of an SAE. Only if cause of death 
is not immediately known can death be reported as the SAE term. In those instances, the 
cause of death must be reported once obtained upon follow-up.
10.3.4.
Follow-up of Serious Adverse Events
Any ongoing SAEs should be followed until the earliest occurrence of one of the following:
•
SAE has resolved
•
SAE has stabilized. An SAE can only be considered “stabilized” if the physical or 
laboratory AE being followed/assessed has remained constant (is not worsening) 
based on the Investigator’s assessment for a minimum of 30 days post study drug 
discontinuation.
•
Start of new antitumor therapy
•
Death
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•
Patient’s refusal of follow-up
10.4.
Other Safety Information
10.4.1.
Pregnancy
If a patient becomes pregnant while in the study, the study treatment must be immediately 
discontinued. Pregnancy information in a female patient (or, with consent, for the female 
partner of a male patient while on study and during contraceptive period after last 
administration of the study drug) should be reported within 24 hours from the time the 
investigator first becomes aware of a pregnancy or its outcome. This should be performed by 
completing a Pregnancy Form and e-mailing it to Sponsor’s Pharmacovigilance department 
or designee.
New and/or corrected information regarding the pregnancy obtained after submitting the 
initial Pregnancy Form must be submitted an updated Pregnancy Form to the Sponsor’s 
Pharmacovigilance department or designee. Pregnancies must be followed to outcome by the 
investigator, even after study completion. 
If the outcome of the pregnancy is a stillbirth, congenital anomaly/birth defect, or a serious 
event in the mother, it should be reported as an SAE to the Sponsor’s Pharmacovigilance 
department or designee. Live births will be followed up by the investigator up to one month 
or per local regulations/practice. Any information that may be associated with the study drug 
should be reported even after study completion.
10.4.2.
Overdose 
An overdose for this clinical study is defined as taking an intentional or unintentional dose of 
TAS3351 beyond the recommended dose for 1 day or beyond the recommended total dose in 
each cycle.
An overdose of TAS3351 must be recorded on the SAE form and/or eCRF (or other specified 
report form) and reported to the Sponsor’s Pharmacovigilance department or designee as 
soon as possible from the time the Investigator first becomes aware of the overdose, whether 
or not the patient developed an AE (even if not fulfilling a seriousness criteria).
An accidental or intentional overdose of concomitant medication should only be reported if it 
is associated with an (S)AE.
There is no known antidote available in case of overdose. Overdose should be managed with 
close monitoring and administration of prophylactic and symptomatic therapies to prevent or 
correct potential side effects.
10.5.
Communication of New Information Affecting the Conduct of the 
Study
The Sponsor will notify investigators within 7 days of receipt of fatal or life-threatening 
suspected unexpected serious adverse reactions (SUSARs) and within 15 days of receipt of 
other SUSARs, or per local requirements. Upon knowledge of serious adverse events which 
could affect patient safety, communication will be sent by the Sponsor to all investigators.
When new information becomes available that may adversely affect the safety of patients or 
the conduct of the study, including serious adverse events judged to have an impact on patient 
safety, the Sponsor will inform all investigators involved in the clinical study and IRBs/IECs 
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of such information, and when needed, will amend the protocol, and update the investigator 
brochure and/or the informed consent. 
The investigators should immediately inform patients whenever new information becomes 
available that may be relevant to the patient’s consent or may influence the patient’s 
willingness to continue participation in the study. The communication should be documented, 
and it should be confirmed whether the patient is willing to remain in the study.
If the informed consent form 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 patients were already informed of the relevant information.
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11.
ANALYSES OF BIOMARKERS
The objectives related to evaluation of biomarkers are presented in Section 3. Biomarkers 
may be explored to identify patients who will be most likely to respond positively or 
negatively to TAS3351. The pharmacodynamic evidence and biological impact of TAS3351 
by characterization of changes in level of gene (DNA or RNA) or protein expression of 
downstream effectors of EGFR and related markers may be used to further investigate 
TAS3351.
11.1.
