Clinical trial NCT04479436
Conditions: Metastatic Colorectal Cancer
Keywords: Metastatic Colorectal Cancer U3-1402
Sponsor: Daiichi Sankyo
Start date: 2020-09-14; Completion date: 2022-02-03
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to primarily evaluate the safety and efficacy of U3-1402 in participants with advanced or metastatic colorectal cancer (CRC) who have received at least 2 prior lines of therapy and will explore clinical benefit according to human epidermal growth factor receptor 3 (HER3) tumor expression level in otherwise refractory tumors.

Detailed description:
There will be 2 cohorts with enrollment in 2 parts. Participants will be treated on Day 1 of each 21-day cycle (every 3 weeks) with U3-1402 5.6 mg/kg intravenous (IV). The estimated treatment period is approximately 8 months and the follow-up period is approximately 4 months.

Arms: arm 1: Cohort 1 participants will have high tumor expression levels of human epidermal receptor 3 (HER3) in a pre-treatment biopsy specimen. arm 2: Cohort 2 participants will have low or negative tumor expression levels of human epidermal receptor 3 (HER3) expression levels in a pre-treatment biopsy specimen.
Interventions: intervention 1: Patritumab Deruxtecan
Intervention descriptions: intervention 1: U3-1402 will be dosed at 5.6 mg/kg as an intravenous (IV) infusion administered on Day 1 of each 21-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
A MULTI-CENTER, OPEN-LABEL, PHASE 2 STUDY TO 
EVALUATE SAFETY AND EFFICACY OF U3-1402 IN 
SUBJECTS WITH ADVANCED OR METASTATIC 
COLORECTAL CANCER (CRC) 
U31402-A-U202 
 
IND NUMBER 148299 
EudraCT NUMBER 2019-004418-32 
 
 
VERSION 4.0, 24 NOV 2020 
 
 
 
DAIICHI SANKYO. INC. 
211 MT. AIRY ROAD 
BASKING RIDGE, NJ 07920-2311 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc. (DSI). The 
information is provided to you in confidence which is requested under an agreed upon and 
signed Confidentiality and Disclosure Agreement.  Do not give this document or any copy of it 
or reveal any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
DSI. 


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INVESTIGATOR AGREEMENT 
A Multi-Center, Open-Label, Phase 2 Study to Evaluate Safety and Efficacy of U3-1402 in 
Subjects with Advanced or Metastatic Colorectal Cancer (CRC) 
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by the Daiichi Sankyo, Inc.  
representative listed below. 
 
 
 
Print Name 
Signature 
 
 
 
Title 
Date (DD MMM YYYY) 
Investigator9s Signature: 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor9s representative. 
I understand that information contained in or pertaining to this protocol is confidential and 
should not be disclosed, other than to those directly involved in the execution or the ethical 
review of the study, without written authorization from the Sponsor.  It is, however, permissible 
to provide information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with the Declaration of Helsinki, International Council for Harmonisation guidelines 
on Good Clinical Practice (ICH E6), and applicable regional regulatory requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant regulatory 
authorities, my subjects9 study records in order to verify the data that I have entered into the case 
report forms.  I am aware of my responsibilities as a Principal Investigator as provided by the 
Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing.  Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the Sponsor. 
 
 
Print Name 
Signature 
 
 
Title 
Date (DD MMM YYYY) 
24-Nov-2020
PPD
PPD
PPD


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SUMMARY OF CHANGES 
The summary of changes below is a top-line summary of main changes in the current 
U31402-A-U202 clinical study protocol (Version 4.0) dated 24 November 2020 by section, as 
compared to Version 3.0, dated 24 August 2020. 
Amendment Rationale: 
This amendment provides greater uniformity in the enrolled population by ensuring the prior use 
of a BRAF inhibitor in patients whose tumors express a BRAF V600E mutation.  It also provides 
further specification regarding the required antibody washout period, conditions under which 
tumor assessments should be conducted, screening, rescreening, and study closure procedures.  
Other minor editorial changes are provided to enhance clarity. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
CONVENTIONS USED IN THIS SUMMARY OF CHANGES 
All locations (section numbers and/or paragraph/bullet numbers) refer to the current protocol 
version, which incorporates the items specified in the Summary of Changes. 
Minor edits, such as an update to language that does not alter original meaning, an update to 
version numbering, formatting, a change in font color, a correction to a typographical error, 
the use of abbreviations, moving verbiage within a section or table, a change in style or 
numbering, or a change in case, are not noted in the table below. 
 
Section # and Title 
Description of Change 
Brief Rationale 
Synopsis, Study Design 
Section 3.1 Study Design 
Section 3.1.2 Duration of Subject 
Participation 
Section 5.7 Discontinuation of 
Study Drug 
Section 6.3.1 Cycle 1 and 
Subsequent Cycles 
Section 6.5 40-day Post-treatment 
Follow-up 
Section 7.1 Tumor Assessments for 
Efficacy 
Specified that tumor assessments 
should continue until documented 
disease progression (RECIST v1.1) 
by BICR, death, lost to follow-up, 
or withdrawal of consent by subject. 
To specify the correct 
conditions under which 
tumor assessments should 
be conducted. 
Synopsis Study Objectives, 
Outcome Measures, and Endpoints 
Table 2.1 Description of 
Objectives, Outcome Measures, and 
Endpoints 
Section 11.5.2.5 Other 
Revised the definition of ADA-
positive and ADA-negative 
subjects. 
To align with the current 
Daiichi Sankyo 
definition. 


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Section # and Title 
Description of Change 
Brief Rationale 
Synopsis, Subject Eligibility 
Criteria: Key Exclusion Criteria 
Section 4.2 Exclusion Criteria 
 
Revised exclusion criterion 2 from 
<OR prior pneumonectomy= to <OR 
prior complete pneumonectomy.= 
To specify that subjects 
with prior partial 
pneumonectomy or prior 
lobectomy will not be 
excluded. 
Synopsis, Subject Eligibility 
Criteria: Key Exclusion Criteria 
Section 4.2 Exclusion Criteria 
Section 5.6 Prior, Concomitant and 
Prohibited Medications 
Specified that subjects who require 
use of topical steroids may be 
included in the study. 
Topical steroids generally 
do not represent 
significant systemic 
exposure; therefore, the 
risks to subjects are low 
with use of topical 
steroids. 
Synopsis, Study Eligibility Criteria 
Section 4.1, Exclusion Criteria 
Clarified exclusion criterion 5 to 
state that subjects who are 
asymptomatic (ie, without 
neurologic signs or symptoms and 
do not require treatment with 
corticosteroids or anticonvulsants) 
may be included in the study and 
added that <Subjects must have a 
stable neurologic status for at least 
2 weeks prior to Cycle 1 Day 1.= 
To align with current U3-
1402 product safety 
requirements. 
Synopsis, Subject Eligibility 
Criteria: Key Exclusion Criteria 
Section 4.2 Exclusion Criteria 
Section 5.6 Prior, Concomitant and 
Prohibited Medications 
Added exclusion criterion 6c 
regarding the required washout 
period: <Monoclonal antibodies 
other than immune checkpoint 
inhibitors, such as bevacizumab 
(anti-VEGF) and cetuximab (anti-
EGFRs) <28 days= and included a 
specification for these therapies in 
Section 5.6: Therapies Requiring a 
Washout. 
In consideration for the 
long half-lives typically 
observed with 
monoclonal antibodies 
and the ascertainment that 
this interval is consistent 
with ensuring patient 
safety. 
Synopsis, Subject Eligibility 
Criteria: Key Exclusion Criteria 
Section 4.2 Exclusion Criteria 
Removed terminology of 
uncontrolled hypertension from 
exclusion criterion 10c. 
To correct an error in the 
description of systolic 
and diastolic blood 
pressure thresholds. 
Synopsis, Indication Under 
Investigation 
Synopsis, Study Design 
Synopsis, Subject Eligibility 
Criteria: Key Inclusion Criteria 
Section 3.1 Overall Design 
Figure 3.1 Study Design Schema 
Section 4.1 Inclusion Criteria 
Added to inclusion criterion 4 to 
state that patients must have 
previously received treatment with 
a BRAF inhibitor, if clinically 
indicated (eg, BRAF V600E 
positive). 
To ensure that patients 
with BRAF 
V600E-positive tumor 
expression have 
previously received 
approved therapy with a 
BRAF inhibitor to align 
with current treatment 
guidelines. 


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Section # and Title 
Description of Change 
Brief Rationale 
Synopsis, Subject Eligibility 
Criteria: Key Inclusion Criteria 
Section 4.1 Inclusion Criteria 
Removed <(eg, RAS/BRAF 
wildtype)= as provided examples of 
an anti-EGFR agent. 
To provide greater 
flexibility for the use of 
an anti-EGFR agent 
according to local 
institutional standards. 
Section 3.1.2 Duration of Subject 
Participation 
Schedule of Events 
Section 6.3.1 Cycle 1 and 
Subsequent Cycles 
Section 6.5 40-day Post-treatment 
Follow-up 
Section 7.1 Tumor Assessments for 
Efficacy 
Removed new anticancer treatment 
as a reason to discontinue tumor 
assessments. 
To obtain all of the 
relevant scans until 
verification that criteria 
for terminating the serial 
evaluation of tumor 
response has been 
verified. 
Section 3.1.2 Duration of Subject 
Participation 
Section 5.6 Prior, Concomitant and 
Prohibited Medications 
Section 6.1.2 Screening 
Schedule of Events 
The Screening period has been 
extended from 28 days to 35 days. 
To accommodate the 
potential for necessary 
administrative delays that 
might occur during the 
Screening period; 
however, all protocol-
specified windows for 
specific assessments 
remain the same. 
Section 3.1.3 Definition of the End 
of Study 
Section 13.2.10 Study and Site 
Closure 
To add the following statement:   
<At the time of study closure, any 
subjects who are continuing 
treatment with U3-1402 and who 
are judged by the Investigator to 
have ongoing benefit may continue 
to receive treatment with U3-1402 
through a rollover protocol or 
another mechanism consistent with 
local requirements.= 
To specify the procedure 
for the potential 
continuation of treatment 
with U3-1402 for subjects 
receiving U3-1402 at the 
time of study closure. 
Schedule of Events 
Added that the PK samples in 
subjects who are administered 
chloroquine or hydroxychloroquine 
will be collected if the subject 
provides consent. 
To specify that subjects 
must provide consent for 
this testing within the 
appropriate ICF. 
Schedule of Events 
Specified the cycles that PK 
samples will be collected prior to 
infusion. 
To align the footnote with 
the Schedule of Events. 


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Section # and Title 
Description of Change 
Brief Rationale 
Schedule of Events 
Section 7.1 Tumor Assessments for 
Efficacy 
Modified the text to include that use 
or nonuse of IV contrast is 
appropriate unless medically 
infeasible, ie, newly developed AE 
or allergy to contrast agent. 
To specify that subjects 
with a newly developed 
AE or allergy to contrast 
agent are not required to 
receive IV contrast if 
medically infeasible. 
Synopsis Key Exclusion Criteria 
Section 4.2 Exclusion Criteria 
Section 5.6 Prior, Concomitant and 
Prohibited Medications 
Clarified that concomitant use of 
chronic systemic (IV or oral) 
corticosteroids dosed at >10 mg 
prednisone or equivalent anti-
inflammatory activity are 
prohibited. 
To distinguish anti-
inflammatory activity 
from mineralocorticoid 
activity, which may have 
a different conversion, 
and to align with 
exclusion criterion 3. 
Section 5.2.4 Administration 
Schedule of Events 
Revised the description for the 
recalculation of weight-based 
dosing. 
 
To correct an error in the 
description for the 
recalculation of weight-
based dosing. 
Section 5.4 Dose Modifications 
(Dose Delay, Reduction, and/or 
Discontinuation) 
Deleted the following statement: 
<Discussion and agreement between 
the Investigator and Sponsor are 
required before discontinuation of 
study treatment due to an AE.= 
The current dose 
modification guidelines 
no longer require 
discussion/agreement 
with Sponsor prior to 
dose 
reduction/discontinuation. 
Section 5.8.4 Subject Rescreening 
Procedures 
Revised text pertaining to 
circumstances for subject 
rescreening. 
To specify that 
rescreening is allowed 
once if a subject fails to 
meet any eligibility 
criterion rather than to 
restrict rescreening to 
those who fail only 
transient or reversible 
eligibility criteria.  The 
text was also updated to 
clarify the rescreening 
process requiring 
consultation with the 
Sponsor and assessments 
required at the time of 
rescreening. 
Section 6.1.2 Screening 
Section 6.4 End of Treatment 
Section 9.10 Electrocardiograms 
Table 13.1 Schedule of Events 
Clarified instruction for ECG 
collection. 
To correct an error in the 
description of ECG 
collection: single and not 
triplicate ECGs will be 
obtained. 


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Section # and Title 
Description of Change 
Brief Rationale 
Section 6.3.1 Cycle 1 and 
Subsequent Cycles 
Section 6.5 40-day Post-treatment 
Follow-up 
Section 7.1 Tumor Assessment for 
Efficacy 
Clarified that imaging of the brain 
is required at Screening and will 
only be required at subsequent 
imaging assessments if there is a 
brain lesion present at baseline, 
within 1 week of achievement of 
CR, or if symptoms are present. 
To correct an error in the 
description of the 
imaging assessment 
procedure. 
Section 8.3.2 Tumor Sample 
Collection 
Section 8.3 Biomarker 
Assessment(s) 
To specify that tumor biopsy will be 
performed if medically feasible. 
To specify that the 
Investigator has 
discretion based on the 
medical feasibility of the 
on treatment biopsy. 
Section 9.12 Other Safety 
Assessments 
Specified that all ophthalmologic 
assessments must be evaluated by 
an ophthalmologist or other 
qualified practitioner rather than by 
the Investigator or delegate. 
To specify the healthcare 
professionals required to 
perform ophthalmologic 
assessments. 
Section 9.6 Pregnancy 
To revise the text from <The 
Sponsor must be notified of any 
female subject or partner of a male 
subject who becomes pregnant 
while receiving or within 7 months 
of last dose of U3-1402.= to <The 
Sponsor must be notified of any 
female subject who becomes 
pregnant while receiving or within 
7 months of the last dose of 
U3-1402.  The Sponsor must be 
notified of any male subject whose 
female partner becomes pregnant 
while the subject is receiving, or 
within 4 months of discontinuing, 
U3-1402.= 
To correct an error in the 
reporting requirements 
for pregnancy in order to 
align with current 
U3-1402 product safety 
requirements.  
Section 9.10 Electrocardiograms 
To remove the following statement:  
<Please refer to the Investigator Site 
Manual for additional information 
on the collection of ECGs.= 
To correct an error in 
Section 9.10, as no 
Investigator Site Manual 
for ECGs is provided for 
this study. 
Section 11.5.2.1 Adverse Event 
Analyses 
SAEs starting or worsening after 
the on-treatment period, if reported 
as related to the study treatment, 
will be listed separately. 
To align with the current 
Daiichi Sankyo definition 
of a TEAE. 
ADA = anti-drug antibody; AE = adverse event; BICR = blinded independent central review; CR = complete 
response; CT = computed tomography; ECG = electrocardiogram; EGFR = epidermal growth factor receptor; ICF = 
informed consent form; IV = intravenous; MRI = magnetic resonance imaging; PK = pharmacokinetics; RECIST = 
Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; TEAE = treatment-emergent adverse 
event; VEGF = vascular endothelial growth factor 




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To investigate 
the durability of 
U3-1402 
antitumor 
activity in 
subjects with 
advanced or 
metastatic CRC 
Title: DoR  
Description:  Tumor response as 
assessed by BICR per RECIST 
v1.1 and death date reported by 
investigator 
Time frame: Data are collected at 
baseline, then from the start of 
study treatment until disease 
progression by BICR, death, lost 
to follow-up, or withdrawal of 
consent by the subject. 
Death date is collected until the 
subject discontinues the study. 
DoR is defined as the 
time from the first 
documented response 
(CR or PR) to the date of 
disease progression or 
death due to any cause.  
Efficacy 
To further 
investigate the 
antitumor 
activity of 
U3-1402 in 
subjects with 
advanced or 
metastatic CRC 
Title: ORR 
Description: Tumor response as 
assessed by the Investigator per 
RECIST v1.1. 
Time frame: Data are collected at 
baseline, then from the start of 
study treatment until disease 
progression or death, lost to 
follow-up, or withdrawal of 
consent by the subject. 
ORR is defined as the 
proportion of subjects 
with a BOR of confirmed 
CR or PR.  
Efficacy 
Title: DoR  
Description:  Tumor response as 
assessed by Investigator per 
RECIST v1.1 and death date 
reported by Investigator 
Time frame: Data are collected at 
baseline, then from the start of 
study treatment until disease 
progression or death, lost to 
follow-up, or withdrawal of 
consent by the subject. 
Death date is collected until the 
subject discontinues the study. 
DoR is defined as the 
duration from the first 
documented response to 
the date of disease 
progression or death due 
to any cause.  
Efficacy 
Title: DCR 
Description: Tumor response as 
assessed by BICR and 
Investigator per RECIST v1.1. 
Time frame: Data are collected at 
baseline, then from the start of 
study treatment until disease 
progression by BICR, death, lost 
to follow-up, or withdrawal of 
consent by the subject. 
DCR is defined as the 
proportion of subjects 
who achieved a 
confirmed BOR of CR, 
PR, or SD.  
Efficacy 


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Title: TTR 
Description: Tumor response as 
assessed by BICR and 
Investigator per RECIST v1.1 
Time frame: Data are collected at 
baseline, then from the start of 
study treatment until disease 
progression by BICR, death, lost 
to follow-up, or withdrawal of 
consent by the subject. 
TTR is defined as the 
time from the start of 
study treatment to the 
date of the first 
documentation of 
objective response (CR 
or PR) that is 
subsequently confirmed.  
Efficacy 
Title: PFS 
Description:  Tumor response as 
assessed by BICR and 
Investigator per RECIST v1.1 and 
death date reported by Investigator 
Time frame: Data are collected at 
baseline, then from the start of 
study treatment until disease 
progression by BICR, death, lost 
to follow-up, or withdrawal of 
consent by the subject. 
Death date is collected until the 
subject discontinues the study. 
PFS is defined as the 
time from the start of 
study treatment to the 
date of the first 
documentation of 
objective PD or death 
due to any cause, 
whichever is earlier. 
Efficacy 
Title: OS 
Description:  Death date as 
reported by Investigator 
Time frame: Death date is 
collected until the subject 
discontinues the study. 
OS is defined as the time 
from the start of study 
treatment to the date of 
death due to any cause. 
Efficacy 
To evaluate the 
safety and 
tolerability of 
U3-1402 in 
subjects with 
advanced or 
metastatic CRC 
Title: TEAEs and other safety 
parameters during the study* 
Description:  Descriptive 
statistics of safety endpoints  
Time frame:  From the time the 
subject signs the main study ICF 
and up to 40 (+ 7) days) after the 
last dose of study drug (ie, 5 half-
lives of the ADC/the follow-up 
period).   
*Although this is a secondary 
objective, this is a primary 
outcome measure. 
Incidence of TEAEs, 
SAEs, AESIs (ILD and 
elevation of 
aminotransferases and 
TBL), ECOG PS, vital 
sign measurements, 
standard clinical 
laboratory parameters.  
AEs will be coded using 
the most recent version 
of MedDRA and will be 
graded using NCI-
CTCAE v5.0. 
Safety 