Biomarker Sample Collection
Collection of biomarker samples will be performed at the time points shown in the Schedule 
of Events (Table 1 and Table 2). Any tumor tissue provided for pre-screening and 
confirmation of C797S EGFRmt status must have been collected after progression of the 
most recent systemic EGFR TKI treatment in a quantity sufficient for analysis. Formalin-
fixed paraffin-embedded (FFPE) blocks or unstained slides of tumor tissue must be collected 
prior to enrollment and are to be sent to the Sponsor-designated central laboratory along with 
a copy of the corresponding pathology / molecular report. Detailed information about 
collection procedures for biomarkers including blood sampling, collection, processing, and 
sample shipment will be described in a separate Laboratory Manual. (Tumor tissue collection 
is optional for Part A1).
11.2.
Biomarkers for Patient Eligibility
In order to meet the eligibility criteria of this study, patients must have documented evidence 
of EGFRmt status as determined by a CLIA certified laboratory (US), locally certified 
laboratory (outside of the US), or the study central laboratory based on tumor tissue or 
plasma cfDNA. For pre-screening, tumor tissue or cfDNA from blood samples are acceptable 
for EGFRmt status testing at the study central laboratory.
For central lab analysis of EGFRmt status, submission of both tumor tissue and blood for 
cfDNA will be mandatory for patients enrolled based on local results in Parts A2, B, and C. 
For patients in Parts A2, B, and C who are prescreened based on blood cfDNA results, tumor 
tissue must also be submitted for central lab analysis. Tumor tissue collection is optional for 
Part A1. If during pre-screening an already sufficient amount of tumor tissue (eg, tumor 
tissue block, see also Lab Manual) was provided, no additional tumor tissue submission will 
be required during screening. The central testing of EGFRmt status post dosing will be 
conducted with the intent to have confirmation of the patient’s C797S EGFRmt status (either 
blood or tissue) by the study central laboratory in temporal proximity to the enrollment of the 
patient rather than at the end of the study (“early confirmation of EGFRmt status”). 
11.3.
Exploratory Biomarkers
Tumor and blood samples will be collected and may be analyzed for exploratory biomarkers 
to assess potential associations with disease activity, effects of the study drug, and clinical 
outcomes. This may include, but is not limited to, changes in pharmacodynamic biomarkers 
in tumor samples (such as EGFR/pEGFR expression if optional baseline and on-treatment 
biopsies are available), molecular profiling to investigate and better understand the tumor’s 
response to TAS3351, and/or development of tissue-based diagnostic tests. Also, cfDNA 
extracted from blood samples collected before and during study treatment may be assessed 
for a range of oncology biomarkers (eg, change of genomic variants following TAS3351 
treatment, co-occurring genomic alterations). Patients will be also asked to consent for the 
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use of these samples to further investigate the relationship between drug response and/or 
disease progression and blood-borne biomarkers, and to develop blood-based diagnostic tests. 
11.4.
Sample Storage and Disposal
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage to ensure confidentiality. After sample processing, samples (including but 
not limited to slides or DNA/RNA extracted) may be stored for a maximum of 15 years for 
the associated exploratory analysis with this study and indication following the completion of 
the study at Sponsor-designated central laboratories after which time they will be destroyed. 
11.5.
Analytical Procedures
Analysis will be conducted using adequately validated assays at Sponsor-designated 
laboratory(ies). The detailed analytical procedures will be described in the SOP at the assay 
laboratory(ies).
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12.
STATISTICAL CONSIDERATIONS
The statistical analysis methods will be documented in detail in the statistical analysis plan 
(SAP). The SAP will be finalized prior to database lock.
12.1.
Timing of Analyses
The primary analyses for Phase 1 Dose Escalation (Part A) will be performed continuously 
until RP2D is identified. 
The primary analysis for Phase 1 Dose Expansion (Part B) will be performed once all patients 
have completed the Safety Follow-up Period or at least 6 months have passed since the last 
patient was enrolled, whichever occurs first.
The primary analysis of the Phase 2 part (Part C) will be conducted when the majority of 
patients responding to TAS3351 have been observed for at least 6 months from their first 
onset of response.
12.2.
Statistical Hypothesis 
No formal statistical hypothesis.
12.3.
Estimation of Sample Size
Part A:
Part A1: Phase 1 Dose Escalation
There will be up to 40 evaluable patients enrolled using the BOIN design, 
 
. Table 4 provides the 
dose-finding decisions given the numbers of patients treated at the current dose level, and the 
observed numbers of patients experiencing toxicity. A minimum of 3 patients at each dose 
level is required. 
Part A2: Backfill patients
Approximately 20 patients will be added for “backfill” cohorts as needed in the Phase 1 Dose 
Escalation. The additional information from these “backfill” patients will broaden the amount 
of safety and preliminary anti-tumor activity data for TAS3351 at a potential active dose 
levels to inform the selection of the RP2D of TAS3351.
Part B: Phase 1 Dose Expansion
Approximately 40 patients (20 patients per cohort) will be enrolled in the Dose Expansion 
part of this study. Sample size considerations were based on estimating the proportion of 
responders with certain precision. If there will be 9 responders, a sample size of 20 patients 
per cohort would allow to exclude the current standard of care ORR of 25% (90% CI: 27.4%, 
68.0%; see also Section 2.1.1)6,7,8,9 at 2-sided significance level of 10%.
Part C: Phase 2
Approximately 100 patients will be enrolled. Sample size considerations were based on 
estimating the proportion of responders with certain precision. The 95% exact CI for ORR 
would exclude the current standard of care ORR of 25%6,7,8,9 if the observed ORR is 35% or 
higher. If there are 35 confirmed responses, a sample size of 100 patients would allow to 
exclude the current standard of care ORR of 25% (95% CI: 25.7%, 45.2%) at 2-sided 
significance level of 5%. See Table 16. 
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Table 16:
ORR 95%CI for Sample Size of 100 Patients
Observed ORR
Exact 95% CI
35%
(25.7%, 45.2%)
40%
(30.3%, 50.3%)
45%
(35.0%, 55.3%)
12.4.
Planned Interim Analyses
No interim analysis is planned.
Unplanned interim analyses may be performed if required for regulatory purposes or at the 
Sponsor’s discretion. 
12.5.
Analysis Populations
The analysis populations in the study are defined in Table 17.
Table 17:
Definitions of Analysis Populations
Analysis Population
Definition
All Consenting Population
All patients who signed the ICF.
All Treated Population
All patients who received at least one dose of the 
study drug. This is the primary population for 
dosing, efficacy, and safety analyses.
DLT Evaluable Population
All patients in the Dose Escalation, except backfill 
patients, who either experienced a DLT during the 
1st cycle of treatment including PK lead-in period, 
or who completed the 1st cycle without 
experiencing a DLT and with at least 80% of 
planned study treatments administered. This is the 
specific population for DLT summarization.
PK Analysis Population
All patients who received at least one dose of study 
drug and have at least one post-dose TAS3351 
and/or TAS-05-14317 plasma concentration 
measurement will be evaluated for PK; unless 
significant protocol deviations may have affected 
the data or if key dosing information is missing. 
This is the primary population for PK analysis.
Pharmacodynamic/Biomarker Analysis 
Population 
All patients in the All-Treated Population who 
have at least one evaluable baseline and one 
evaluable post-dose pharmacodynamic/biomarker 
data point for analyses.
Abbreviations: DLT=dose-limiting toxicity; ECG=electrocardiogram; PK=pharmacokinetic
12.6.
Criteria for Handling of Patient Data
The criteria for handling patient data will be provided in the SAP.
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12.7.
Statistical Analyses
12.7.1.
Demographic and Baseline Characteristics
The number of patients in each population and the reasons for exclusion will be summarized. 
In addition, patients who discontinue study treatment will also be summarized, along with the 
reasons for study discontinuation.
Patient demographics, baseline and disease characteristics will be summarized as appropriate.
12.7.2.
Study Drug Administration 
The following data will be summarized descriptively:
•
Administration status
•
The total dose, total duration of administration, and the number of administration 
cycles
•
Status of administration completion
•
The presence or absence of study discontinuation and reasons for study 
discontinuation
•
Dose intensity. Actual dose intensity and relative dose intensity in each patient 
will be calculated, and descriptive statistics will be presented
12.7.3.
Efficacy Analyses
12.7.3.1.
Primary Endpoint Analyses
Part A: Phase 1 Dose Escalation
Not applicable.