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To evaluate 
HER3 protein 
expression in 
tumor tissue 
and its 
relationship 
with efficacy   
Title: Correlation between HER3 
protein expression (as determined 
by HER3 IHC assay) and efficacy 
Description: Based on a 
descriptive summary of the 
efficacy endpoints and HER3 
status, a correlative analysis 
between HER3 protein expression 
level (as determined by HER3 
IHC assay) and efficacy may be 
performed. 
Time frame: Efficacy data are 
collected at baseline, then from 
the start of study treatment until 
disease progression or death, lost 
to follow-up, or withdrawal of 
consent by the subject. 
HER3 data are collected at 
baseline (archival and pre-
treatment tumor biopsy) and at 
Cycle 2. 
HER3 protein expression 
in tumor tissue (as 
determined by IHC) and 
correlation with efficacy 
Efficacy/ 
Biomarker 
To assess the 
immunogenicity 
incidence 
against 
U3-1402 
Title: Immunogenicity 
Description: ADA prevalence, 
incidence, and titer for U3-1402 
Time frame: Data are collected 
from the start of study treatment 
until the end of treatment. 
Additional timepoints are 
specified in Table 13.1. 
ADA prevalence: The 
proportion of all subjects 
having a confirmed 
positive ADA sample at 
any point in time.   
ADA incidence: The 
proportion of subjects 
having treatment-
emergent ADA.   
ADA titer will be 
determined for 
confirmed ADA-positive 
samples.   
Neutralizing antibodies: 
When neutralizing assay 
becomes available, 
confirmed ADA-positive 
samples may be analyzed 
for neutralizing activity. 
Immunogenicity 


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To characterize 
the 3 PK 
analytes of 
U3-1402 in 
subjects with 
advanced or 
metastatic CRC 
Title: PK endpoints  
Description: Serum concentration 
and PK parameters of U3-1402 
(ADC, total anti-HER3 antibody, 
and MAAA-1181a) 
Time frame: Data are collected at 
baseline, then from the start of 
study treatment until Cycle 8.  
Additional timepoints are 
specified in Table 13.1.   
Cmax, Tmax, Ctrough, 
AUClast, and AUCtau 
PK 
ADA = anti-drug antibody; ADC = antibody drug conjugate; AESIs = adverse events of special interest; 
AUClast = area under the serum concentration-time curve up to the last quantifiable time ; AUCtau = area under 
the serum concentration-time curve during dosing interval; BICR = blinded independent central review; 
BOR = best overall response; Cmax = maximum serum concentration; CR = complete response; 
CRC = colorectal cancer; CTCAE = Common Terminology Criteria for Adverse Events; Ctrough = trough serum 
concentration; DCR = disease control rate; DoR = duration of response; ECOG PS = Eastern Cooperative 
Oncology Group performance status; EOT = end of treatment; HER3 = human epidermal growth factor receptor 
3; ICF = informed consent form; IHC = immunohistochemistry; ILD = interstitial lung disease; 
MedDRA = Medical Dictionary for Regulatory Activities;  mRNA = messenger ribonucleic acid; NCI = National 
Cancer Institute; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; 
PK = pharmacokinetic; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; 
SAEs = serious adverse events; SD = stable disease; TBL = total bilirubin; TEAEs = treatment-emergent adverse 
events; Tmax = time to reach maximum serum concentration; TTR = time to tumor response; v = version. 
Study Design: 
Phase 2, global, multicenter, open-label, 2-cohort study of U3-1402 monotherapy in 
subjects with advanced or metastatic CRC who are resistant, refractory, or intolerant 
to at least 2 prior lines of systemic therapy, that must include all of the following 
agents: a fluoropyrimidine, irinotecan, a platinum agent, an anti-EGFR agent (if 
clinically indicated), an anti-VEGF agent (if clinically indicated), an immune 
checkpoint inhibitor (if clinically indicated), and a BRAF inhibitor (if clinically 
indicated). 
Part 1 
Archival tumor biopsy and pre-treatment tumor biopsy will be collected from all 
subjects at the time of screening, and human epidermal growth factor receptor 3 
(HER3) protein expression will be measured by an investigational device (HER3 
immunohistochemistry [IHC] assay).   
Results of the prospective HER3 IHC assay from the pre-treatment tumor biopsy 
will be used to assign subjects into 1 of 2 cohorts:  
÷ 
Cohort 1: HER3 High (IHC 3+, 2+) (approximately 24 treated subjects) or,  
÷ 
Cohort 2: HER3 Low/Negative (IHC 1+, 0) (approximately 12 treated 
subjects). 
Subjects will be treated on Day 1 of each 21-day cycle (every 3 weeks [Q3W]) with 
U3-1402 5.6 mg/kg intravenous (IV). 
Interim Analysis 
For each study cohort, review of the preliminary data from Part 1 will be used to 
determine whether to open Part 2.  The decision to advance from Part 1 to Part 2 will 
be made separately in Cohort 1 and Cohort 2; the interim futility analysis will be 
conducted with approximately 24 subjects in Cohort 1 and approximately 12 


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subjects in Cohort 2 after all subjects have had the opportunity to complete two 
tumor assessments.  The tumor assessment period may be extended if emerging data 
show responses are occurring later, or if the tumor assessment for the final evaluated 
subject in each cohort is delayed.  At the time of the interim analysis for each cohort, 
enrollment into the respective cohort will be paused until the determination that 
criteria for advancement to Part 2 have been achieved.  Note it is possible for the 
futility criterion to be passed before the above specified analysis timing.  These 
analyses will be conducted based on BICR assessment in the Full Analysis Set 
(FAS). 
After review of the data from Part 1 based on criteria outlined in Section 11.6, if the 
Sponsor decides to enroll subjects irrespective of HER3 expression status in Part 2 
(ie, Scenario 1 below, continuing enrollment of Cohort 2 into Part 2), the decision 
and preliminary data from Cohort 2 Part 1 will be provided as part of a protocol 
amendment. 
Part 2 
÷ 
Dose: U3-1402 5.6 mg/kg IV Q3W 
ý 
Scenario 1: Enrollment continues in Cohort 1 and Cohort 2: 
approximately 44 subjects will be enrolled, regardless of HER3 IHC 
status, and receive treatment with U3-1402. 
ý 
Scenario 2: Enrollment continues in Cohort 1 only: approximately 44 
subjects with HER3 High (IHC 3+, 2+) status will be enrolled and 
receive treatment with U3-1402. 
Treatment with U3-1402 in all cohorts will continue until the time of progressive 
disease (PD) per RECIST v1.1, unacceptable toxicity, withdrawal of consent, death, 
termination of the study by Sponsor, or the occurrence of any of the other events 
specified in Section 5.7.  If PD is suspected by Investigator tumor assessment, 
imaging must be submitted to blinded independent central review (BICR) for 
expedited confirmation of disease progression.  The decision to discontinue 
U3-1402 is according to Investigator judgment and should consider BICR 
assessment. 
Study Duration: The study start date is the date when the first subject has signed an ICF.  A subject is 
eligible to be enrolled into the interventional portion of the study when the 
Investigator or designee has obtained written informed consent from the subject, has 
confirmed all eligibility criteria have been met by the subject, and all screening 
procedures have been completed.   
The enrollment period is approximately 15 months.  For each cohort, enrollment 
will occur in 2 parts separated by an interim futility analysis.  The estimated 
treatment period is approximately 8 months and the follow-up period is 
approximately 4 months.  The total estimated duration of the study is approximately 
27 months. 
The primary analysis data cut-off will occur when all subjects have had a minimum 
of 9 months of follow-up or have discontinued from the study earlier.  The DCO 
may be shifted if emerging data indicate responses are occurring at a different time. 
The final analysis will be performed after all subjects have discontinued from the 
study for any reason.   


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The Sponsor may terminate the study at any time, and study termination may also be 
requested by a competent authority.   
Study Sites and 
Location: 
The study will be conducted at approximately 40 sites in the United States, Europe, 
and Asia, including Japan.  Additional study sites may be added as needed. 
Subject Eligibility 
Criteria: 
Key Inclusion Criteria 
÷ 
Subject has provided written informed consent prior to the start of any study-
specific procedures. 
÷ 
Subjects g18 years (follow local regulatory requirements if the legal age of 
consent for study participation is >18 years old). 
÷ 
Pathological/histological confirmation of advanced or metastatic colon or rectal 
adenocarcinoma. 
÷ 
Must be resistant, refractory, or intolerant to at least 2 prior lines of systemic 
therapy, that must include all of the following agents: 
a. Fluoropyrimidine  
b. Irinotecan 
c. Platinum agents (eg, oxaliplatin) 
d. An anti-EGFR agent, if clinically indicated 
e. An anti-VEGF agent, if clinically indicated (eg, bevacizumab) 
f. An immune checkpoint inhibitor, if clinically indicated (eg, 
microsatellite instability-high [MSI-H] status) 
g. A BRAF inhibitor, if clinically indicated (eg, BRAF V600E positive) 
 
÷ 
Has at least 1 measurable lesion confirmed by BICR as per Response 
Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1. 
÷ 
Willing to provide a required pre-treatment tumor biopsy and an additional 
archival tissue sample for the assessment of HER3 expression levels by IHC 
and exploratory biomarkers, defined as:  
a. Pre-treatment tumor biopsy. Subjects may be exempted from the 
requirement to provide a pre-treatment tumor biopsy if archival tumor 
tissue was collected within 3 months of screening during or after 
treatment with the last prior cancer treatment and is of sufficient 
quantity (2 cores or 20 slides with adequate tumor tissue content).  
b. An additional archival tissue sample collected greater than 3 months 
prior to screening must be available and of sufficient quantity, as 
defined above, at the time of screening.  If an archival tissue sample 
(collected greater than 3 months prior to screening) is not available, a 
subject may be included provided the pre-treatment tumor biopsy is 
obtained and after discussion and agreement from Sponsor (Medical 
Monitor or designee).  
c. Consent to provide on-treatment tumor biopsy. When at least 10 on-
treatment tumor biopsies per cohort have been collected, the Sponsor 
will provide written notification of a change to the requirement.   
÷ 
Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. 


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÷ 
Life expectancy g3 months. 
÷ 
Has adequate bone marrow reserve and organ function at baseline based on 
local laboratory data defined as follows within 14 days prior to Cycle 1 Day 1: 
Parameter 
Laboratory Value 
Platelet count 
g100,000/mm3 or g100 × 109/L (platelet 
transfusions are not allowed up to 14 days prior 
to Cycle 1 Day 1 to meet eligibility) 
Hemoglobin  
g9.0 g/dL (transfusion and/or growth factor 
support is allowed) 
Absolute neutrophil count 
g1500/mm3 or g1.5 × 109/L  
SCr OR CrCl 
SCr f 1.5 × ULN, OR  
CrCl g 30 mL/min as calculated using the 
Cockcroft-Gault equation or measured CrCl; 
confirmation of CrCl is only required when 
creatinine is >1.5 × ULN 
Alanine aminotransferase 
/aspartate aminotransferase  
f3 × ULN (if liver metastases are present, f5 × 
ULN) 
Total bilirubin 
f1.5 × ULN if no liver metastases (<3 × ULN in 
the presence of documented Gilbert9s syndrome 
[unconjugated hyperbilirubinemia] or liver 
metastases) 
Serum albumin  
g2.5 g/dL 
PT or PT-INR and aPTT/PTT 
f1.5 × ULN except for subjects on coumarin-
derivative anticoagulants or other similar 
anticoagulant therapy, who must have PT-INR 
within therapeutic range as deemed appropriate 
by the Investigator 
aPTT = activated partial thromboplastin time; CrCl = creatinine clearance; INR = 
international normalized ratio; PT = prothrombin time; PTT = partial thromboplastin 
time; SCr = serum creatinine; ULN = upper limit of normal 
Key Exclusion Criteria 
÷ 
Any history of interstitial lung disease (including pulmonary fibrosis or 
radiation pneumonitis), has current interstitial lung disease (ILD), or is 
suspected to have such disease by imaging during screening. 
÷ 
Clinically severe pulmonary compromise (based on Investigator9s assessment) 
resulting from intercurrent pulmonary illnesses including, but not limited to: 
a. any underlying pulmonary disorder (eg, pulmonary emboli, severe 
asthma, severe chronic obstructive pulmonary disease, restrictive lung 
disease, pleural effusion) 
b. any autoimmune, connective tissue or inflammatory disorder with 
pulmonary involvement (eg, rheumatoid arthritis, Sjögren's syndrome, 
sarcoidosis)  


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OR prior complete pneumonectomy. 
÷ 
Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or 
equivalent anti-inflammatory activity or any form of immunosuppressive 
therapy prior to Cycle 1 Day 1. Subjects who require use of bronchodilators, 
inhaled or topical steroids, or local steroid injections may be included in the 
study. 
÷ 
Evidence of leptomeningeal disease 
÷ 
Evidence of clinically active spinal cord compression or brain metastases, 
defined as untreated and symptomatic, or requiring therapy with corticosteroids 
or anticonvulsants to control associated symptoms.  Subjects with clinically 
inactive or treated brain metastases who are asymptomatic (ie, without 
neurologic signs or symptoms and do not require treatment with corticosteroids 
or anticonvulsants) may be included in the study.  Subjects must have a stable 
neurologic status for at least 2 weeks prior to Cycle 1 Day 1. 
÷ 
Inadequate washout period prior to Cycle 1 Day 1 of U3-1402: 
a. Whole brain radiation therapy <14 days or stereotactic brain radiation 
therapy <7 days; 
b. Any cytotoxic chemotherapy, investigational agent or other anticancer 
drug(s) from a previous cancer treatment regimen or clinical study 
<14 days or 5 half-lives, whichever is longer; 
c. Monoclonal antibodies other than immune checkpoint inhibitors, 
such as bevacizumab (anti-VEGF) and cetuximab (anti-EGFRs) 
<28 days; 
d. Immune checkpoint inhibitor therapy <21 days; 
e. Major surgery (excluding placement of vascular access) <4 weeks;  
f. Radiotherapy treatment to >30% of the bone marrow or with a wide 
field of radiation <28 days or palliative radiation therapy <14 days;  
g. Chloroquine or hydroxychloroquine f14 days. 
÷ 
Prior treatment with an anti-HER3 antibody and/or antibody drug conjugate 
(ADC) that consists of an exatecan derivative that is any topoisomerase I 
inhibitor (eg, trastuzumab deruxtecan). 
÷ 
Has unresolved toxicities from previous anticancer therapy, defined as toxicities 
(other than alopecia) not yet resolved to National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 Grade f1 or 
baseline.   
÷ 
Had primary malignancies other than CRC within 3 years, except adequately 
resected non-melanoma skin cancer, curatively treated in-situ disease, or other 
solid tumors curatively treated. 
÷ 
Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1, 
including: 


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a. QT interval corrected for heart rate using Fridericia9s formula 
prolongation interval of >470 ms for females and >450 ms for males 
within 28 days; 
b. Left ventricular ejection fraction (LVEF) <50% by either 
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan 
within 28 days; 
c. Resting systolic blood pressure >180 mmHg or diastolic blood pressure 
>110 mmHg; 
d. Myocardial infarction within 6 months; 
e. New York Heart Association Classes 2 to 4 congestive heart failure (See
Section 13.5) within 28 days; 
f. Uncontrolled angina pectoris within 6 months; 
g. Cardiac arrhythmia requiring antiarrhythmic treatment within 28 days. 
÷ 
Active hepatitis B and/or hepatitis C infection, such as those with serologic 
evidence of viral infection within 28 days of Cycle 1 Day 1. 
a. Subjects with past or resolved hepatitis B virus (HBV) infection are 
eligible if: 
i. 
Hepatitis B surface antigen (HBsAg) negative and hepatitis B core 
antibody (anti-HBc) positive; OR 
ii. HBsAg positive and HBV deoxyribonucleic acid (DNA) viral load 
is documented to be f2000 IU/mL in the absence of anti-viral 
therapy and during the previous 12 weeks prior to the viral load 
evaluation with normal transaminases values (in the absence of liver 
metastasis); OR 
iii. HBsAg positive and HBV DNA viral load is documented to be 
f2000 IU/mL in the absence of anti-viral therapy and during the 
previous 12 weeks prior to the viral load evaluation for subjects 
with liver metastasis and abnormal transaminases with a result of 
AST/ALT <3 × ULN. 
b. Subjects with a history of hepatitis C infection will be eligible for 
enrollment only if the viral load according to local standards of 
detection is documented to be below the level of detection in the 
absence of anti-viral therapy during the previous 12 weeks (ie, sustained 
viral response according to the local product label but no less than 
12 weeks, whichever is longer).  
÷ 
Subject with any human immunodeficiency virus (HIV) infection.  
÷ 
Any evidence of severe or uncontrolled disease (including active bleeding 
diatheses, active infection), psychiatric illness/social situations, geographical 
factors, substance abuse, or other factors which in the Investigator9s opinion 
makes it undesirable for the subject to participate in the study or which would 
jeopardize compliance with the protocol.  Screening for chronic conditions is 
not required. 


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Dosage Form, 
Dose and Route 
of 
Administration: 
U3-1402 will be supplied as a 100 mg sterile lyophilized powder (Lyo-DP) to be 
reconstituted with 5 mL of commercially available water for injection to 20 mg/mL 
prior to use.  Each vial of sterile U3-1402 drug product is designed for single use 
only and is not to be used to treat more than 1 subject. 
Once reconstituted, U3-1402 Lyo-DP will be diluted with 250 mL commercially 
available 5% dextrose injection infusion and dosed at 5.6 mg/kg as an intravenous 
(IV) infusion administered on Day 1 of each 21-day cycle.   
Planned Sample 
Size: 
In Part 1 of the study, approximately 36 subjects will be evaluated in the two 
cohorts.  If both Cohort 1 and Cohort 2 advance to Part 2 of the study, 
approximately 44 additional subjects will be enrolled in Part 2 (regardless of HER3 
IHC status).  In such a circumstance, approximately 80 subjects will be enrolled in 
total. If only Cohort 1 advances to Part 2 of the study, approximately 44 additional 
subjects will be enrolled in Part 2. In such a circumstance, approximately 
80 subjects will be enrolled in total (68 of 80 subjects will have HER3 high 
expressing tumors).  
The clinically meaningful objective response rate (ORR) is considered as 20%, and 
the ORR based on historical data is considered as 5%. 
With sample size of 68 subjects, if 8 responses are observed, the observed ORR will 
be 11.8% with a 95% exact confidence interval (CI) of (5.2%, 21.9%). The 
probability of observing 8 or more responders in 68 subjects is approximately 97.4% 
when the true ORR is 20%. If the true ORR is 5%, the probability of observing 8 or 
more responders in 68 subjects is approximately 2%. 
With a sample size of 80 subjects, if 9 responses are observed, the observed ORR 
will be 11.25% with a 95% exact CI of (5.3%, 20.3%).  The probability of observing 
9 or more responders in 80 subjects is approximately 98.7% when the true ORR is 
20%.  If the true ORR is 5%, the probability of observing 9 or more responders in 80 
subjects is approximately 1.8%. 
Statistical 
Analyses: 
Primary and Final Analyses 
÷ 
The primary analysis data cut-off will occur when all subjects have either a 
minimum of 9 months of follow-up or have discontinued from the study 
earlier.  The DCO may be shifted if emerging data indicate responses are 
occurring at a different time.  The primary analysis will be included in the 
clinical study report.  
÷ 
The final analysis will be performed after all subjects have discontinued 
from the study for any reason.   
Interim Analysis 
For each study cohort, review of the preliminary data from Part 1 will be used to 
determine whether to open Part 2.  The decision to advance from Part 1 to Part 2 will 
be made separately in Cohort 1 and Cohort 2; the interim futility analysis will be 
conducted with approximately 24 subjects in Cohort 1 and approximately 12 
subjects in Cohort 2 after all subjects have had the opportunity to complete two 
tumor assessments.  The tumor assessment period may be extended if emerging data 
show responses are occurring later, or if the tumor assessment for the final evaluated 
subject in each cohort is delayed.  At the time of the interim analysis for each cohort, 
enrollment into the respective cohort will be paused until the determination that 


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criteria for advancement to Part 2 has been achieved.  Note it is possible for the 
futility criterion to be passed before the above specified analysis timing.  These 
analyses will be conducted based on BICR assessment in the FAS. 
Cohort 1 Decision Criteria at Interim: 
1. If at least 3 responders out of 24 subjects in Cohort 1 are observed, then 
further enrollment in this cohort may proceed.   
2. If 0 or 1 responder out of 24 subjects in Cohort 1 is observed at the interim, 
then further enrollment in this cohort may stop.  
3. If 2 responders out of 24 subjects in Cohort 1 are observed, then a decision 
will be made, after further review of the data, to either continue or stop 
further enrollment in this cohort.   
Cohort 2 Decision Criteria at Interim: 
1. If at least 2 responders out of 12 subjects in Cohort 2 are observed, further 
enrollment in this cohort may proceed after submission of a protocol 
amendment which includes the preliminary data from Cohort 2 Part 1.  
2. If 0 responder out of 12 subjects in Cohort 2 is observed at the interim, then 
further enrollment in this cohort may stop.  
3. If 1 responder out of 12 subjects in Cohort 2 is observed, then a decision 
will be made, after further review of the data, to either continue or stop 
further enrollment in this cohort.  Further enrollment will be contingent 
upon submission of a protocol amendment which includes the preliminary 
data from Cohort 2 Part 1. 
The determination of whether to advance a cohort to Part 2 of the study may also 
take into consideration the PK properties of U3-1402 among subjects enrolled in this 
study, the subject or disease characteristics of enrolled subjects, among others.  The 
decision to advance the study to Part 2 might be deferred based on the collective 
evaluation of such information.  If indicated, the Sponsor may amend the protocol to 
evaluate other doses, dose regimens, or selected subject populations with advanced 
or metastatic CRC prior to advancing the study to Part 2. 
Efficacy Analyses 
The primary efficacy endpoint is ORR as assessed by BICR per RECIST v1.1.  
ORR is defined as the proportion of subjects who achieve a best overall response 
(BOR) of complete response (CR) or partial response (PR).  CR/PR will be 
confirmed with a follow-up tumor assessment at least 4 weeks apart.  ORR as 
assessed by BICR will be summarized with the 2-sided 95% CI using the Clopper-
Pearson method in the FAS.  For the computation of ORR, subjects with BOR of 
<not evaluable (NE)= will be included in the FAS and will be considered non-
responders.  Data will be summarized by cohort if applicable.  No formal 
comparison between the 2 cohorts is planned.   
The key secondary efficacy endpoint is duration of response (DoR) as assessed by 
BICR per RECIST v1.1.  Its distribution will be estimated using Kaplan-Meier 
method and results will be presented graphically.  Median DoR and its 2-sided 95% 
CIs will be calculated using Brookmeyer and Crowley methods.  In addition, the 
event-free probability at different time points (eg, 3, 6, 9, 12 months) will be 
estimated with corresponding 2-sided 95% CIs using the Greenwood formula for 
variance derivation.  Other secondary efficacy endpoints include DoR as assessed by 


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Investigator, ORR as assessed by Investigator, disease control rate (DCR), time to 
response (TTR), PFS as assessed by BICR and Investigator, and overall survival 
(OS).  Response endpoints (ORR and DCR) will be analyzed in the same manner as 
the primary efficacy endpoint.  Distribution of time-to-event endpoints (DoR, PFS, 
and OS) will be analyzed in the same manner as the key secondary endpoint (DoR 
by BICR).  TTR will be summarized using descriptive statistics. 
Descriptive statistics for the best percent change from baseline in the sum of 
diameters will be provided by cohort if applicable. A waterfall plot of the best 
percent change in the sum of diameters and a swimmer9s plot for response over time 
will be also prepared for each cohort if applicable.  
No formal comparison between the 2 cohorts is planned. 
Safety Analyses 
Safety analyses in general will be descriptive and will be presented in tabular format 
with summary statistics presented by treatment group for the Safety Analysis Set 
(defined as all subjects who receive at least 1 dose of study drug). 
Pharmacokinetic Analyses 
Serum concentrations for U3-1402 (ADC, total anti-HER3 antibody, and MAAA-
1181a) will be listed, plotted, and summarized using descriptive statistics.  PK 
parameters will be listed and summarized by treatment group using descriptive 
statistics. 
 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
SUMMARY OF CHANGES ...........................................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................8 
LIST OF ABBREVIATIONS ........................................................................................................28 
1. 
INTRODUCTION ........................................................................................................32 
1.1. 
Background ...................................................................................................................32 
1.1.1. 
Colorectal Cancer Background and Treatments ...........................................................32 
1.1.2. 
Human Epidermal Growth Factor Receptor 3 ..............................................................32 
1.1.3. 
U3-1402 ........................................................................................................................33 
1.1.4. 
In Vivo and In Vitro Models .........................................................................................33 
1.1.5. 
Clinical Studies .............................................................................................................34 
1.2. 
Study Rationale .............................................................................................................35 
1.2.1. 
Justification for Dose Selection for Study ....................................................................36 
1.2.2. 
Benefit/Risk Assessment for Study Subjects ................................................................37 
2. 
STUDY OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS ...................38 
3. 
STUDY DESIGN ..........................................................................................................43 
3.1. 
Overall Design ..............................................................................................................43 
3.1.1. 
Duration of the Study ....................................................................................................45 
3.1.2. 
Duration of Subject Participation ..................................................................................45 
3.1.3. 
Definition of the End of Study ......................................................................................46 
4. 
STUDY POPULATION ...............................................................................................47 
4.1. 
Inclusion Criteria ...........................................................................................................47 
4.2. 
Exclusion Criteria..........................................................................................................49 
5. 
STUDY TREATMENT(S) ...........................................................................................52 
5.1. 
Assigning Subjects to Treatments .................................................................................52 
5.1.1. 
Treatment Group(s)/Sequences .....................................................................................52 
5.1.2. 
Method of Treatment Allocation ...................................................................................52 
5.1.3. 
Blinding .........................................................................................................................52 
5.1.4. 
Emergency Unblinding Procedure ................................................................................52 
5.2. 
Study Drug(s) ................................................................................................................52 
5.2.1. 
Description ....................................................................................................................52 


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5.2.2. 
Labeling and Packaging ................................................................................................53 
5.2.3. 
Preparation ....................................................................................................................53 
5.2.4. 
Administration ..............................................................................................................53 
5.2.5. 
Storage...........................................................................................................................53 
5.2.6. 
Drug Accountability ......................................................................................................53 
5.3. 
Control Treatment .........................................................................................................54 
5.4. 
Dose Modifications (Dose Delay, Reduction, and/or Discontinuation) .......................54 
5.4.1. 
Dose Delay and Reductions ..........................................................................................54 
5.4.1.1. 
Dose Delay and Discontinuation ...................................................................................54 
5.4.1.2. 
Dose Reductions ...........................................................................................................54 
5.4.1.3. 
Dose Modifications .......................................................................................................55 
5.5. 
Method of Assessing Treatment Compliance ...............................................................65 
5.6. 
Prior, Concomitant and Prohibited Medications ...........................................................65 
5.6.1. 
Membrane Transport Inhibitors ....................................................................................67 
5.7. 
Discontinuation of Study Drug .....................................................................................68 
5.8. 
Subject Withdrawal/Discontinuation from the Study ...................................................69 
5.8.1. 
Reasons for Withdrawal ................................................................................................69 
5.8.2. 
Withdrawal Procedures .................................................................................................69 
5.8.3. 
Subject Replacement .....................................................................................................69 
5.8.4. 
Subject Rescreening Procedures ...................................................................................69 
5.8.5. 
Lost to Follow-up ..........................................................................................................70 
6. 
STUDY PROCEDURES ..............................................................................................71 
6.1. 
Screening .......................................................................................................................71 
6.1.1. 
Tissue Requirement .......................................................................................................71 
6.1.2. 
Screening .......................................................................................................................71 
6.2. 
Randomization ..............................................................................................................73 
6.3. 
Study Assessments ........................................................................................................73 
6.3.1. 
Cycle 1 and Subsequent Cycles ....................................................................................73 
6.4. 
End of Treatment...........................................................................................................75 
6.5. 
40-day Post-treatment Follow-up ..................................................................................76 
6.6. 
Every 3 Month Follow-up .............................................................................................77 
7. 
EFFICACY ASSESSMENTS .......................................................................................78 


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7.1. 
Tumor Assessments for Efficacy ..................................................................................78 
7.2. 
Appropriateness of Selected Efficacy Assessment(s) ...................................................78 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ........................79 
8.1. 
Pharmacokinetic (PK) Assessment(s) ...........................................................................79 
8.2. 
Pharmacodynamic Assessment(s) .................................................................................80 
8.3. 
Biomarker Assessment(s)..............................................................................................80 
8.3.1. 
HER3 Protein Expression .............................................................................................80 
8.3.2. 
Tumor Sample Collection .............................................................................................81 
8.3.3. 
Biomarker Assessments in Tumor Tissue and Blood Samples .....................................82 
8.4. 
Immunogenicity ............................................................................................................82 
8.4.1. 
Genomic or Genetic Banking and Analysis ..................................................................83 
8.4.1.1. 
Sample Collection and Analysis ...................................................................................83 
8.4.1.2. 
Instructions for Collection of Specimens ......................................................................83 
8.4.1.3. 
Storage and Disposal of Specimens ..............................................................................83 
8.4.1.4. 
Disclosure of the Results ...............................................................................................83 
9. 
SAFETY EVALUATION AND REPORTING ...........................................................84 
9.1. 
Assessment of Safety Endpoint(s) ................................................................................84 
9.2. 
Adverse Event Collection and Reporting ......................................................................84 
9.3. 
Adverse Events of Special Interest ...............................................................................85 
9.3.1. 
Pulmonary Toxicity (Interstitial Lung Disease) ............................................................85 
9.3.1.1. 
Interstitial Lung Disease Adjudication Committee .......................................................85 
9.3.2. 
Elevation of Aminotransferase(s) and Bilirubin: Hepatic Events .................................86 
9.4. 
Adverse Event ...............................................................................................................86 
9.4.1. 
Definition of Adverse Event .........................................................................................86 
9.4.2. 
Serious Adverse Event ..................................................................................................86 
9.4.3. 
Severity Assessment .....................................................................................................87 
9.4.4. 
Causality Assessment ....................................................................................................87 
9.4.5. 
Action Taken Regarding Study Drug(s) .......................................................................88 
9.4.6. 
Other Action Taken for Event .......................................................................................88 
9.4.7. 
Adverse Event Outcome ...............................................................................................88 
9.5. 
Serious Adverse Events Reporting Procedure For Investigators ..................................89 
9.5.1. 
Overdose .......................................................................................................................90 


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9.6. 
Pregnancy ......................................................................................................................90 
9.7. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee ...............................................................................................91 
9.8. 
Clinical Laboratory Evaluations ...................................................................................91 
9.9. 
Vital Signs .....................................................................................................................92 
9.10. 
Electrocardiograms .......................................................................................................92 
9.11. 
Physical Examinations ..................................................................................................93 
9.12. 
Other Safety Assessments .............................................................................................93 
10. 
OTHER ASSESSMENTS .............................................................................................94 
10.1. 
Patient Reported Outcomes ...........................................................................................94 
10.2. 
Pharmacoeconomic Assessments ..................................................................................94 
11. 
STATISTICAL CONSIDERATIONS ..........................................................................95 
11.1. 
General Statistical Considerations ................................................................................95 
11.2. 
Statistical Hypothesis ....................................................................................................95 
11.3. 
Sample Size Determination ...........................................................................................95 
11.4. 
Population for Analysis Sets .........................................................................................97 
11.5. 
Statistical Analyses .......................................................................................................97 
11.5.1. 
Efficacy Analyses..........................................................................................................97 
11.5.1.1. Primary Efficacy Analyses ............................................................................................97 
11.5.1.2. Secondary Efficacy Analyses ........................................................................................97 
11.5.1.3. Exploratory Efficacy Analyses .....................................................................................98 
11.5.1.4. Multiplicity Adjustment ................................................................................................98 
11.5.2. 
Safety Analyses .............................................................................................................99 
11.5.2.1. Adverse Event Analyses ...............................................................................................99 
11.5.2.2. Clinical Laboratory Evaluation Analyses .....................................................................99 
11.5.2.3. ECG .............................................................................................................................100 
11.5.2.4. Vital Signs ...................................................................................................................100 
11.5.2.5. Other ............................................................................................................................100 
11.5.3. 
Other Analyses ............................................................................................................100 
11.5.3.1. Pharmacokinetics ........................................................................................................100 
11.5.3.2. Pharmacodynamics .....................................................................................................101 
11.5.3.3. Biomarker Analyses ....................................................................................................101 
11.6. 
Interim Analyses .........................................................................................................101 


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11.7. 
Statistical Analysis Process .........................................................................................102 
12. 
REFERENCES ............................................................................................................103 
13. 
APPENDICES ............................................................................................................107 
13.1. 
Schedule of Events ......................................................................................................107 
13.2. 
Regulatory and Ethical Considerations .......................................................................113 
13.2.1. 
Regulatory Compliance ...............................................................................................113 
13.2.2. 
Informed Consent ........................................................................................................114 
13.2.3. 
Subject Confidentiality................................................................................................114 
13.2.4. 
Data Integrity and Quality Assurance .........................................................................115 
13.2.5. 
Committees .................................................................................................................116 
13.2.6. 
Study Documentation and Storage ..............................................................................117 
13.2.7. 
Finances.......................................................................................................................118 
13.2.8. 
Publication and Public Disclosure Policy ...................................................................118 
13.2.9. 
Protocol Deviations .....................................................................................................118 
13.2.10. Study and Site Closure ................................................................................................119 
13.2.11. Product Complaints .....................................................................................................119 
13.3. 
Cockcroft-Gault Equation ...........................................................................................120 
13.4. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 ......................................120 
13.4.1. 
Measurability of Tumor at Baseline ............................................................................120 
13.4.1.1. Definitions ...................................................................................................................120 
13.4.1.2. Specifications by Methods of Measurements .............................................................122 
13.4.2. 
Tumor Response Evaluation .......................................................................................122 
13.4.2.1. Assessment of Overall Tumor Burden and Measurable Disease ................................122 
13.4.2.2. Baseline Documentation of <Target= and <Non-target= Lesions ................................122 
13.4.2.3. Response Criteria ........................................................................................................123 
13.4.2.4. Evaluation of Overall Response ..................................................................................125 
13.5. 
New York Heart Association ......................................................................................128 
13.6. 
Eastern Cooperative Oncology Group (ECOG) Performance Status .........................128 
13.7. 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 ..................................................................................................................129 
13.8. 
Highly Effective Contraception ..................................................................................129 
13.9. 
Instructions Related to Coronavirus Disease 2019 (COVID-19) ................................130 
13.10. 
Membrane Transport Inhibitors ..................................................................................131 


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LIST OF TABLES 
Table 2.1: Description of Objectives, Outcome Measures, and Endpoints .................................38 
Table 5.1: Dose Reductions for the Fixed Dose 5.6 mg/kg Regimen ..........................................55 
Table 5.2: Dose Modification Criteria .........................................................................................55 
Table 8.1: Pharmacokinetic Parameters .......................................................................................80 
Table 9.1: Clinical Laboratory Tests ...........................................................................................92 
Table 11.1: Total Sample Size Pre- and Post-futility Analysis .....................................................96 
Table 11.2: Statistical Properties for Different Sample Sizes........................................................96 
Table 11.3: Exact Confidence Interval for Different Observed Objective Response Rates ..........97 
Table 13.1: Schedule of Events ...................................................................................................108 
Table 13.2: Overall Response: Subjects with Target (± Non-target) Disease .............................126 
Table 13.3: Best Overall Response when Confirmation of CR and PR Required .......................127 
Table 13.4: Eastern Cooperative Oncology Group Performance Status Scale Grade 
Description ................................................................................................................128 
Table 13.5: COVID-19 Dose Modification Criteria ....................................................................130 
 