Parts B and C: Phase 1 Dose Expansion and Phase 2
ORR per RECIST v1.1 by ICR will be summarized descriptively. ORR will be estimated and 
the 2-sided 95% confidence interval (CI) will be calculated using the Clopper–Pearson 
method. 
12.7.3.2.
Secondary Endpoint Analyses
Parts A: Phase 1 Dose Escalation
ORR, DCR, and DOR per RECIST v1.1 by Investigator will be summarized descriptively. 
ORR and DCR will be calculated and the 2-sided 95% CI will be estimated using the 
Clopper–Pearson method. For time to event endpoint, DOR, the Kaplan-Meier method will 
be used to estimate the median and percentile with the 2-sided 95% CI calculated using the 
Brookmeyer and Crowley method.
Parts B and C: Phase 1 Expansion and Phase 2
A key secondary endpoint is DOR per RECIST v1.1 by ICR and will be summarized 
descriptively. Further secondary endpoints include ORR, DCR, and PFS per RECIST v1.1 by 
Investigator assessment and intracranial ORR and DOR by ICR and Investigator assessment. 
ORR and DCR will be calculated and the 2-sided 95% CI will be estimated using the 
Clopper–Pearson method. 
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For time to event endpoints, including DORs and PFS, the Kaplan-Meier method will be used 
to estimate the median and percentile with the 2-sided 95% CI calculated using the 
Brookmeyer and Crowley method. These endpoints will also be summarized based on 
Investigator assessment. 
OS will be summarized descriptively as a time to event endpoint in the same way as PFS.
12.7.4.
Safety Analyses
12.7.4.1.
Primary Endpoint Part A1 Dose Escalation 
During the Dose Escalation part of the trial, the rates of DLT will be controlled by the BOIN 
algorithms. Incidence of DLT will be summarized by dose level and the analysis will be 
based on the DLT-evaluable Population. The RP2D will be based on the accumulated DLT 
data, taking the totality of data into account.
Dose escalation will follow a BOIN design 28,13 to find the MTD. The decision to escalate 
or de-escalate the dose of TAS3351 will be based on the cumulative DLT rate at the current 
dose level and the predetermined DLT rate threshold for dose escalation/de-escalation 
boundaries as defined by the BOIN model. 
The target DLT rate for the MTD is set to Φ = 0.30 with the assumptions that Φ1 = 0.6Φ is 
the highest sub-therapeutic DLT rate and Φ2 = 1.4Φ is the lowest DLT rate that has excessive 
toxicity. Under these assumptions, the thresholds that minimize the decision error at end of 
each cohort are λ1 = 0.236 and λ2 = 0.359.28 
As shown below, the BOIN design uses the following rule, optimized to minimize the 
probability of incorrect dose assignment, to guide dose escalation/de-escalation:
1. If the observed DLT rate at the current dose level is ≤0.236, escalate.
2. If the observed DLT rate at the current dose level is ≥0.359, de-escalate.
3. Otherwise, stay at the same dose level.
12.7.4.2.
Safety Analysis for All Parts
Safety analysis will be performed using the All Treated Population except for DLT analysis 
which will be based on the DLT Evaluable Population. 
All AEs will be summarized by incidence, and by grade according to the CTCAE v5.0 and 
listed by the MedDRA System Organ Class, preferred term, toxicity/severity grade, and 
causal relationship to study treatment. 
AEs leading to death or to discontinuation of study treatment, and SAEs will be summarized.
On study laboratory parameters including hematology, chemistry, liver function, and renal 
function will be graded according to the CTCAE v5.0 where applicable. The worst severity 
grade, time to maximum Grade 3 or 4 value, and time to resolution (return to baseline grade 
or below) will be summarized for selected laboratory parameters. In addition, concomitant 
medications, physical examination, vital sign measurements, ECG results, ECOG 
performance status, and other safety observations at the time points indicated in the Study 
Schedule of Events will be analyzed.
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12.7.5.
Other Analyses
Refer to Section 8 for PK analysis.
The relationship between exposures of TAS3351 and its active metabolite (TAS-05-14317) in 
plasma and QT prolongation will be explored. 