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LIST OF FIGURES 
Figure 1.1: Waterfall Plot for Tumor Xenograft Models. .............................................................34 
Figure 3.1: Study Design Schema .................................................................................................43 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
Ab 
antibody 
AC 
Adjudication Committee 
ADA 
anti-drug antibody 
ADC 
antibody drug conjugate 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUClast 
area under the serum concentration-time curve up to the last quantifiable 
time 
AUCtau 
area under the serum concentration-time curve during dosing interval 
BCRP 
breast cancer resistance protein 
BI 
before infusion 
BICR 
blinded independent central review 
BOR 
best overall response 
CA 19-9 
cancer antigen 19-9 
CEA 
carcinoembryonic antigen 
cfDNA 
circulating free DNA 
cfRNA 
circulating free RNA 
CI 
confidence interval 
Cmax 
maximum serum concentration 
COVID-19 
coronavirus 2019 
CR 
complete response 
CRC 
colorectal cancer 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CRP 
C-reactive protein 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough serum concentration 


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ABBREVIATION 
DEFINITION 
DCO 
data cut-off 
DCR 
disease control rate 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EIU 
exposure in utero 
EOI 
end of infusion 
EOT 
end of treatment 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EU 
European Union 
FAS 
Full Analysis Set 
FSH 
follicle-stimulating hormone 
F/U 
Follow-up (Visit) 
GCP 
Good Clinical Practice  
G-CSF 
granulocyte-colony stimulating factor 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER 
human epidermal growth factor receptor 
HER2 
human epidermal growth factor receptor 2 
HER3 
human epidermal growth factor receptor 3 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB 
Investigator9s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 


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ABBREVIATION 
DEFINITION 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
Kel 
elimination rate constant associated with the terminal phase 
LVEF 
left ventricular ejection fraction 
Lyo-DP 
lyophilized powder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MRP-1 
Multidrug resistance-associated protein-1 
MSI-H 
microsatellite instability-high 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 
NCI 
National Cancer Institute 
NGS 
next generation sequencing 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
preferred term 
Q3W 
every 3 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia9s formula 
RDE 
recommended dose for expansion 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 


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ABBREVIATION 
DEFINITION 
RT-PCR 
reverse-transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Suspected severe acute respiratory syndrome coronavirus 2 
SAVER 
Serious Adverse Event Report 
SD 
stable disease 
SOC 
system organ class 
SoD 
sum of diameters 
SOP 
standard operating procedure 
SpO2 
peripheral oxygen saturation 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum serum concentration 
TTR 
time to tumor response 
ULN 
upper limit of normal 
US 
United States 
v 
version 
VEGF 
vascular endothelial growth factor 


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1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. 
Colorectal Cancer Background and Treatments 
Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer 
death worldwide.  In 2020, it is projected that approximately 147,950 individuals will be newly 
diagnosed in the United States with an estimated 53,200 cancer deaths (including 17,930 cases 
and 3,640 deaths in patients <50 years).1  CRC incidence rates vary regionally, with higher rates 
observed in East Asia and Europe (13.1% and 11.8%, respectively, of the total cancer incidence 
in these regions) compared to lower rates observed in North America (7.6% the total cancer 
incidence).2  At diagnosis, 39% of patients with CRC have localized disease, 35% of patients 
have regional stage disease, and 22% are diagnosed with distant metastases.  The 5-year survival 
rate in localized disease is approximately 90%; fewer than 20% of patients with metastatic CRC 
are expected to survive 5 years.3   
Current guidelines for the management of metastatic CRC recommend a multidisciplinary 
approach that involves surgical resection, chemotherapy with or without targeted therapy, and/or 
radiation therapy, as appropriate.4,5  Individual patient data from 22 first-line metastatic CRC 
trials demonstrated a median overall survival (OS) of 18.2 months and progression-free survival 
(PFS) of 8.3 months.6  First-line combination treatments have yielded median OS durations of up 
to 30 months.7,8  Approved agents in the third-line and higher treatment setting following 
treatment with fluoropyrimidine, irinotecan, oxaliplatin, and anti-vascular endothelial growth 
factor (VEGF) or anti-epidermal growth factor receptor (EGFR) antibody (Ab) therapy include 
regorafenib (a multi-kinase inhibitor) and Trifluridine/Tipiracil (TAS-102; a thymidine-based 
nucleoside analog/thymidine phosphorylase inhibitor).  The RECOURSE trial of the TAS-102 
arm in patients with refractory metastatic CRC demonstrated an OS of 7.1 months, an objective 
response rate (ORR) of 1.6% (compared to 0.4% for placebo), a PFS of 2.0 months, and a 
disease control rate (DCR) of 44%.9  The CORRECT trial results of regorafenib demonstrated an 
OS of 6.4 months, an ORR of 1% (compared to 0.4% for placebo), a PFS of 1.9 months, and a 
DCR of 41%.10  Thus, among patients with previously treated locally advanced or metastatic 
CRC, the prognosis remains poor. 11  
1.1.2. 
Human Epidermal Growth Factor Receptor 3 
Human epidermal growth factor receptor 3 (HER3), a member of the human epidermal growth 
factor receptor (HER) family of proteins, is known to mediate oncogenic transformation in 
multiple tumor types.11,12  There is mechanistic evidence also for the role of HER3 in CRC.  In 
CRC cells, HER3 promotes cell proliferation and mediates resistance to cytotoxic chemotherapy 
and to targeted therapeutics.13  In vitro, ERBB3 (the gene encoding the HER3 protein) 
knockdown decreases cell proliferation, induces apoptosis, and blocks the migration of colon 
cancer cells.14  Moreover, in BRAF-V600E mutant colon cancer stem cells, HER3 mediates 
cellular proliferation and is associated with resistance to the BRAF inhibitor vemurafenib.14 
Multiple lines of evidence indicate that HER3 signaling is functionally important in mediating 
resistance to standard cancer treatment.13,15,16,17  Elevated expression of the HER3 protein in 
multiple tumor types has been observed in approximately 69%-83% of CRC patients.18,19,20  


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Elevated HER3 expression has been associated with worse clinical outcome in CRC.21,22  A 
meta-analysis of the association between the high expression of HER3and clinical pathologic 
features and prognosis of CRC showed that there was a significant association between an 
increase in HER3 expression and tumor differentiation, tumor, node, metastasis tumor stage, and 
anatomic location.13  Patients with high expression of HER3 demonstrated an inferior tumor 
response and OS after treatment with cetuximab.13   
1.1.3. 
U3-1402 
U3-1402 is an antibody drug conjugate (ADC) comprised of a recombinant fully human 
anti-HER3 immunoglobulin G1 monoclonal Ab (patritumab, U3-1287) covalently linked to 
MAAA-1162a (glycine-glycine-phenylalanine-glycine) tetrapeptide linker containing a 
topoisomerase I inhibitor [MAAA-1181a]).  MAAA-1181a is a derivative of the topoisomerase I 
inhibitor exatecan (DX-8951f),23,24,25 which has shown activity in a wide range of advanced solid 
tumors.  MAAA-1181a is released after internalization and leads to apoptosis of the target tumor 
cells via the inhibition of topoisomerase I.   
1.1.4. 
In Vivo and In Vitro Models 
Nonclinical studies have shown that U3-1402 binds specifically to the HER3 extracellular 
domain and does not bind to other HER family proteins.  U3-1402 exhibited HER3 
expression-dependent cell growth inhibition activity in multiple HER3-expressing in vivo CRC 
models in various molecular sub-types.  Antitumor activity was demonstrated following different 
prior treatments, including several that were derived from irinotecan refractory tumors, with a 
trend toward higher antitumor activity in higher HER3-expression models.  Therefore, U3-1402 
is expected to show antitumor activity in HER3-expressing tumors.  For additional details, refer 
to Section 1.2.1 of the Investigator9s Brochure (IB).26   
To evaluate antitumor activity in a tumor xenograft model, U3-1402 was administered at 
10 mg/kg every 3 weeks (Q3W) (Days 0, 7, and 14).26  Activity of U3-1402 was assessed by the 
maximum tumor regression during the treatment (Figure 1.1).27  Tumor regression was observed 
in xenografted tumors derived from 5 of the 9 cell lines (DiFi, DLD-1, LoVo, SW480, and 
SW620). The highest regression was seen in tumors from SW620 cells (high HER3 with KRAS 
G12C activation mutation) and DiFi (high HER3 expression with KRAS wild type and EGFR 
gene amplification).  These results showed that antitumor activity of U3-1402 was associated 
with higher levels of HER3 expression in xenograft models, regardless of the KRAS mutation 
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Figure 1.1: 
Waterfall Plot for Tumor Xenograft Models. 
 
HER3 = human epidermal growth factor receptor 3; Q3W = every 3 weeks. 
U3-1402 (10 mg/kg) was administered Q3W (Days 0, 7, and 14) via intraperitoneal injection. 
Source: Koganemaru 201927  
1.1.5. 
Clinical Studies 
For additional details regarding the studies summarized below, refer to Section 1.3.2 of the IB.26   
Study U31402-A-J101 Breast Cancer (Ongoing) 
Study U31402-A-J101 is a Phase 1/2, multicenter, open-label, multiple-dose, first-in-human 
study of U3-1402 in subjects with HER3-positive metastatic breast cancer.  The study design 
includes a Dose Escalation Part to identify the maximum tolerated dose (MTD) of U3-1402; a 
Dose Finding Part to determine the recommended doses for expansion (RDEs) of U3-1402 and 
to assess multiple drug administration schedules, to determine the safety of alternative dosing 
schedules; and a global Dose Expansion Part to evaluate the safety and efficacy of U3-1402 at 
the RDEs for subjects with HER3-positive metastatic breast cancer.  As of the data cut-off 
(DCO) date of 05 Aug 2019, 144 of the 145 subjects enrolled had received U3-1402.  At the 
DCO, 50 subjects were continuing study drug and 94 subjects had discontinued treatment 
including 74 subjects due to disease progression (68 subjects due to progressive disease [PD] by 
Response Evaluation Criteria in Solid Tumors [RECIST] and 6 subjects due to clinical PD), 10 
subjects due to an adverse event (AE), 4 subjects due to withdrawal by subject, 5 subjects due to 
other reasons, and 1 due to death.  Treatment-emergent adverse events (TEAEs), all grades 
regardless of causality, were reported in 141 (97.9%) treated subjects; nausea (113 [78.5%] 
subjects) and decreased appetite (74 [51.4%] subjects) were experienced by >50% of subjects.  
TEAEs of Grade 3 or higher were reported in 92 (63.9%) subjects.  The most common Grade g3 
TEAEs experienced by >5% of subjects were neutrophil count decreased (37 [25.7%] subjects), 
platelet count decreased (32 [22.2%] subjects), anaemia (25 [17.4%] subjects), white blood cell 
count decreased (21 [14.6%] subjects), thrombocytopenia (12 [8.3%] subjects), neutropenia (11 
[7.6%] subjects), hypokalaemia (10 [6.9%] subjects), and aspartate aminotransferase (AST) 
increased (8 [5.6%] subjects).   


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Efficacy data are available as of the previous DCO (8 Nov 2018) and are as follows: subjects 
from Dose Escalation and Dose Finding (N=42) demonstrated a confirmed ORR of 42.9%, a 
DCR of 90.5%, and a median PFS of 8.3 months (median follow-up of 10.5 months).28  
Study U31402-A-U102 (Ongoing) 
Study U31402-A-U102 is a multicenter, open-label, Phase 1 study of U3-1402 in subjects with 
metastatic or unresectable non-small cell lung cancer (NSCLC).  This study includes a Dose 
Escalation Part in which subjects receive intravenous (IV) U3-1402 in 21-day cycles with a 
starting dose of 3.2 mg/kg, and a Dose Expansion Part in which subjects receive U3-1402 at the 
RDE determined in the Dose Escalation Part.  As of the DCO date of 05 Aug 2019, 36 subjects 
had received U3-1402 in the Dose Escalation Part.  Four subjects were enrolled in the 3.2 mg/kg 
cohort, 15 subjects were enrolled in the 4.8 mg/kg cohort, 12 subjects were enrolled in the 
5.6 mg/kg cohort, and 5 subjects were enrolled in the 6.4 mg/kg cohort. At the DCO, 12 subjects 
were continuing study drug.  Eighteen subjects had discontinued due to disease progression, 
2 subjects due to clinical progression, 1 subject due to death caused by disease progression, 
2 subjects due to an AE, and 1 subject had discontinued due to withdrawal of consent by subject.  
All (100%) subjects had at least one TEAE; nausea (23 [63.9%] subjects) and vomiting 
(15  41.7%] subjects) were experienced by >40% of subjects.  TEAEs of Grade 3 or higher were 
reported in 16 (44.4%) subjects as of 05 Aug 2019.  The most common Grade g3 TEAEs 
reported in more than 5% of subjects included platelet count decreased (7 [19.4%] subjects), 
troponin increased (3 [8.3%] subjects), and anaemia and hypoxia (2 [5.6%] subjects each). 
Preliminary efficacy data are available as of the previous DCO (May 2019) and are as follows: of 
the 26 efficacy-evaluable patients, 6 had confirmed partial responses (PRs; 2 each at 4.8, 5.6, and 
6.4 mg/kg). Median best percentage change in sum of diameters (SoD) was 225.7% (range, 
282.6% to 13.3%), including decreases in SoD in patients with CDK4 amplification (325.7% 
and -17.8%), human epidermal growth factor receptor 2 (HER2) amplification (328.6%), and 
both CCNE1 amplification and PIK3CA mutation (-28.8%).29  
1.2. 
Study Rationale 
In the setting of advanced or metastatic CRC conventional approved therapies as well as targeted 
therapies confer minimal efficacy29 (Section 1.1.1).  Further, limited effective targeted options 
for this disease have become available over the last decade and very few experimental 
compounds are in development in the advanced setting.  Therefore, there is a great unmet 
medical need in advanced or metastatic CRC as the standard of care is insufficient for treatment 
in this patient population. 
In CRC cells, HER3 promotes cell proliferation and mediates resistance to cytotoxic 
chemotherapy and to targeted therapy.  High expression of HER3 has been shown to be 
associated with tumor differentiation.  There is a large patient population with metastatic CRC 
with high prevalence of HER3 expression. HER3 is expressed in a majority of CRC patients 
(~50%-75% immunohistochemistry [IHC] 3+ and 2+) (Section 1.1.2).18,19,20 
Due to the high prevalence of HER3 expression, U3-1402 in advanced or metastatic CRC is 
hypothesized to show efficacy based on the following:  


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÷ Significant tumor regression with U3-1402 was observed in several tumor xenograft 
models with both KRAS wild type and KRAS mutant (Section 1.1.4).30   
÷ Topoisomerase I inhibition with irinotecan is one of the cornerstones of systemic 
therapy regimens in advanced or metastatic CRC.  Exatecan (DX-8951f), a compound 
from which the topoisomerase I inhibitor payload (MAAA-1181a) of U3-1402 is 
derived, showed proof of activity in a CRC study with an irinotecan resistant patient 
population.30  The exatecan conjugate (MAAA-1181a) payload of the U3-1402 ADC 
has a similar mechanism of action and may, therefore show activity in patients whose 
tumors express HER3. 
÷ Preliminary clinical evidence from the studies of U3-1402 in metastatic breast cancer 
(U31402-A-J101) and in NSCLC (U31402-A-U102) is consistent with this 
hypothesis where a high rate of HER3 expression and tumor reduction is observed in 
a majority of subjects.  U3-1402 has also demonstrated a manageable safety profile in 
U31402-A-J101 and U31402-A-U102 (Section 1.1.5).28,29 
The large population of patients with advanced or metastatic CRC for whom clinical outcomes 
remain poor due to minimally efficacious standard of care options, the high prevalence of 
HER3-expressing tumors in CRC, the clinical activity of exatecan (from which MAAA-1118a 
was derived) in irinotecan-resistant CRC, and preliminary clinical evidence of safety and 
efficacy of U3-1402 in metastatic breast cancer and NSCLC highlights the opportunity for 
U3-1402 to improve the care of patients with advanced or metastatic CRC. 
This Phase 2, multicenter, open-label study was designed to primarily evaluate the safety and 
efficacy of U3-1402 in subjects with advanced or metastatic CRC who have received at least 
2 prior lines of therapy and will explore clinical benefit according to HER3-expression level in 
otherwise refractory tumors.   
1.2.1. 
Justification for Dose Selection for Study 
The regimen to be evaluated will be a fixed dose of 5.6 mg/kg administered as a continuous IV 
infusion on Day 1 of each 21-day cycle.   
Data from two studies have been considered for the selection of the 5.6 mg/kg dose.  Study 
U31402-A-J101 included 1.6 mg/kg, 3.2 mg/kg, 6.4 mg/kg and 8.0 mg/kg Q3W in subjects with 
breast cancer, the MTD was established at 6.4 mg/kg. Study U31402-A-U102 included 
3.2-mg/kg, 4.8 mg/kg, 5.6 mg/kg and 6.4 mg/kg Q3W in NSCLC patients, the MTD was 
established at 5.6 mg/kg. In addition, 4.2 mg/kg every 2 weeks and an up-titration dose regimen 
were studied in the J101 study, with 3.2 mg/kg in Cycle 1, 4.8 mg/kg in Cycle 2, and 6.4 mg/kg 
in Cycle 3 and after. Exposure of intact U3-1402 ADC, total anti-HER3 Ab and released payload 
MAAA-1181a increased as dose increased. Population pharmacokinetics (PK), and exposure 
response analyses for efficacy and safety were conducted using data from both the 
U31402-A-J101 and U31402-A-U102 studies. Exposure-efficacy relationship was established 
for intact U3-1402 ADC and the exposure safety relationship was established for released 
payload MAAA-1181a. 


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The rationale for the selection of 5.6 mg/kg is based on an exposure-response analysis of 
efficacy, and 5.6 mg/kg is predicted to provide a lower probability of gGrade 3 
thrombocytopenia compared to 6.4 mg/kg, and an improved ORR compared to 4.8 mg/kg.   
More data are being collected in the ongoing U3-1402 studies to further evaluate this dosing 
regimen.   
1.2.2. 
Benefit/Risk Assessment for Study Subjects 
U3-1402 is being developed for the treatment of HER3-expressing malignant tumors.  
Nonclinical studies have demonstrated the antitumor activity of U3-1402 in HER3 tumor-bearing 
mouse models. Thus, U3-1402 is hypothesized to demonstrate efficacy in treating 
HER3-expressing tumors in patients. 
In nonclinical toxicology studies, intestinal toxicity, lymphatic/hematopoietic system toxicity, 
skin toxicity, pulmonary toxicity, reproductive and accessory organ toxicities, hepatic toxicity, 
cardiotoxicity, and renal toxicity were found in association with the administration of U3-1402. 
As with any therapeutic Abs, there is a possibility of infusion-related reactions and immune 
responses causing allergic or anaphylactic reactions to U3-1402. Considering the toxicity data 
from the nonclinical studies, the important potential risk is hepatotoxicity, and the potential risks 
are infusion-related reaction, dry eye, keratitis, photosensitivity, dry skin, rash, rash 
maculopapular, and skin pigmentation in humans from exposure to U3-1402, and these have 
been closely monitored and evaluated in the U3-1402 clinical development program. 
Based on the preliminary clinical safety data from the ongoing U3-1402 studies, the important 
identified risk is interstitial lung disease (ILD); the important potential risk is hepatotoxicity, and 
the identified risks are nausea, decreased appetite, platelet count decreased/thrombocytopenia, 
white blood cell count decreased/leukopenia, neutrophil count decreased/neutropenia, vomiting, 
anemia, diarrhea, fatigue, malaise, stomatitis, constipation, alanine aminotransferase (ALT) 
increased, AST increased, febrile neutropenia, and alopecia, and will continue to be closely 
monitored and evaluated in the U3-1402 clinical development program. 
Preliminary data as of 06 Nov 2018 from the ongoing study U31402-A-J101 in breast cancer 
subjects from Dose Escalation and Dose Finding (N=42) demonstrated a confirmed ORR of 
42.9%, a DCR of 90.5%, and a median PFS of 8.3 months (median follow-up of 10.5 months).28  
Further, preliminary data as of May 2019 from the ongoing study U31402-A-U102 are as 
follows: of the 26 efficacy-evaluable patients, 6 had confirmed PRs (2 each at 4.8, 5.6, and 
6.4 mg/kg). Median best percentage change in SoD was -25.7% (range, -82.6% to 13.3%), 
including decreases in SoD in patients with CDK4 amplification (-25.7% and -17.8%), HER2 
amplification (-28.6%), and both CCNE1 amplification and PIK3CA mutation (-28.8%).29   
In conclusion, based on the efficacy and safety data from the nonclinical studies and the 
preliminary clinical safety and efficacy data from the ongoing studies, the benefit/risk balance 
supports continued clinical development of U3-1402. 
See the current IB for updated benefit/risk assessment.26  












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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a Phase 2, multicenter, open-label, 2-cohort study of U3-1402 single agent therapy in 
subjects with advanced or metastatic CRC who are resistant, refractory, or intolerant to at least 
2 prior lines of systemic therapy that must include all of the following agents: fluoropyrimidine, 
irinotecan, platinum agent, an anti-EGFR agent (if clinically indicated), an anti-VEGF agent (if 
clinically indicated), an immune checkpoint inhibitor (if clinically indicated), and a BRAF 
inhibitor (if clinically indicated).  Figure 3.1 shows the study design.   
This study will be conducted at approximately 40 sites in the United States, Europe, and Asia 
(including Japan).  Additional sites may be added as needed. 
Figure 3.1: 
Study Design Schema 
 
BICR = blinded independent central review; CRC = colorectal cancer; DCR = disease control rate; DoR = duration 
of response; EGFR = epidermal growth factor receptor; HER3 = human epidermal growth factor receptor 3; 
IHC = immunohistochemistry; IV = intravenous; ORR = objective response rate; OS = overall survival; PD = 
progressive disease; PFS = progression-free survival; Q3W = every 3 weeks; RECIST = Response Evaluation 
Criteria in Solid Tumors; TTR = time to tumor response; VEGF = vascular endothelial growth factor. 
Part 1 
Archival tumor biopsy and pre-treatment tumor biopsy will be collected from all subjects at 
screening and HER3 protein expression will be measured by an investigational device 
(HER3 IHC assay).   
Subjects may be exempted from the requirement to provide a pre-treatment tumor biopsy if the 
archival tumor tissue: 


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÷ Was collected within 3 months of screening during or after treatment with the last 
prior cancer treatment and 
÷ Is of sufficient quantity, defined as 2 cores or 20 slides with adequate tumor tissue 
content. 
Results of the prospective HER3 IHC assay from the pre-treatment tumor biopsy will be used to 
assign subjects into 1 of 2 cohorts:  
÷ Cohort 1: HER3 High (IHC 3+, 2+) (approximately 24 treated subjects), or  
÷ Cohort 2: HER3 Low/Negative (IHC 1+, 0) (approximately 12 treated subjects). 
See Section 8.3.1 for additional details regarding the HER3 IHC assay. 
Subjects will be treated on Day 1 of each 21-day cycle with U3-1402 5.6 mg/kg IV. 
For each study cohort, review of the preliminary data from Part 1 will be used to determine 
whether to open Part 2.  The decision to advance from Part 1 to Part 2 will be made separately in 
Cohort 1 and Cohort 2; the interim futility analysis will be conducted with approximately 
24 subjects in Cohort 1 and approximately 12 subjects in Cohort 2 after all subjects have had the 
opportunity to complete two tumor assessments.  The tumor assessment period may be extended 
if emerging data show responses are occurring later, or if the tumor assessment for the final 
evaluated subject in each cohort is delayed.  At the time of the interim analysis for each cohort, 
enrollment into the respective cohort will be paused until the determination that criteria for 
advancement to Part 2 have been achieved.  Note it is possible for the futility criterion to be 
passed before the above specified analysis timing.  These analyses will be conducted based on 
BICR assessment in the Full Analysis Set (FAS).   
After review of the data from Part 1 based on criteria outlined in Section 11.6, if the Sponsor 
decides to enroll subjects irrespective of HER3 expression status in Part 2 (ie, Scenario 1 below, 
continuing enrollment of Cohort 2 into Part 2), the decision and preliminary data from Cohort 2 
Part 1 will be provided as part of a protocol amendment.   
Part 2 
÷ Dose: U3-1402 5.6 mg/kg IV Q3W  
ý Scenario 1: Enrollment continues in Cohort 1 and Cohort 2: approximately 
44 subjects will be enrolled, regardless of HER3 IHC status, and receive treatment 
with U3-1402. 
Total sample size at end of study: approximately 80 = Part 1 (Cohort 1 
[approximately 24 subjects] + Cohort 2 [approximately 12 subjects]) + Part 2 
(Cohorts 1 and 2 [approximately 44 subjects]) 
ý Scenario 2: Enrollment continues in Cohort 1 only: approximately 44 subjects 
with HER3 High (IHC 3+, 2+) status will be enrolled and receive treatment with 
U3-1402. 
Total sample size at end of study: approximately 80 = Part 1 (Cohort 1 
[approximately 24 subjects] + Cohort 2 [approximately 12 subjects]) + Part 2 
(Cohort 1 [approximately 44 subjects]) 


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Treatment with U3-1402 in all cohorts will continue until the time of PD (confirmed by BICR) 
per RECIST v1.1, unacceptable toxicity, withdrawal of consent, death, termination of the study 
by Sponsor, or the occurrence of any of the other events specified in Section 5.7.  If progressive 
disease is suspected by Investigator tumor assessment, imaging must be submitted to BICR for 
expedited confirmation of disease progression.  The decision to discontinue U3-1402 is 
according to Investigator judgment and should consider BICR assessment. 
3.1.1. 
Duration of the Study 
The study start date is the date when the first subject has signed an informed consent form (ICF).   
The enrollment period is approximately 15 months.  It will occur in 2 parts separated by an 
interim futility analysis for each cohort.  The estimated treatment period is approximately 
8 months, and the follow-up period is approximately 4 months. 
The total estimated duration of the study is approximately 27 months.  The primary analysis data 
cut-off will occur when all subjects have had either a minimum of 9 months of follow-up or have 
discontinued from the study earlier.  The DCO may be shifted if emerging data indicate 
responses are occurring at a different time.  The final analysis will be performed after all subjects 
have discontinued from the study for any reason.  In addition, the Sponsor may terminate the 
study at any time and study termination may also be requested by a competent authority; in such 
an instance the data cut-off date will be the date of study termination.   
3.1.2. 
Duration of Subject Participation 
The screening period is up to 35 days.  Each cycle of treatment will be 21 days.  The number of 
treatment cycles with U3-1402 is not limited.  Subjects may continue study treatment until the 
time of progressive disease  per RECIST v1.1, unacceptable toxicity, withdrawal of consent, 
death, termination of the study by Sponsor or the occurrence of any of the other events specified 
in Section 5.7.  If PD is suspected by Investigator tumor assessment, imaging must be submitted 
to BICR for expedited confirmation of disease progression.  The decision to discontinue 
U3-1402 is according to Investigator judgment and should consider BICR assessment. 
Tumor assessments will be performed every 6 weeks (± 7 days) from Cycle 1 Day 1 for the first 
24 weeks then every 12 weeks (± 7 days) thereafter, independent of treatment cycle, until 
documented disease progression by BICR per RECIST Version (v) 1.1 , death, lost to follow-up, 
or withdrawal of consent. 
There is an End-of-Treatment (EOT) Visit that takes place within 7 days after the final dose of 
U3-1402 or before the start of new anticancer treatment, whichever comes first.  Subjects will be 
asked to attend a 40-Day Follow-up (F/U) Visit (+7 days) 40 days after the last U3-1402 
administration.  If the subject begins another anticancer therapy before the end of the 40 days 
(+7 days), every effort will be made to complete all of the F/U assessments prior to starting the 
new therapy.  For further details concerning assessments performed at the EOT and F/U Visits 
refer to the Schedule of Events (Table 13.1). 
After discontinuation from study treatment, follow-up information for determining anti-drug 
antibodies (ADAs) as well as survival information and subsequent anticancer therapy, if 
available, should be collected every 3 months (±14 days).  Survival F/U contact can occur via 
telephone contact or unscheduled visit and will continue until death, withdrawal of consent, lost 


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to follow-up, or study closure, whichever occurs first.  Refer to Table 13.1 for details.  Subjects 
who discontinue study treatment for any reason other than documented disease progression by 
BICR, death, lost to follow-up, or withdrawal of consent by the subject will continue to undergo 
tumor assessments at the same frequency of every 6 weeks (±7 days) from Cycle 1 Day 1 for the 
first 24 weeks then every 12 weeks (±7 days) during the follow-up period. 
3.1.3. 
Definition of the End of Study 
The overall end of study will occur after the last subject last visit has occurred; or after all 
subjects have discontinued from the study or have died; or an alternative study becomes 
available for subjects continuing to derive benefit from treatment with U3-1402 where the drug 
is offered to these subjects; or the study is discontinued by the Sponsor for other reasons. 
At the time of study closure, any subjects who are continuing treatment with U3-1402 and who 
are judged by the Investigator to have ongoing benefit may continue to receive treatment with 
U3-1402 through a rollover protocol or another mechanism consistent with local requirements. 


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4. 
STUDY POPULATION 
Each subject will sign and date a study ICF provided by the site.  A subject is considered 
enrolled in the study upon the Investigator or a designee obtaining written informed consent from 
the subject at the time of screening and upon determination that all inclusion and exclusion 
criteria have been satisfied. 
Investigators will maintain a confidential Screening Log of all potential study candidates that 
includes limited subject information and outcome of the screening process (ie, enrollment in the 
study, reason for ineligibility, withdrew consent). 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study numbers. 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study: 
1. Sign and date the ICF prior to the start of any study-specific qualification procedures. 
2. Male or female subjects g18 years (follow local regulatory requirements if the legal age 
of consent for study participation is >18 years old). 
3. Pathological or histological confirmation and documentation of colon or rectum 
adenocarcinoma with advanced or metastatic disease. 
4. Must be resistant, refractory, or intolerant to at least 2 prior lines of therapy, that must 
include all of the following agents: 
a. Fluoropyrimidine  
b. Irinotecan 
c. Platinum agents (eg, oxaliplatin) 
d. An anti-EGFR agent, if clinically indicated 
e. An anti-VEGF agent, if clinically indicated (eg, bevacizumab) 
f. An immune checkpoint inhibitor, if clinically indicated (eg, microsatellite 
instability-high [MSI-H] status) 
g. A BRAF inhibitor, if clinically indicated (eg, BRAF V600E positive) 
5. Has at least 1 measurable lesion confirmed by BICR as per RECIST v1.1. 
6. Willing to provide a required pre-treatment tumor biopsy and an additional archival tissue 
sample for the assessment of HER3 expression levels by IHC and exploratory 
biomarkers, defined as:  
a. Pre-treatment tumor biopsy. Subjects may be exempted from the requirement to 
provide a pre-treatment tumor biopsy if archival tumor tissue was collected within 
3 months of screening during or after treatment with the last prior cancer treatment 
and is of sufficient quantity (2 cores or 20 slides with adequate tumor tissue content).  
b. An additional archival tissue sample collected greater than 3 months prior to 
screening must be available and of sufficient quantity, as defined above, at the time of 
screening.  If an archival tissue sample (collected greater than 3 months prior to 
screening) is not available, a subject may be included provided the pre-treatment 


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tumor biopsy is obtained and after discussion and agreement from Sponsor (Medical 
Monitor or designee). 
c. Consent to provide on-treatment tumor biopsy. When at least 10 on-treatment tumor 
biopsies per cohort have been collected, the Sponsor will provide written notification 
of a change to the requirement.   
7. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. 
8. Life expectancy g3 months. 
9. Has adequate bone marrow reserve and organ function, based on local laboratory data, 
defined as within 14 days prior to Cycle 1 Day 1: 
Parameter 
Laboratory Value 
Platelet count 
g100,000/mm3 or g100 × 109/L (platelet transfusions 
are not allowed up to 14 days prior to Cycle 1 Day 1 
to meet eligibility) 
Hemoglobin  
g9.0 g/dL (transfusion and/or growth factor support is 
allowed) 
Absolute neutrophil count 
g1500/mm3 or g1.5 × 109/L  
SCr OR CrCl 
SCr f 1.5 × ULN, OR  
CrCl g 30 mL/min as calculated using the Cockcroft-
Gault equation or measured CrCl; confirmation of 
CrCl is only required when creatinine is >1.5 × ULN 
Alanine aminotransferase /aspartate 
aminotransferase 
f3 × ULN (if liver metastases are present, f5 × ULN) 
Total bilirubin 
f1.5 × ULN if no liver metastases (<3 × ULN in the 
presence of documented Gilbert9s syndrome 
[unconjugated hyperbilirubinemia] or liver 
metastases) 
Serum albumin  
g2.5 g/dL 
PT or PT-INR and aPTT/PTT 
f1.5 × ULN except for subjects on coumarin-
derivative anticoagulants or other similar 
anticoagulant therapy, who must have PT-INR within 
therapeutic range as deemed appropriate by the 
Investigator 
aPTT = activated partial thromboplastin time; CrCl = creatinine clearance; INR = international normalized ratio; 
PT = prothrombin time; PTT = partial thromboplastin time; SCr = serum creatinine; ULN = upper limit of normal 
10. If the subject is a female of childbearing potential, she must have a negative serum 
pregnancy test at screening and must be willing to use a highly effective form of birth 
control as detailed in Section 13.8, upon enrollment during the Treatment Period, and for 
7 months following the last dose of study drug.  


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A female is considered of childbearing potential following menarche and until becoming 
postmenopausal (no menstrual period for a minimum of 12 months) unless permanently 
sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy) 
with surgery at least 1 month before the first dose or confirmed by follicle-stimulating 
hormone (FSH) test.  See Section 9.6 for further details regarding confirmation of 
post-menopausal status. 
11. Female subjects must not donate, or retrieve for their own use, ova from the time of 
screening and throughout the study treatment period, and for at least 7 months after the 
final study drug administration. 
12. If male, the subject must be surgically sterile or willing to use highly effective 
contraception (Section 13.8) upon enrollment, during the treatment period, and for at 
least 4 months following the last dose of study drug. 
13. Male subjects must not freeze or donate sperm starting at screening and throughout the 
study period, and for at least 4 months after the final study drug administration. 
14. Is willing and able to comply with scheduled visits, drug administration plan, laboratory 
tests, other study procedures, and study restrictions. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be denied entry to the study: 
1. Any history of ILD (including pulmonary fibrosis or radiation pneumonitis), has current 
ILD, or is suspected to have such disease by imaging during screening. 
2. Clinically severe pulmonary compromise (based on Investigator9s assessment) resulting 
from intercurrent pulmonary illnesses including, but not limited to: 
a. any underlying pulmonary disorder (eg, pulmonary emboli, severe asthma, severe 
chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion) 
b. any autoimmune, connective tissue or inflammatory disorder with pulmonary 
involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis)  
OR prior complete pneumonectomy.   
3. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent 
anti-inflammatory activity or any form of immunosuppressive therapy prior to Cycle 1 
Day 1.  Subjects who require use of bronchodilators, inhaled or topical steroids, or local 
steroid injections may be included in the study. 
4. Evidence of leptomeningeal disease 
5. Evidence of clinically active spinal cord compression or brain metastases, defined as 
untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants 
to control associated symptoms.  Subjects with clinically inactive or treated brain 
metastases who are asymptomatic (ie, without neurologic signs or symptoms and do not 
require treatment with corticosteroids or anticonvulsants) may be included in the study.  
Subjects must have a stable neurologic status for at least 2 weeks prior to Cycle 1 Day 1.   
6. Inadequate washout period prior to Cycle 1 Day 1 of U3-1402: 