Biomarkers and pharmacodynamic data specified in Section 11 will be summarized 
descriptively by dose level and schedule. Where possible, relationship between plasma PK 
parameters or concentration of TAS3351 will be evaluated by correlation analysis or visual 
inspections. When further exploratory analyses are performed, the methods and the results 
may be reported in the main CSR or a Pharmacodynamic Analysis Report.
For patients enrolled in Part C, patients’ health-related quality of life, symptoms, functioning, 
and general well-being will be captured using two PRO measures: EORTC-QLQ-C30 and 
EQ-5D-5L. They will be analyzed using the statistical methods which are described in the 
SAP.
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13.
ADMINISTRATIVE CONSIDERATIONS
13.1.
Protocol Compliance
The Investigator will agree to comply with the protocol by signing the Declaration of 
Investigator. In the event that the Investigator is unable to continue the study and another 
suitable person is designated as the Investigator, the Sponsor must be notified in advance. 
The new Investigator must accept the responsibility in writing and be approved by the 
Sponsor and the IRB.
13.2.
Protocol Deviations
The Investigator may implement a deviation from, or a change in, the protocol to eliminate an 
immediate hazard(s) to study patients without prior IRB approval/favorable opinion. As soon 
as possible, the implemented deviation or change and the reasons for it should be documented 
and submitted to the IRB and Sponsor.
The Investigator is to record any deviation from the protocol in the source documents, 
describing this departure and the circumstances under which it was required.
13.3.
Protocol Amendments
All protocol amendments must be issued by the Sponsor and signed and dated by the 
Investigator. Documentation of the amendment approval by the Investigator and IRB must be 
provided to the Sponsor.
If the changes involve only logistic or administrative aspects of the study, these changes will 
be notified in writing by the Sponsor.
13.4.
Study Termination
If the Sponsor and/or the Investigator should discover conditions arising during the study that 
indicate it should be terminated, an appropriate schedule for termination will be instituted. 
The Sponsor also reserves the right to discontinue this study for administrative or 
discretionary reasons at any time.
13.5.
Case Report Forms
The Investigator should complete all eCRFs in accordance with the eCRF Completion 
Guidelines. Data in the eCRFs shall be consistent with source documents.
An eCRF should be completed for each screened and enrolled patient.
The Investigator, or assigned personnel, should verify the data and correct as necessary prior 
to approval of the eCRFs.
13.6.
Access to Source Data/Documents
The Investigator and the site must make all study-related records available for study-related 
monitoring, audit, IRB review, and regulatory inspection.
13.6.1.
Source Data/Documents
Source documents are original documents, data, and records such as hospital records, clinical 
and office charts, laboratory notes, memoranda, patient’s evaluation checklists, pharmacy 
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dispensing records, recorded data from automated instruments, microfilm or magnetic media, 
X-ray, patient files, and records kept at the pharmacy, laboratories, and medical-technical 
departments involved in the study.
Specific details regarding source documents and source data to be recorded directly on the 
eCRFs for the study should be documented with the Investigator prior to and during the 
study.
13.6.2.
Access to Source Data
The Sponsor’s study monitor, or its representatives, should verify the entries in the eCRF and 
source documents to confirm the completeness and accuracy of the data. If there are any 
discrepancies between the entries in eCRFs and source documents, the monitor, data manager 
or Medical Monitor will query the Investigator.
13.7.
Data Handling
All study information is confidential. The patient’s and Investigator’s personal data which 
may be included in the Sponsor’s database shall be treated in compliance with all applicable 
laws and regulations.
When processing and archiving personal data pertaining to the Investigator and to the 
patients, the Sponsor or its representatives shall take all appropriate measures to safeguard 
and prevent access to this data by any unauthorized third party.
13.8.
Responsibilities of Recordkeeping
13.8.1.
Investigator and Study Site
The Investigator and the study site are responsible for the retention of all study documents 
according to institutional policies, local laws, and ICH E6 Guidelines.
The Investigator and the study site agree to inform the Sponsor in writing of the intention to 
remove or destroy any study-related records. Prior to contacting the Sponsor, the Investigator 
and study site must ensure that the applicable regulatory requirements have been satisfied. 
The Sponsor will evaluate the requests from the Investigator and the study site and will 
provide authorization for destruction of such records in writing.
In the event that all retention of records requirements has been fulfilled, but the Sponsor 
requests that the Investigator and study site maintain the records for a longer period of time, 
additional arrangements will be made.