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a. Whole brain radiation therapy <14 days or stereotactic brain radiation therapy 
<7 days; 
b. Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a 
previous cancer treatment regimen or clinical study <14 days or 5 half-lives, 
whichever is longer; 
c. Monoclonal antibodies other than immune checkpoint inhibitors, such as 
bevacizumab (anti-VEGF) and cetuximab (anti-EGFRs) <28 days; 
d. Immune checkpoint inhibitor therapy <21 days; 
e. Major surgery (excluding placement of vascular access) <4 weeks;  
f. Radiotherapy treatment to >30% of the bone marrow or with a wide field of radiation 
<28 days or palliative radiation therapy <14 days;  
g. Chloroquine /Hydroxychloroquine f14 days. 
7. Prior treatment with an anti-HER3 antibody and/or ADC that consists of an exatecan 
derivative that is any topoisomerase I inhibitor (eg, trastuzumab deruxtecan). 
8. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other 
than alopecia) not yet resolved to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) v5.0 Grade f1 or baseline.   
9. Had primary malignancies other than CRC within 3 years prior to Cycle 1 Day 1, except 
adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other 
solid tumors curatively treated. 
10. Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1, including: 
a. QT interval corrected for heart rate using Fridericia9s formula (QTcF) prolongation 
interval of >470 ms for females and >450 ms for males within 28 days; 
b. Left ventricular ejection fraction (LVEF) <50% by either echocardiogram (ECHO) or 
multiple-gated acquisition (MUGA) scan within 28 days; 
c. Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg; 
d. Myocardial infarction within 6 months;  
e. New York Heart Association (NYHA) Classes 2 to 4 (See Section 13.5) within 
28 days; 
f. Uncontrolled angina pectoris within 6 months;  
g. Cardiac arrhythmia requiring antiarrhythmic treatment within 28 days. 
11. Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of 
viral infection within 28 days of Cycle 1 Day 1. 
a. Subjects with past or resolved hepatitis B virus (HBV) infection are eligible if: 
i. Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody  
positive; OR 
ii. HBsAg positive and HBV deoxyribonucleic acid (DNA) viral load is documented 
to be f2000 IU/mL in the absence of anti-viral therapy and during the previous 
12 weeks prior to the viral load evaluation with normal transaminases values (in 
the absence of liver metastasis); OR 
iii. HBsAg positive and HBV DNA viral load is documented to be f2000 IU/mL in 
the absence of anti-viral therapy and during the previous 12 weeks prior to the 


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viral load evaluation for subjects with liver metastasis and abnormal 
transaminases with a result of AST/ALT <3 × ULN. 
b. Subjects with a history of hepatitis C infection will be eligible for enrollment only if 
the viral load according to local standards of detection is documented to be below the 
level of detection in the absence of anti-viral therapy during the previous 12 weeks 
(ie, sustained viral response according to the local product label but no less than 
12 weeks, whichever is longer).  
12. Subject with any human immunodeficiency virus (HIV) infection. 
13. Any evidence of severe or uncontrolled systemic diseases (including active bleeding 
diatheses, active infection), psychiatric illness/social situations, geographical factors, 
substance abuse, or other factors which in the Investigator9s opinion makes it undesirable 
for the subject to participate in the study or which would jeopardize compliance with the 
protocol.  Screening for chronic conditions is not required. 
14. Has history of hypersensitivity to either the drug substances or inactive ingredients in the 
drug product. 
15. Female who is pregnant or breastfeeding or intends to become pregnant during the study.  
16. Has a concomitant medical condition that would increase the risk of toxicity, in the 
opinion of the Investigator 
17. Has clinically significant corneal disease. 


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5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatments 
5.1.1. 
Treatment Group(s)/Sequences 
All subjects will receive treatment with U3-1402 5.6 mg/kg IV Q3W. 
5.1.2. 
Method of Treatment Allocation 
Subjects must meet all eligibility criteria and provide signed informed consent prior to initiating 
any study-specific procedures.  
Part 1 
Prior to interim futility analysis, results of the prospective HER3 IHC assay from the 
pre-treatment tumor biopsy will be used to assign subjects to the following cohorts: 
÷ Cohort 1 3 HER3 High (IHC 3+, 2+)  
÷ Cohort 2 3 HER3 Low/Negative (IHC 1+, 0) 
All subjects will receive treatment with U3-1402 5.6 mg/kg IV Q3W. 
Part 2 
Post interim futility analysis, all subjects will receive treatment with U3-1402 5.6 mg.kg Q3W.  
÷ Enrollment continues in Cohort 1 and Cohort 2, regardless of HER3 IHC status 
ý Cohort 1 3 HER3 High (IHC 3+, 2+) 
ý Cohort 2 3 HER3 Low/Negative (IHC 1+, 0) 
÷ Enrollment continues in Cohort 1 only 
ý Cohort 1 3 HER3 High (IHC 3+, 2+) 
5.1.3. 
Blinding 
This study has an open-label design, and no blinding will be performed. 
5.1.4. 
Emergency Unblinding Procedure 
Not applicable. 
5.2. 
Study Drug(s) 
5.2.1. 
Description 
U3-1402 for Injection 100 mg (Lyo-DP) is a sterile lyophilized powder in an amber glass vial for 
intravenous infusion that must be stored at 5°C ±3°C and protected from light.  Each vial of 
sterile U3-1402 drug product is designed for single use only and is not to be used to treat more 
than 1 subject. 


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5.2.2. 
Labeling and Packaging 
U3-1402 for Injection 100 mg will be supplied by the Sponsor and will be packaged and labeled 
in compliance with local regulatory requirements.  The packaging will clearly display the name 
of product, storage condition, and other required information as applicable in accordance with 
local regulations. 
5.2.3. 
Preparation 
Preparation of U3-1402 will be conducted in accordance with instructions detailed in the Dose 
Preparation Instructions provided by the Sponsor.  Procedures for proper handling and disposal 
of anticancer drugs should be followed in compliance with the standard operating procedures 
(SOPs) of the study site. 
Prior to use, Lyo-DP will be reconstituted with 5 mL of commercially available water for 
injection to provide a solution with the concentration of 20 mg/mL U3-1402 at a pH range of 
5.4 ± 0.5 formulated with L-histidine, L-histidine hydrochloride monohydrate, sucrose, and 
polysorbate 20.  Five mL of reconstituted solution is withdrawn from each vial to deliver 100 mg 
of U3-1402.  Following reconstitution, U3-1402 will be diluted in dextrose solution and dosed at 
5.6 mg/kg.  Please reference the Pharmacy Instructions for specific details.   
5.2.4. 
Administration 
U3-1402 will be infused as a continuous IV infusion over approximately 90 minutes on Day 1 of 
Cycle 1.  If there are no infusion-related reactions after this initial dose, then subsequent doses of 
U3-1402 will be infused over approximately 30 minutes on Day 1 of each subsequent cycle 
Q3W.  Record start and stop times and amount of drug administered.  Refer to Table 5.2 for 
additional information on drug administration following infusion-related reactions.   
The subject9s weight at Screening (baseline)  will be used to calculate the initial dose.  The 
subject9s weight will be determined at the beginning of each cycle.  If during Cycle 1 Day 1 or 
throughout the course of treatment, the subject9s weight changes by g ± 10% from the baseline 
weight, the dose will be recalculated using this new weight and will be considered the new 
baseline weight for all subsequent dosing calculations. 
5.2.5. 
Storage 
Drug supplies must be stored in a secure, limited access storage area under the recommended 
storage conditions.  
If storage conditions are not maintained per specified requirements, the Sponsor and/or contract 
research organization (CRO) should be contacted. 
Refer to the Pharmacy Instructions for more information regarding drug storage. 
5.2.6. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label, and check the drug 
expiration date.  In addition, the Investigator or designee shall contact the Sponsor and CRO as 
soon as possible if there is a problem with the shipment. 


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A Drug Accountability Record will be maintained for the investigational product.  The record 
must be kept current and should contain the dates and quantities of drug received, subject9s 
information for whom the investigational product was dispensed, the date and quantity of 
investigational product dispensed and the remaining quantity. 
At the end of the study, or as directed, all unused, used and/or partially used U3-1402 will be 
destroyed at the site per institutional policy (and documented).  If the site9s institutional policy 
does not allow for destruction on site, U3-1402 will be returned to a designee as instructed by the 
Sponsor or destroyed in accordance with the Sponsor9s instructions.  Investigational product will 
be returned only after the study monitor has completed a final inventory to verify the quantity to 
be returned.  The return of investigational product must be documented, and the documentation 
included in the shipment.  At the end of the study, a final investigational product reconciliation 
statement must be completed by the Investigator or designee and provided to the Sponsor.  
Unused drug supplies may be destroyed by the Investigator and the supervisor of investigational 
products in Japan when approved in writing by the Sponsor, and after the Sponsor has received 
copies of the site9s drug handling and disposition SOPs. 
All investigational product inventory forms must be made available for inspection by a Sponsor 
authorized representative or designee and regulatory agency inspectors.  The Investigator or 
supervisor of investigational products in Japan is responsible for the accountability of all used 
and unused study supplies at the site. 
5.3. 
Control Treatment 
Not applicable. 
5.4. 
Dose Modifications (Dose Delay, Reduction, and/or Discontinuation) 
All dose modifications (delay, reduction and/or discontinuation) should be based on the worst 
grade toxicity of the event preceding the dose modification.  Dose modifications are applicable 
only to TEAEs that are assessed as related to use of U3-1402 by the Investigator(s).  For 
non-drug related TEAEs, follow standard clinical practice.  Appropriate clinical experts should 
be consulted as deemed necessary.  All dose modifications must be recorded on the AE and drug 
administration electronic case report form (eCRF) pages. 
5.4.1. 
Dose Delay and Reductions 
5.4.1.1. 
Dose Delay and Discontinuation 
The dose can be delayed for up to 28 days from the planned date of administration (ie, 49 days 
from the last infusion date).  If a subject is assessed as requiring a dose delay longer than 
28 days, the subject should be discontinued from the study treatment.   
5.4.1.2. 
Dose Reductions 
If dose reduction is required, U3-1402 dosing should be reduced by 1 dose level at a time 
(Table 5.1).  Once the dose of U3-1402 has been reduced due to an AE, all subsequent cycles 
should be administered at that lower dose level unless further dose reduction is required. 
Dose reductions for the fixed dose 5.6 mg/kg regimen are described in Table 5.1. 


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Table 5.1: 
Dose Reductions for the Fixed Dose 5.6 mg/kg Regimen 
Starting Dose 
Dose Level -1 
Dose Level -2 
5.6 mg/kg IV infusion Q3W 
4.8 mg/kg IV infusion Q3W 
3.2 mg/kg IV infusion Q3W 
IV = intravenous; Q3W = every 3 weeks 
Subjects will be withdrawn from the study treatment if further toxicity meeting the requirement 
for dose reduction occurs. 
5.4.1.3. 
Dose Modifications 
Table 5.2 provides schedule modifications for specific toxicities.   
Table 5.2: 
Dose Modification Criteria 
 
Worst Toxicity NCI-
CTCAE Version 5.0 
Grade (unless 
otherwise specified) 
Schedule Modification for U3-1402 
General disorders and administration site conditions 
Infusion related 
reaction (eg, same 
reduced rate as 
previous infusion) 
Grade 1 
Mild transient reaction; 
infusion interruption not 
indicated; intervention 
not indicated 
If infusion related reaction (such as fever and chills, with and 
without nausea/vomiting, pain, headache, dizziness, 
dyspnea, hypotension) is observed during infusion, the rate 
must be reduced by 50% and subjects must be closely 
monitored. 
If no other reactions appear, the subsequent infusion rate can 
be resumed at the initial planned rate. 
Grade 2 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
nonsteroidal anti-
inflammatory drugs 
[NSAIDs], narcotics, 
intravenous [IV] 
injection fluids); 
prophylactic medications 
indicated for f24 hours 
U3-1402 infusion must be interrupted. 
Symptomatic treatment (eg, antihistamines, NSAIDs, 
narcotics, IV fluids) administered as needed. 
If the event resolves or improves to Grade 1, infusion can be 
re-started at a 50% reduced infusion rate. 
Upon restart, if Grade 2 symptoms recur, no further U3-1402 
must be administered at that visit. The amount of U3-1402 
infused must be recorded in the eCRF. 
Subsequent infusions must be conducted at the 50% reduced 
infusion rate (ie, same reduced rate as previous infusion). 


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Worst Toxicity NCI-
CTCAE Version 5.0 
Grade (unless 
otherwise specified) 
Schedule Modification for U3-1402 
Grade 3 
Prolonged (eg, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae 
 
Grade 4 
Life-threatening 
consequences; urgent 
intervention indicated 
Administration of U3-1402 must be discontinued 
immediately and permanently. 
Urgent intervention indicated.  Antihistamines, steroids, 
epinephrine, bronchodilators, vasopressors, IV fluid therapy, 
oxygen inhalation etc., must be administered as clinically 
indicated. 
Fatigue/Asthenia/ 
Malaise 
Grade 3  
Delay dose until resolved to fGrade 1 or baseline values, 
then: 
÷ If resolved to fGrade 1 or baseline values in f14 days, 
resume U3-1402; 
÷ If resolved to fGrade 1 or baseline values in >14 days, 
reduce U3-1402 by 1 dose level and resume. 
Blood and lymphatic system disorders 
Neutrophil count 
decreased 
Grade 3 
(500 to <1000/mm3; 0.5-
1 × 109/L) 
Delay dose until resolved to fGrade 2, then resume 
U3-1402. 
Grade 4 
(<500/mm3; <0.5 × 
109/L) 
Delay dose until resolved to fGrade 2, then reduce U3-1402 
by 1 dose level and resume. 
Febrile neutropenia 
(ANC <1000/mm3; 
<1 × 109/L, fever 
>38.3°C or a 
sustained 
temperature of 
g38°C for more 
than 1 hour) 
Grade 3 
Delay dose until resolved, then resume U3-1402.  Consider 
reducing U3-1402 by 1 dose level.   
Consider administration of G-CSF as prophylaxis for all 
subsequent cycles and according to local guidelines. 
Febrile neutropenia 
(ANC <1000/mm3; 
<1 × 109/L, fever 
>38.3°C or a 
sustained 
temperature of 
g38°C for more 
than 1 hour) 
Grade 4 
Delay dose until resolved, then reduce U3-1402 by 1 dose 
level and resume. 
Administer G-CSF as prophylaxis for all subsequent cycles 
and according to local guidelines. 


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Worst Toxicity NCI-
CTCAE Version 5.0 
Grade (unless 
otherwise specified) 
Schedule Modification for U3-1402 
Lymphocyte count 
decreased 
Grade 4  
(<0.2 × 109/L) 
Delay dose until resolved to fGrade 2, then: 
÷ If resolved in f14 days, resume U3-1402. 
÷ If resolved in >14 days, reduce U3-1402 by 1 dose 
level and resume. 
Anemia 
Grade 3  
(Hemoglobin <8.0 g/dL) 
Delay dose until resolved to fGrade 2 or baseline, then 
resume U3-1402. 
For recurrent anemia, delay dose until resolved to fGrade 2 
or baseline, then reduce U3-1402 by 1 dose level and 
resume. 
Consider transfusion per institutional guidelines. 
Grade 4  
Life-threatening 
consequences; urgent 
intervention indicated 
Delay dose until resolved to fGrade 2 or baseline, then 
reduce U3-1402 by 1 dose level and resume. 
Consider transfusion per institutional guidelines. 
Platelet count 
decreased 
Grade 3 
(Platelets <50 - 25 × 
109/L) 
Delay dose until resolved to fGrade 1, then: 
÷ If resolved in f14 days, resume U3-1402; 
÷ If resolved in >14 days, U3-1402 may be resumed.  
Consider reducing U3-1402 by 1 dose level. 
Consider transfusion per institutional guidelines. 
Grade 4 
(Platelets <25 × 109/L) 
Delay dose until resolved to fGrade 1, then reduce U3-1402 
by 1 dose level and resume. 
Consider transfusion per institutional guidelines. 
Cardiac disorders 
Heart failure 
Grade g2 
(Symptoms with 
moderate activity or 
exertion) 
Cardiologist consultation as necessary. 
Delay dose until resolved to fGrade 1, then reduce U3-1402 
by 1 dose level and resume. 
Ejection fraction 
decreased 
Decrease in LVEF 10% 
to 20% (absolute value), 
but LVEF >45% 
Continue U3-1402. 
LVEF 40% to f45% and 
decrease is <10% 
(absolute value) from 
baseline 
Continue U3-1402. 
Repeat LVEF assessment within 3 weeks. 
LVEF 40% to f45% and 
decrease is 10% to 20% 
(absolute) from baseline 
Delay U3-1402 dosing. 
Repeat LVEF assessment within 3 weeks. 
If LVEF has not recovered to within 10% (absolute value) 
from baseline, discontinue subject from study treatment. 


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Worst Toxicity NCI-
CTCAE Version 5.0 
Grade (unless 
otherwise specified) 
Schedule Modification for U3-1402 
LVEF <40% or >20% 
(absolute) drop from 
baseline 
Delay U3-1402 dosing. 
Repeat LVEF assessment within 3 weeks; if LVEF <40% or 
>20% (absolute) drop from baseline is confirmed, 
discontinue U3-1402. 
Cardiologist consultation as necessary. 
Electrocardiogram 
QT corrected 
interval prolonged 
Grade 3 (Average 
QTcF g501 ms; >60 ms 
change from baseline) 
Delay U3-1402 until resolved to fGrade 1 (QTcF f480 ms). 
Determine if another medication the subject was taking may 
be responsible and can be adjusted or if there are any 
changes in serum electrolytes that can be corrected. 
If QTcF prolongation is attributed to U3-1402, then reduce 
U3-1402 by 1 dose level. 
Cardiologist consultation as necessary. 
Grade 4 (Torsade de 
pointes; polymorphic 
ventricular tachycardia; 
signs/symptoms of 
serious arrhythmia) 
Discontinue subject from U3-1402. 
Cardiologist consultation as necessary 


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Worst Toxicity NCI-
CTCAE Version 5.0 
Grade (unless 
otherwise specified) 
Schedule Modification for U3-1402 
Respiratory, thoracic and mediastinal disorders 
Pulmonary toxicity 
See next rows 
If a subject develops radiographic changes potentially 
consistent with ILD or an acute onset of new or worsening 
pulmonary or other related signs/symptoms such as dyspnea, 
cough or fever, rule out ILD.  
If ILD is suspected, delay U3-1402 dosing pending further 
evaluation and start corticosteroid treatment promptly per 
consensus statement 39 unless clinically contraindicated. 
Evaluation must include CT (preferably high-resolution CT) 
and pulmonologist consultation (when the Investigator is not 
a pulmonologist).  The following evaluations must also be 
obtained, as indicated: 
÷ Infectious disease consultation as clinically indicated 
÷ Blood culture and CBC (other blood tests could be 
considered as needed) 
÷ Bronchoscopy and bronchoalveolar lavage if clinically 
indicated and feasible 
÷ Pulmonary function tests 
÷ Pulse oximetry (SpO2) 
÷ Arterial blood gases, as clinically indicated 
÷ Diffusing capacity of the lungs for carbon monoxide 
(DLCO), as clinically indicated 
÷ One blood sample collection for PK analysis as soon 
as ILD is suspected, if feasible 
÷ Other tests, as clinically indicated 
If a non-inflammatory/infectious etiology is confirmed by 
the Investigator, treat accordingly and resumption of 
U3-1402 may occur after discussion between the 
Investigator and Sponsor. 
All events of ILD regardless of severity or seriousness will 
be followed until resolution including after drug 
discontinuation. 


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Worst Toxicity NCI-
CTCAE Version 5.0 
Grade (unless 
otherwise specified) 
Schedule Modification for U3-1402 
Grade 1 
The administration of U3-1402 must be delayed.  U3-1402 
can be restarted only if the event is fully resolved to Grade 0: 
÷ If resolved in f28 days from day of onset, maintain 
dose. 
÷ If resolved in >28 days from day of onset, reduce dose 
1 level. 
Toxicity management: 
÷ Monitor and closely follow-up in 2 to 7 days for onset 
of clinical symptoms and pulse oximetry. 
÷ Consider follow-up imaging in 1-2 weeks (or as 
clinically indicated). 
÷ Consider starting systemic steroids (eg, at least 0.5 
mg/kg/day prednisone or equivalent) until 
improvement, followed by gradual taper over at least 
4 weeks. 
÷ If worsening of diagnostic observations despite 
initiation of corticosteroids, then follow Grade 2 
guidelines (if subject is asymptomatic, then subject 
must still be considered as Grade 1 even if steroid 
treatment is given). 
Grade 2 
Permanently discontinue subject from study treatment. 
Toxicity management: 
÷ Promptly start systemic steroids (eg, at least 
1 mg/kg/day prednisone or equivalent) for a minimum 
of 14 days or until complete resolution of clinical 
symptoms and CT chest findings, followed by gradual 
taper over at least 4 weeks. 
÷ Monitor symptoms closely. 
÷ Re-image as clinically indicated. 
÷ If worsening or no improvement in diagnostic 
observations in 5 days, 
÷ Consider increasing dose of steroids (eg, 2 
mg/kg/day prednisone or equivalent) and 
administration may be switched to IV (eg, 
methylprednisolone). 
÷ Re-consider additional work-up for alternative 
etiologies as described above. 
÷ Escalate care as clinically indicated. 


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Worst Toxicity NCI-
CTCAE Version 5.0 
Grade (unless 
otherwise specified) 
Schedule Modification for U3-1402 
Grade 3 and 4 
Permanently discontinue subject from study treatment. 
Toxicity management: 
÷ Hospitalization required. 
÷ Promptly initiate empiric high-dose 
methylprednisolone IV treatment (eg, 500-1000 
mg/day for 3 days), followed by at least 1.0 mg/kg/day 
of prednisone (or equivalent) for a minimum of 
14 days or until complete resolution of clinical 
symptoms and chest CT findings, followed by gradual 
taper over at least 4 weeks. 
÷ Re-image as clinically indicated. 
÷ If still no improvement within 3 to 5 days, 
÷ Re-consider additional work-up for alternative 
etiologies as described above. 
÷ Consider other immuno-suppressants and/or treat 
per local practice. 
Eye disorders 
Ocular 
Grade 3 
Delay dose until resolved to fGrade 2, then: 
÷ If resolved in f7 days, resume U3-1402; 
÷ If resolved in >7 days, then reduce U3-1402 by 1 dose 
level. 
Ophthalmologist consultation as necessary. 
Grade 4 
Discontinue subject from U3-1402. 
Ophthalmologist consultation as necessary. 
Renal and urinary disorders 
Creatinine 
increased 
Grade 3 (>3.0 × 
baseline; >3.0 - 6.0 × 
ULN) 
Delay dose until resolved to fGrade 1 or baseline, then 
reduce U3-1402 by 1 dose level. 
Grade 4 (>6.0 × ULN) 
Discontinue subject from U3-1402. 
Hepatobiliary disorders 
AST or ALT 
increased without 
TBL increased 
Grade 2 (>3.0 - 5.0 × 
ULN if baseline was 
normal; >3.0 - 5.0 × 
baseline if baseline was 
abnormal) 
Continue U3-1402. 
In subjects without liver metastasis, monitor AST/ALT 24 
to 72 hours later, and continue regular monitoring until 
resolution. 


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Worst Toxicity NCI-
CTCAE Version 5.0 
Grade (unless 
otherwise specified) 
Schedule Modification for U3-1402 
Grade 3 (>5.0 - 20.0 × 
ULN if baseline was 
normal; >5.0 - 20.0 × 
baseline if baseline was 
abnormal)  
In subjects without liver 
metastases and subjects 
with liver metastases and 
baseline level f 3 x 
ULN. 
Delay U3-1402 dose until resolved to fGrade 1, then: 
÷ If resolved in f7 days, resume U3-1402; 
÷ If resolved in >7 days, then reduce U3-1402 by 1 dose 
level. 
>8.0 - 20.0 x ULN if 
baseline was normal; 
>8.0 - 20.0 x baseline if 
baseline was abnormal 
In subjects with liver 
metastases, if the 
baseline level was > 3 x 
ULN. 
Delay U3-1402 dose until resolved to f baseline level, then: 
÷ If resolved in f7 days, resume U3-1402; 
÷ If resolved in >7 days, then reduce U3-1402 by 1 dose 
level. 
Grade 4 (>20.0 × ULN if 
baseline was normal; 
>20.0 × baseline if 
baseline was abnormal) 
Discontinue subject from U3-1402. 
Gastroenterologist or hepatologist consultation as necessary. 
TBL increased 
Grade 2 (>1.5 - 3.0 × 
ULN if baseline was 
normal; >1.5 - 3.0 × 
baseline if baseline was 
abnormal) 
If no documented Gilbert9s syndrome or liver metastases at 
baseline, delay U3-1402 dose until resolved to fGrade 1, 
then: 
÷ If resolved in f7 days, resume U3-1402; 
÷ If resolved in >7 days, reduce U3-1402 by 1 dose 
level. 
If documented Gilbert9s syndrome or liver metastases at 
baseline, continue U3-1402. 
Grade 3 (>3.0 - 10.0 × 
ULN if baseline was 
normal; >3.0 - 10.0 × 
baseline if baseline was 
abnormal) 
If no documented Gilbert9s syndrome or liver metastases at 
baseline, delay U3-1402 dose until resolved to fGrade 1, 
then: 
÷ If resolved in f7 days, reduce U3-1402 by 1 dose 
level; 
÷ If resolved in >7 days, discontinue subject from 
U3-1402. 
If documented Gilbert9s syndrome or liver metastases at 
baseline, delay U3-1402 dose until resolved to fGrade 2, 
then: 
÷ If resolved in f7 days, reduce U3-1402 by 1 dose 
level; 
÷ If resolved in >7 days, discontinue subject from 
U3-1402. 


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Worst Toxicity NCI-
CTCAE Version 5.0 
Grade (unless 
otherwise specified) 
Schedule Modification for U3-1402 
Grade 4 (>10.0 × ULN if 
baseline was normal; 
>10.0 × baseline if 
baseline was abnormal) 
Discontinue subject from U3-1402. 
AST or ALT 
increased and TBL 
increased 
AST or ALT g3 × ULN 
with simultaneous TBL 
þ2 × ULN 
Delay U3-1402 until drug-induced liver injury can be ruled 
out.  The Investigator must consult with a gastroenterologist 
or hepatologist as needed, and the subject must be treated 
accordingly. 
Monitor AST/ALT and TBL twice weekly until resolution or 
return to baseline. 
It is strongly recommended to perform a full diagnostic 
workup, to exclude alternative causes such as viral or 
autoimmune hepatitis, alcoholic liver injury, biliary tract 
disorders, or hemodynamic abnormalities.  Results from 
diagnostic workup (including, for example: INR, direct 
bilirubin, serologic tests for Hepatitis A, B, and C; alcohol 
use, ultrasound, MRI, CT scan, concomitant medication use, 
immunoglobulin levels, ECHO) must be recorded within the 
eCRF. 
If drug-induced liver injury is ruled out, the subject must be 
treated accordingly, and resumption of U3-1402 may occur 
after discussion between the Investigator and Sponsor.  
U3-1402 will be permanently discontinued if drug induced 
liver injury cannot be ruled out from diagnostic workup. 
AST or ALT > 3.0 x 
ULN (if liver 
metastases are 
present, >5 ×ULN) 
for those subjects 
with known 
Hepatitis B and/or 
Hepatitis C 
infection at baseline 
-- 
Delay U3-1402 until reactivation of Hepatitis B and/or 
Hepatitis C can be ruled out.   
Perform HBV DNA and/or HCV RNA to rule out 
reactivation of Hepatitis B and/or Hepatitis C, respectively. 
Hepatologist and infectious disease consultations are 
recommended.  
If reactivation of Hepatitis B and/or Hepatitis C is 
confirmed, permanently discontinue U3-1402. 
Gastrointestinal disorders 
Nausea 
Grade 3 (inadequate oral 
caloric or fluid intake; 
tube feeding, TPN, or 
hospitalization indicated) 
Delay U3-1402 until resolved to fGrade 1, and consider 
treatment with anti-emetics and/or corticosteroids as per 
Investigator9s judgment and local/institutional guidelines, 
then: 
÷ If resolved to fGrade 1 in f14 days resume U3-1402; 
÷ If does not resolve to fGrade 1 in >14 days reduce 
U3-1402 dose by 1 level. 


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Worst Toxicity NCI-
CTCAE Version 5.0 
Grade (unless 
otherwise specified) 
Schedule Modification for U3-1402 
Vomiting 
Grade 3 (Tube feeding, 
TPN, or hospitalization 
indicated) 
Delay U3-1402 until resolved to fGrade 1, and consider 
treatment with antiemetics and/or corticosteroids as per 
Investigator9s judgment and local/institutional guidelines, 
then: 
÷ If resolved to fGrade 1 in f7 days, resume U3-1402; 
÷ If does not resolve to fGrade 1 in >7 days, reduce 
U3-1402 by 1 dose level. 
Grade 4 
Discontinue subject from U3-1402 
Based on currently available clinical safety data for U3-1402, it is recommended that subjects receive 
premedication with antiemetic agents. Suggested agents include a 5-HT3 blocker in combination with another 
antiemetic or corticosteroid approximately 30 minutes prior to U3-1402 infusion. Choice of agents is based on 
investigator9s discretion as per local/institutional guidelines. Investigators must also consider providing subjects 
with an antiemetic regimen for subsequent use as needed. 
Diarrhea/ 
Colitis 
Grade 3 
Delay U3-1402 until resolved to fGrade 1, and consider 
treatment per local practice/guidelines, then: 
÷ If resolved to fGrade 1 in f7 days, resume U3-1402; 
÷ If resolved to fGrade 1 in >7 days, then reduce 
U3-1402 by 1 dose level. 
Grade 4 
Life-threatening 
consequences; urgent 
intervention indicated 
Discontinue subject from U3-1402. 
Mucositis oral 
Grade 3 
Delay U3-1402 until resolved to fGrade 1, and consider 
treatment per local practice/guidelines, then: 
÷ If resolved to fGrade 1 in f14 days, resume U3-1402; 
÷ If resolved to fGrade 1 in >14 days, then reduce 
U3-1402 by 1 dose level. 
Grade 4  
Life-threatening 
consequences; urgent 
intervention indicated 
Discontinue subject from U3-1402. 
Other adverse 
events (non-
laboratory or 
laboratory) 
Grade 3 
Delay U3-1402 until resolved to fGrade 1, or baseline level, 
then: 
÷ If resolved in f7 days, resume U3-1402; 
÷ If resolved in >7 days, then reduce U3-1402 by 1 dose 
level. 
Grade 4  
Life-threatening 
consequences; urgent 
intervention indicated 
Discontinue subject from U3-1402. 
ANC = absolute neutrophil count; AST = aspartate aminotransferase; ALT = alanine aminotransferase; 
CBC = complete blood count; CT = computerized tomography; DNA = deoxyribonucleic acid; ECHO = 
echocardiogram; eCRF = electronic case report form; G-CSF = granulocyte-colony stimulating factor; HBV = 
hepatitis B virus; HCV = hepatitis C virus; INR = international normalized ratio; ILD = interstitial lung disease; 


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LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; NCI-CTCAE = National Cancer 
Institute Common Terminology Criteria for Adverse Events; PK = pharmacokinetics; QTcF = QT interval corrected 
for heart rate using Fridericia9s formula; RNA = ribonucleic acid;SpO2 = peripheral capillary oxygen saturation; 
TBL = total bilirubin; TPN = total parenteral nutrition; ULN = upper limit of normal. 
During study treatment, subjects who develop systolic and/or diastolic hypertension that is 
deemed by the Investigator to be clinically significant should receive treatment with 
anti-hypertensive therapy according to the Investigator9s judgment and local institutional 
guidelines. 
In addition, Investigators may consider dose reductions or discontinuations of the study drug 
according to the subject9s condition and after discussion with Daiichi Sankyo9s Medical Monitor 
or designee. 
5.5. 
Method of Assessing Treatment Compliance 
All drugs used for the study treatment will be administered by the Investigator or other 
designated study personnel.  Therefore, treatment compliance will be guaranteed as long as the 
subject attends each visit for the administration of study treatment. 
5.6. 
Prior, Concomitant and Prohibited Medications 
Therapies used from the time the subject signs the ICF for study participation to the 40-Day F/U 
Visit (+ 7 days) after the last administration of U3-1402 will be recorded in the eCRF.  
Prophylactic therapies (including any required premedications), prior therapies and all 
concomitant therapies will be recorded in the eCRF.  Based on currently available clinical safety 
data for U3-1402, it is recommended that patients receive premedication with antiemetic agents. 
Refer to Table 5.2. 
All therapies received by subjects within 35 days prior to enrollment will be recorded as prior 
therapies.  Concomitant therapies include all prescription, over-the- counter, and herbal 
remedies. 
Therapies Requiring a Washout Period Before Enrollment 
The following medications/therapies and products require a washout period before enrollment: 
÷ Whole brain radiation therapy g14 days or stereotactic brain radiation therapy 
g7 days; 
÷ Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a 
previous cancer treatment regimen or clinical study, g14 days or 5 half-lives, 
whichever is longer; 
÷ Monoclonal antibodies other than immune checkpoint inhibitors, such as 
bevacizumab (anti-VEGF) and cetuximab (anti-EGFRs) g28 days; 
÷ Immune checkpoint inhibitor therapy g21 days; 
÷ Major surgery (excluding placement of vascular access) g28 days; 
÷ Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of 
radiation g28 days or palliative radiation therapy g14 days. 


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÷ Chloroquine or hydroxychloroquine >14 days 
Prohibited Therapies/Products 
The following medications/therapies and products will be prohibited during the Treatment Period 
through 40 days after the last dose of U3-1402: 
÷ Other anticancer therapy, including cytotoxic chemotherapy, immune checkpoint 
inhibitors, or targeted agents 
÷ Live virus vaccination (beginning from 28 days prior to Cycle 1 Day) 
÷ Other investigational therapeutic agents 
÷ Radiotherapy, except for palliative radiation (as long as the radiation field does not 
include a measurable lesion or does not interrupt treatment for more than 28 days 
from the planned date of administration [ie, 49 days from the last infusion date]). 
Radiotherapy to the thorax is also prohibited.  
÷ Concomitant use of chronic systemic (IV or oral) corticosteroids (ie, >10 mg 
prednisone or equivalent anti-inflammatory activity) or other immunosuppressive 
medications except for managing AEs 
÷ Chloroquine or hydroxychloroquine 
Refer to Section 13.9 for further instructions. 
Restricted Therapies/Products 
Subjects are permitted to receive the following only when absolutely necessary: 
÷ Investigators9 discretion/clinical judgment is recommended in accordance with the 
institutional guidelines for the following: 
ý Prophylactic or supportive treatment for expected toxicities, including 
management of study drug  
ý Hematopoietic growth factors used for prophylaxis or treatment  
ý Bisphosphonates (eg, pamidronate or zoledronate) or denosumab for pain 
management and palliation of bony metastases, or treatment of osteoporosis 
÷ Subjects who wear contact lenses must discontinue wearing their lenses if they have 
any mild to moderate eye symptoms (CTCAE Grade f2) while receiving treatment 
until at least 1 week after symptoms have resolved.  If a subject has a recurrence of 
eye symptoms or experiences any severe (CTCAE Grade g3) ocular events they must 
discontinue wearing their contact lenses until at least 1 week after treatment is 
permanently discontinued.  Subjects must not use any eye drops or ointment for 
treatment of eye symptoms, unless agreed upon by a study doctor, at any time during 
the study and g1 week after permanent discontinuation of study treatment. 
Permitted Therapies/Products 
Subjects are permitted to receive prophylactic or supportive treatment as standard of care during 
the Treatment Period, per Investigator9s discretion and institutional guidelines. 