13.8.2.
Sponsor
The Sponsor must retain all Sponsor-specific essential documents in conformance with the 
applicable regulatory requirements of the countries where the product is approved, and where 
the Sponsor intends to apply for approvals.
If the Sponsor discontinues the clinical development of the study drug, the Sponsor must 
maintain all Sponsor-specific essential documents in conformance with the applicable 
regulatory requirements.
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13.9.
Monitoring
The Sponsor and designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study. The Investigator and the site agree to 
allow the monitor to inspect the drug storage area, study drug stocks, drug accountability 
records, patient charts and study source documents, and other records relative to study 
conduct.
13.10.
Financial Disclosure
Financial disclosure for Investigators will be obtained and record keeping of financial records 
will be in accordance with local regulatory requirements. Investigators will provide the 
Sponsor with sufficient, accurate financial information upon the Sponsor’s request.
13.11.
Compensation for Health Injury
The clinical study is insured according to applicable regulatory requirements. The 
Compensation Policy Document will be provided to the study site by the Sponsor.
Sponsor should address the policies and payment procedures of compensation for the event of 
study-related injuries as the Compensation Policy Document.
When patients receive compensation, the policies and payment procedure of compensation 
should comply with the Compensation Policy Document.
13.12.
Study Administrative Structure
The study organization details will be maintained in a supplement.
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14.
QUALITY CONTROL AND QUALITY ASSURANCE
The Sponsor will perform quality control and quality assurance procedures in accordance 
with the Sponsor's standard operating procedures (SOPs) to ensure the quality of the clinical 
study.
14.1.
Quality Control
The Sponsor is responsible for controlling the quality of the clinical study according to the 
SOPs regarding study operation, monitoring, data collection and management, statistical 
analysis, and handling of safety information to verify that the study-related activities have 
been fulfilled.
14.2.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit. Authorized representatives of the Sponsor, a regulatory 
authority, or an IRB may visit the site to perform audits or inspections, including source data 
verification. The Investigator and the site will make every effort to help with the performance 
of the audits and inspections, giving access to all necessary facilities, data and documents 
pertaining to the clinical study. 
The purpose of an audit or inspection is to systematically and independently examine all 
study-related activities and documents to ensure that these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, ICH GCP E6 
Guidelines, and any applicable local regulatory requirements. The Investigator and the site 
should contact the Sponsor immediately if contacted by a regulatory agency regarding an 
inspection.
Any results arising from such inspections will be immediately communicated by the 
Investigator and the site to the Sponsor. The Investigator and the Sponsor will take corrective 
actions for all findings and observations found during audits and/or inspections. The auditors 
and inspectors will not disclose private information unless required by law.
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15.
ETHICS
15.1.
Ethical Conduct of the Study
It is mandatory that all considerations regarding the protection of patients be carried out in 
accordance with the latest versions of the protocol, ICH GCP Guidelines, the ethical 
principles that have their origin in the Declaration of Helsinki, and all applicable regulatory 
requirements.
15.2.
Written Informed Consent
The ICF(s) must be approved by the IRB/IEC before patients sign consent for any study-
related activity. It must be in a language that the patient can read and understand. The ICF 
process should be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH and GCP Guidelines, and applicable regulatory requirements. Each patient must 
give written consent according to local requirements. 
The Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF must be 
given to the patient.
There must be documentation in each patient’s case history/medical record that informed 
consent was obtained prior to any study procedure being performed. Patients must be 
re-consented to the most current version of the ICF(s) during their participation in the study.
15.3.
Institutional Review Board/Independent Ethics Committee
The study must be approved by an appropriately constituted IRB/IEC, as required in the 
applicable local regulation such as ICH E6 Guidelines before the study is initiated. At the end 
of the study, the Investigator will notify the IRB/IEC of the conclusion of the study and its 
outcome.
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16.
PUBLICATION POLICY
16.1.
Publication Policy
The Sponsor maintains the right to use the results of this study in their original form and/or in 
a global report for submission to governmental and regulatory authorities of any country or 
region.
The results of the study may be presented during scientific symposia and/or published in a 
scientific journal only after review by the Sponsor in accordance with the guidelines set forth 
in the applicable publication.
The Investigator(s) and the Sponsor will discuss and determine the presenter(s) or author(s) 
and timing of any presentation or publication related to this study and/or its results. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
16.2.
Secondary Use of Data
The Sponsor maintains the right to secondary use of data in this study.
Secondary use of data describes the use of data from this study for other study/studies for 
purposes including, but not limited to, drug development and/or academic research. 
Secondary use of data also includes external offerings of study data to domestic and/or 
foreign organization(s), other companies and researcher(s), on a case-by-case basis.
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17.
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APPENDIX A. EXAMPLES OF CLINICAL SUBSTRATES, 
INHIBITORS, AND INDUCERS OF CYP ENZYMES 
AND TRANSPORTERS  
The classification below is based on the Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers. This is not an exhaustive list. An updated list can be 
found at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers
Clinical Substrates of CYP Enzymes
CYP 
Enzyme
Sensitive Clinical Substrates
Moderate Clinical Substrates
CYP1A2
alosetron, caffeine, duloxetine, melatonin, ramelteon, 
tasimelteon, tizanidine
clozapine, pirfenidone, 
ramosetron, theophylline
CYP2C8
repaglinide
montelukast, pioglitazone, 
rosiglitazone
CYP2C9
celecoxib
glimepiride, phenytoin, 
tolbutamide, warfarin
CYP2C19
S-mephenytoin, omeprazole
diazepam, lansoprazole, 
rabeprazole, voriconazole
alfentanil, avanafil, buspirone, conivaptan, darifenacin, 
darunavir, ebastine, everolimus, ibrutinib, lomitapide, 
lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, 
simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, 
vardenafil 
CYP3A
budesonide, dasatinib, dronedarone, eletriptan, eplerenone, 
felodipine, indinavir, isavuconazole, ivabradine, 
lemborexant, lurasidone, maraviroc, mobocertinib, 
quetiapine, sildenafil, ticagrelor, tolvaptan, venetoclax
alprazolam, aprepitant, 
atorvastatin, colchicine, 
eliglustat, pimozide, rilpivirine, 
rivaroxaban, tadalafil
Note: Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors of a given 
metabolic pathway in clinical DDI studies. Moderate sensitive substrates are drugs that demonstrate an increase in AUC 
of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Sensitive substrates 
of CYP3A with ≥10-fold increase in AUC by co-administration of strong index inhibitors are shown above the dashed line.
Clinical Inhibitors of CYP3A Enzymes
CYP Enzyme
Strong Clinical Inhibitors
Moderate Clinical Inhibitors
cobicistat, danoprevir and ritonavir, 
elvitegravir and ritonavir, grapefruit juice, 
indinavir and ritonavir, itraconazole, 
ketoconazole, lopinavir and ritonavir, 
paritaprevir and ritonavir and ombitasvir 
(and/or dasabuvir), posaconazole, 
ritonavir, saquinavir and ritonavir, 
tipranavir and ritonavir, telithromycin, 
troleandomycin, voriconazole
CYP3A
ceritinib, clarithromycin, idelalisib, 
nefazodone, nelfinavir
aprepitant, ciprofloxacin, conivaptan, 
crizotinib, cyclosporine, diltiazem, 
dronedarone, erythromycin, fluconazole, 
fluvoxamine, grapefruit juice, imatinib, 
isavuconazole, tofisopam, verapamil
Note: Strong, moderate, and weak inhibitors are drugs that increase the AUC of sensitive index substrates of a given 
metabolic pathway ≥5-fold, ≥2 to <5-fold, and ≥1.25 to <2-fold, respectively. Strong inhibitors of CYP3A causing ≥10-fold 
increase in AUC of sensitive index substrate(s) are shown above the dashed line.
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Clinical Inducers of CYP3A Enzymes
CYP Enzyme
Strong Clinical Inducers
Moderate Clinical Inducers
CYP3A
apalutamide, carbamazepine, enzalutamide, 
ivosidenib, lumacaftor, mitotane, phenytoin, 
rifampin, St. John’s wort
bosentan, cenobamate, dabrafenib, 
efavirenz, etravirine, lorlatinib, 
pexidartinib, phenobarbital, primidone, 
sotorasib
Note: Strong, moderate, and weak inducers are drugs that decreases the AUC of sensitive index substrates of a given 
metabolic pathway by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively.
Clinical Substrates of P-gp and BCRP
Transporter
Clinical Substrates
P-gp
dabigatran etexilate, digoxin, edoxaban, fexofenadine
BCRP
rosuvastatin, sulfasalazine
Note: A clinical substrate should meet the following criteria:
P-gp: (1) AUC fold-increase is ≥1.5 with itraconazole, quinidine, or verapamil co-administration; (2) not extensively 
metabolized in humans; and (3) in vitro transported by P-gp expression systems.
BCRP: (1) AUC fold-increase is ≥1.5 with pharmacogenetic alteration of ABCG2 (421C>A) and (2) in vitro transported by 
BCRP expression systems.
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Document Name: TAS3351 10073010 Study Protocol Amendment 2
Document Number: 1000200753
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Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Biostatistics Approval
07-Jul-2023
19:24:43
Clinical Approval
08-Jul-2023
05:34:53
Clinical Approval
07-Jul-2023
18:03:50

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SUMMARY OF CHANGES
The purpose of this amendment was to address the FDA’s comments. All changes have been 
incorporated into the study synopsis as appropriate; the Table of Contents has also been updated.
In addition to these substantive changes, minor administrative alterations were made as 
necessary throughout the protocol, including formatting adjustments and correction of 
typographical errors. These editorial changes do not affect the rationale or planned conduct of 
the study or analyses, and therefore are not summarized in the table below.
Section #
Section Name
Description of Change
Section 1.3
Schedule of Activities
Table 1: Schedule of Activities 
Phase1 (Parts A and Part B)
Table 2: Schedule of Activities 
Phase 2 (Part C)
Updated lab collection window.
Added table number specifying PK sampling and ECG collection schedule 
Added Echocardiography to procedures 
Updated notes in Table 2 local ECG to monitor as clinically indicated.
Updated notes in Table 2 for ECOG performance status appendix
Section 4.2
Study Design
Updated text to dosing description of Part 1.
Section 4.2.4
Study Stopping Criteria
Added new heading.
Section 4.11
Randomization and Blinding
Added text for Part B randomization.
Section 5.1
Inclusion Criteria
Modified inclusion criterion #3 to include cytologically confirmed
Modified inclusion criterion #9(e) Creatine Clearance to account for broader 
patient disposition.
Modified exclusion criterion #5 to include chemotherapy, biologic therapy, 
targeted therapy, immunotherapy, or investigational agents within the 
specified time period.
Section 5.2
Exclusion Criteria
Modified exclusion criterion #4 to include moderate inhibitors/inducers of 
cytochrome P450.
Modified exclusion criterion # 6 baseline QT interval.
Modified exclusion criterion # 7 to remove Investigator judgement language.
Section 5.2
Discontinuation of Treatment
Modified #3
Section 6.1.1 
Part 1: Dose Escalation
Updated dose levels
Updated text to allow for re-escalation or intrapatient dose escalation.
Section 6.1.2
Dose Limiting Toxicities
Table 9: Dose-Limiting Toxicity 
Definition
DLT criteria in Table 9 were modified for “Hepatic” and “Other” categories.
Section 6.2.1
Dose Reduction, Interruption, 
and Resumption
Added language for maximum dose reductions allowed.
Updated Table 9 Dose Reduction.
Section 6.2.1.2
Dose Modifications for Non-
hematologic Toxicities
Modified other non-hematologic toxicities management.

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Section #
Section Name
Description of Change
Section 6.2.1.2
Discontinuation of Study 
Treatment
Clarified discontinuation reason #3.
Section 6.4.1
Prohibited Concomitant 
Medication
Added ARAs language and prohibited use of PPI language.
Section 6.4.2
Concomitant Medications and 
Therapies Requiring Precautions
Added language for dose reduction when concomitant treatment is used.
Added ARAs and prohibited use of PPI language.
Section 6.5.1
Dietary
Added language for prohibited food consumption 
Section 7.1
Study Assessments and 
Procedures
Updated Table 13 to account for Echocardiography/MUGA.
Section 7.1.3
Cardiac Function Evaluation
Added new section.