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÷ Palliative radiation to known metastatic sites as long as the radiation field does not 
include a measurable lesion or interrupts treatment for more than 28 days from the 
planned date of administration (ie, 49 days from the last infusion date).  Palliative 
radiotherapy to the thorax is permitted one week after infusion; however, the next 
infusion should start at least two weeks after the radiotherapy.  Whenever possible, 
subjects should have a tumor assessment of the lesion(s) prior to receiving 
radiotherapy in order to rule out progression of disease.  In cases of progression of 
disease, subjects should be discontinued from U3-1402. 
÷ Inhaled or topical steroids or intra-articular steroid injections 
÷ Inactive/killed virus vaccinations  
÷ Menstruating females may receive Depo-Provera or another suppressant of menses 
during the entire course of study treatment.  In addition, after completion of study 
treatment, suppression of menses should be continued until the platelet count is 
g50,000/mm3 without transfusion support 
÷ Subjects taking warfarin should be monitored regularly for changes in prothrombin 
time or international normalized ratio. 
5.6.1. 
Membrane Transport Inhibitors 
A clinical drug-drug interaction study (DS8201-A-A104) fam-trastuzumab deruxtecan, an ADC 
that shares the same linker and payload (MAAA-1181a) as U3-1402, showed that co-
administration of ritonavir (a dual inhibitor of OATP1B/CYP3A) or itraconazole (a strong 
CYP3A inhibitor) increased the MAAA-1181a AUC by 22% and 18%, respectively. This 
magnitude of increase of MAAA-1181a is not considered to indicate a clinically meaningful 
impact on the PK of DS-8201. Although a dedicated study with a P-glycoprotein (P-gp) inhibitor 
was not conducted, since itraconazole and ritonavir have been reported to be strong P-gp 
inhibitors31, the increases in exposure of MAAA-1181a (22% and 18%) can be considered as a 
summed impact of a strong CYP3A4 inhibitor and strong P-gp inhibitor. Therefore, the impact of 
a strong P-gp inhibitor alone on the exposure of MAAA-1181a is expected to be no greater than 
that observed for a dual inhibitor such as itraconazole or ritonovir. 
Although MAAA-1181a was identified in vitro to be a substrate of the efflux transporters breast 
cancer resistance protein (BCRP) and multidrug resistance-associated protein-1MRP-1, no 
dedicated study was conducted to evaluate the effects of BCRP and MRP-1 inhibitors on the 
exposure of MAAA-1181a. Ritonavir has been reported to be an inhibitor of BCRP32,33 and 
MRP134, supporting the conclusion that BCRP and MRP-1 inhibitors are also unlikely to have a 
clinically meaningful effect on exposure of MAAA-1181a. In addition, since the expression of 
MRP-1 in the liver (which mediates the efflux of glucuronidated or sulfateds bile salt 
conjugates35) is low36, the inhibition of MRP1 is expected to have a low impact on the exposure 
of MAAA-1181a. 
In rats, the major excretion pathway of radiolabeled MAAA-1181a was feces via the biliary 
route, and the urinary excretion of MAAA-1181a is low37,38.  MATE2-K (which is involved in 
the excretion of substrates into urine) is expected to have minimal impact on the exposure of 
MAAA-1181a in patients. 


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Section 13.10 provides a link to a Food and Drug Administration list of clinical inhibitors for 
transporters. 
5.7. 
Discontinuation of Study Drug 
The primary reason for permanent discontinuation of U3-1402 treatment administration must be 
recorded.  Reasons for treatment discontinuation include:  
÷ PD per RECIST v1.1 
÷ Clinical progression: provide date (ie, definitive clinical signs of disease progression, 
but a recent radiographic assessment did not meet the criteria for PD according to 
RECIST v1.1) 
÷ AE (See Section 5.4) 
÷ Death 
÷ Pregnancy 
÷ Withdrawal by subject (to discontinue study drug).  NOTE: In this section, this is 
only withdrawal for treatment with study drug and is NOT the same thing as a 
complete withdrawal from the study.  Discuss with the subject that they will remain 
in the study (ie, continue with study visits and assessments, including survival 
follow-up). 
÷ Lost to follow-up 
÷ Protocol violation (specify) 
÷ Study terminated by Sponsor 
÷ Other, specify (eg, Investigator discretion) 
If there is evidence that the subject is receiving benefit from treatment even though the subject 
has met a criterion for discontinuation as listed above, the subject may remain on study treatment 
after discussion with and approval from the Sponsor. 
Discontinued subjects will be followed for survival, either through direct contacts or by 
collecting public records (eg, death certificates) as allowed by local laws. 


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5.8. 
Subject Withdrawal/Discontinuation from the Study 
5.8.1. 
Reasons for Withdrawal 
Subjects may discontinue from the study for any of the following reasons: 
÷ Death 
÷ Withdrawal by subject (from the study).  NOTE: This indicates that the subject 
withdraws consent and refuses to undergo any further study procedures or be 
followed for long-term survival. 
÷ Lost to follow-up  
÷ Study terminated by Sponsor 
÷ Other, specify 
If the reason for study discontinuation is the death of the subject, the options for categorizing the 
primary cause of death are PD or AE.  If the reason of death is unknown, every effort should be 
made to obtain the primary cause of death.  Only one AE will be recognized as the primary cause 
of death. 
5.8.2. 
Withdrawal Procedures 
If a subject is withdrawn from both the interventional and follow-up portions of the study: 
÷ The Investigator will complete and report the observations as thoroughly as possible 
up to the date of withdrawal, including the date of last dose, date of last contact, and 
the reason for withdrawal. 
÷ If consent for disclosure of future information is also withdrawn, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
÷ The subject may request destruction of any samples taken and not tested, and the 
Investigator must document this in the site study records. 
÷ Study site personnel may use local, regional, and national public records (in 
accordance with local law) to monitor vital status. 
See the Schedule of Events (Table 13.1) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
5.8.3. 
Subject Replacement 
Subjects will not be replaced. 
5.8.4. 
Subject Rescreening Procedures 
The study will allow rescreening once for any subject who has failed to meet the eligibility 
criteria during the time of initial Screening or whose Screening window has elapsed.  The 
Investigator will consult with the Sponsor prior to making the decision to rescreen a subject.  A 
unique subject identification number will be assigned at the time of rescreening.  The initial 
reason that the subject was ineligible for the initial evaluation will be recorded on the Screening 
Log at the site and will be entered into the clinical database.  If a subject undergoes rescreening, 


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the subject must repeat all out-of-window assessments, as specified in the protocol (i.e., 
procedures performed beyond the specified window prior to Cycle 1 Day 1). 
5.8.5. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he/she fails to return for 2 consecutive scheduled 
visits and is unable to be contacted by the study site staff.  Before a subject is deemed lost to 
follow-up, the Investigator or designee will make every effort to regain contact with the subject 
(where possible, using telephone calls, texts, emails, and if necessary, a certified letter to the 
subject9s last known mailing address or local equivalent methods).  These contact attempts 
should be documented. 
If direct contact with the subject is not possible, the site must make every effort to collect 
survival status from public records (eg, obituaries, death certificates) in accordance with local 
laws. 


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6. 
STUDY PROCEDURES 
6.1. 
Screening 
6.1.1. 
Tissue Requirement 
All subjects will be required to provide a pre-treatment tumor biopsy and archival tumor sample 
prior to Cycle 1 Day 1.  A HER3 IHC assay will be used to assign subjects to cohorts.  
The following procedures should be conducted for all subjects: 
Before enrollment 
÷ Obtain a separate signed and dated ICF for tumor screening before any study-related 
procedures or assessments are performed. 
÷ Perform a pre-treatment tumor biopsy and request an archival tumor tissue sample 
(see details in Section 8.3.2).   
ý Subjects may be exempted from the requirement to provide a pre-treatment tumor 
biopsy if the archival tumor tissue was collected within 3 months of screening 
during or after treatment with the last prior cancer treatment and is of sufficient 
quantity defined as 2 cores or 20 slides with adequate tumor tissue content. 
ý An additional archival tissue sample collected greater than 3 months prior to 
screening must be available and of sufficient quantity, as defined above, at the 
time of screening.  If an archival tissue sample (collected greater than 3 months 
prior to screening) is not available, a subject may be included provided the 
pre-treatment tumor biopsy is obtained and after discussion and agreement from 
Sponsor. 
÷ Send tumor tissue to the IHC central testing lab for determination of the HER3 status.  
Refer to the Laboratory Manual for information regarding archival and pre-treatment 
tumor tissue requirements and shipping. 
6.1.2. 
Screening 
The following activities and/or assessments will be performed during the Eligibility Screening 
period.  The Screening period is 35 days; however, a more restrictive window may be specified 
for certain Screening assessments prior to the first dose (see the Schedule of Events [Table 13.1] 
for detailed information): 
÷ Have the subject sign the appropriate ICF(s) prior to initiating any study procedures.   
÷ Review the subject9s demographics, medical and target disease history, and results of 
tests done as part of routine care.  Assess whether subject meets inclusion/exclusion 
criteria specified in Section 4.   
÷ Subject9s medical history, prior cancer history, prior cancer biomarker history, and 
prior cancer medical therapy will be obtained by the Investigator or a qualified 
designee. 


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÷ Untoward medical occurrence (including clinically relevant laboratory values that are 
not symptoms of CRC/vital signs that are out of range) that were diagnosed or known 
to exist prior to the main ICF signature will be recorded in Medical History in the 
eCRF.  Record the start date of any medical occurrence that started after the ICF was 
signed and is ongoing at the time of the Cycle 1 Day 1 on the AE eCRF. 
÷ Perform tumor assessment by computed tomography (CT) or magnetic resonance 
imaging MRI scans of the brain, chest, abdomen, pelvis, and any other sites of disease 
within 28 days prior to Cycle 1 Day 1 (Section 13.4).   
÷ Perform Hepatitis B (Hepatitis B surface antigen [HBsAg]) and Hepatitis C virus 
(HCV Ab) and viral load assessment (if indicated) as described in the eligibility 
criteria within 28 days prior to Cycle 1 Day 1 (see Section 4.2). 
÷ An HIV Ab test is optional unless required by local regulations or Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). If required, perform 
within 28 days prior to Cycle 1 Day 1. 
÷ Urinalysis (Section 9.8).  Urinalysis assessment should be performed within 72 hours 
prior to Cycle 1 Day 1.  Assessments may be repeated as clinically indicated as part of 
a scheduled or unscheduled visit and should include microscopic evaluation as 
clinically indicated. 
÷ Obtain a serum sample for pregnancy testing in women of childbearing potential 
within 72 hours of enrollment for all female subjects of childbearing potential.  A 
positive urine pregnancy test result must immediately be confirmed using a serum 
test.  Perform repeat pregnancy tests (urine or serum test per institutional guideline) 
72 hours before infusion (BI) of each cycle and at end of treatment. 
÷ Vital sign assessments include systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature.  Blood pressure and pulse rate should be 
measured after the subject has rested in a supine position for 5 minutes.  Vital sign 
assessments should be performed within 28 days prior to Cycle 1 Day 1 (Section 9.9). 
÷ Peripheral oxygen saturation (SpO2) within 28 days prior to Cycle 1 Day 1 (Note: 
When CT/MRI is conducted, SpO2 should also be obtained per Investigator 
discretion.) (Section 9.12) 
÷ Ophthalmologic assessments include visual acuity test (Early Treatment Diabetic 
Retinopathy Study [ETDRS], Snellens, or Landolt), slit lamp examination, 
fundoscopy, and tonometry and have to occur within 7 days prior to Cycle 1 Day 1. 
Assessment may be repeated as clinically indicated as part of an unscheduled visit. 
(Section 9.12). 
÷ Perform a complete physical examination and record weight and height within 
28 days prior to Cycle 1 Day 1 (Section 9.11). 
÷ Assess functional status using the ECOG PS Scale within 28 days prior to Cycle 1 
Day 1 (Section 13.6).   
÷ Perform a 12-lead electrocardiogram (ECG) within 28 days prior to Cycle 1 Day 1.  
Subjects should rest supine for at least 10 minutes prior to the ECG assessment.  The 
same test must be used for screening, EOT, and as clinically indicated (Section 9.10). 


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÷ LVEF measured by ECHO or MUGA within 28 days prior to Cycle 1 Day 1.  The 
same test must be used for the subject at screening, EOT, and as clinically indicated.  
(Section 9.12). 
÷ Obtain blood samples for safety laboratories (Section 9.8).  Hematology/chemistry 
assessments should be obtained within 14 days prior to Cycle 1 Day 1. 
÷ Assess for AEs/serious adverse events (SAEs) and review prior medications 
(Section 9). 
÷ Coagulation test within 14 days prior to Cycle 1 Day 1 - Subjects taking warfarin 
should be monitored regularly for changes in prothrombin time or international 
normalized ratio. 
6.2. 
Randomization 
Randomization is not applicable for this study. 
6.3. 
Study Assessments 
6.3.1. 
Cycle 1 and Subsequent Cycles  
The following activities and/or assessments will be performed during the Treatment Period 
(details are provided in the Schedule of Assessments; see Table 13.1). 
Day 1; BI (all cycles) 
÷ Obtain a urine sample for pregnancy testing in women of childbearing potential 
within 72 hours of enrollment for all female subjects of childbearing potential.  A 
positive urine pregnancy test result must immediately be confirmed using a serum 
test.  Perform repeat pregnancy tests (urine or serum test per institutional guideline) 
72 hours before infusion of each cycle and at end of treatment. 
÷ Complete physical examination and record weight (Section 9.11). 
÷ Assess functional status using the ECOG PS Scale (Section 13.6). 
÷ Carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA 19-9), C-reactive protein 
(CRP) (Section 9.8).  
÷ Obtain blood samples for safety laboratories (Section 9.8).  Collect additional safety 
samples on Cycle 1 Day 1, Day 8, Day 15, Cycle 2 Day 1, and Cycle 3, Day 1, Day 8 
and Day 15, Cycle 4 and subsequent cycles on Day 1.   
÷ Obtain the biomarker samples Day 1 of each cycle and on Cycle 2 Day 3 (rather than 
Day 1) to coincide with collection of the on-treatment tumor biopsy (Section 8.3).   
÷ Administer U3-1402 (Section 5.2.4) 
Day 1; BI and/or end of infusion (EOI; per cycle) 
÷ Obtain blood samples for PK analyses (Section 8.1) on visits per the Schedule of 
Events (Table 13.1).   


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ý Initial 12 subjects in each cohort (12 subjects in Cohort 1 and 12 subjects in 
Cohort 2):  Prior to interim futility analysis, PK blood samples will be collected 
intensively in Cycle 1 and 3 and sparsely in Cycles 2, 4, 6 and 8 (for specific PK 
sampling timepoints, see Table 13.1).   
ý Blood samples for PK from all other subjects in each cohort will be collected 
under a less-intensive schedule (see Table 13.1). 
÷ Vital signs including SpO2 measured BI and EOI on Day 1 of all cycles and 
additionally on Day 8 and Day 15 of Cycle 1 (Section 9.9).  Assessments will include 
systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature.  Blood pressure and pulse rate should be measured after the subject has 
rested in a supine position for 5 minutes.   
Other 
÷ Collect a single blood sample for pharmacogenomic analysis at EOI on Cycle 1 Day 1 
or at any time during the study (Section 8.4.1). 
÷ Collect blood samples for ADA analysis on Cycles 1 and 2, Day 1 (BI), on Cycle 1 
Day 8, and on Cycle 4, Day 1 (-5 days), and every 2 cycles thereafter (Section 8.4).  
÷ Collect on-treatment tumor biopsy Cycle 2, Day 3 (±1 day) (Section 8.3.2).  The 
on-treatment tumor biopsy sample (with minimum of 2 cores or 20 slides) will be 
analyzed for HER3 protein expression using IHC and ribonucleic acid (RNA) 
expression profiling and genomic alteration using next generation sequencing (NGS).  
One core will be flash frozen for analysis of MAAA-1181a using fit-for-purpose 
qualified assay at the bioanalytical laboratory.  Consent for this biopsy should be 
documented in the tissue consent portion of the appropriate ICF.  Soft tissue tumor 
biopsy should be obtained from the primary tumor or metastatic site.  Blood for 
hematology must be obtained within 2 days of the tumor biopsy and results must be 
reviewed by the Investigator prior to obtaining a tumor biopsy.  After approximately 
10 on-treatment tumor biopsies per cohort have been collected, the Sponsor will 
notify the Investigator of a change in this requirement. If the subject does not consent 
to the mandatory on-treatment tumor biopsy, blood sample for biomarkers will be 
collected on Cycle 2 Day 1.  If consent is not obtained to perform the mandatory on-
treatment tumor biopsy, the PK sample at Cycle 2 Day 3 is not needed. 
÷ Perform tumor assessment by CT or MRI scans of the brain (if stable brain metastasis 
was present at baseline), chest, abdomen, pelvis, and any other sites of disease every 
6 weeks (± 7 days) from Cycle 1 Day 1 for the first 24 weeks then every 12 weeks 
(± 7 days) thereafter, independent of treatment cycle, until documented disease 
progression by BICR per RECIST v1.1, death, lost to follow-up, or withdrawal of 
consent (Section 7.1). 
÷ AE/SAE assessments at all visits and review concomitant medications (Section 9). 


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6.4. 
End of Treatment 
The EOT is defined as the date the Investigator decides to discontinue study treatment.  The 
following EOT procedures will be performed as specified in the Schedule of Events.  This visit 
occurs within 7 days after the final dose of U3-1402 or before the start of new anticancer 
treatment, whichever comes first.  If the decision to withdraw/discontinue U3-1402 occurs more 
than 7 days after the final dose of U3-1402, then this visit should occur within 7 days after this 
decision or before the start of new anticancer treatment; whichever comes first.  If the EOT 
assessments have been performed within 30 d (± 7 d) of their last treatment, they can be 
considered to be the EOT data and there is no need to repeat them; otherwise, these assessments 
need to be repeated.  If the EOT Visit occurs g40 days after the final dose of U3-1402, the 
40-Day F/U Visit does not need to be conducted. 
The following procedures should be obtained/performed per the Schedule of Events 
(Table 13.1): 
÷ On-treatment tumor biopsy (optional) (Section 8.3.2).  An optional EOT on-treatment 
tumor biopsy will also be performed at the time of progression or discontinuation 
from study treatment with minimal 2 cores or 20 slides (if provided as slides).  
Consent for this biopsy should be documented in the tissue consent portion of the 
appropriate ICF.  Tumor biopsy should be obtained from primary tumor or metastatic 
site, preferably from a site of recent radiographic progression, within 40 days of the 
last dose of U3-1402, and prior to starting any new anticancer treatment. 
÷ Collect urine for urinalysis (Section 9.8). 
÷ Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential within 72 hours of enrollment for all female subjects of childbearing 
potential.  A positive urine pregnancy test result must immediately be confirmed 
using a serum test.  Perform repeat pregnancy tests (urine or serum test per 
institutional guideline) 72 hours before infusion of each cycle and at end of treatment.   
÷ Complete physical examination and record weight (Section 9.11). 
÷ Vital signs (Section 9.9). Assessments will include systolic and diastolic blood 
pressure, pulse rate, respiratory rate, and body temperature.  Blood pressure and pulse 
rate should be measured after the subject has rested in a supine position for 5 minutes.   
÷ Perform SpO2 (Section 9.12).  When CT/MRI is conducted, SpO2 should also be 
obtained per Investigator discretion. 
÷ Assess functional status using the ECOG PS Scale (Section 13.6).  
÷ Obtain blood samples for the following: 
ý Safety laboratories (Section 9.8); 
ý Biomarkers (Section 8.3); 
ý CEA, CA 19-9, CRP (Section 9.8); 
ý ADA (Section 8.4); 


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ý PK analysis (Section 8.1).  PK assay can be performed on the ADA sample 
collected. 
÷ LVEF measured by ECHO or MUGA.  The same test must be used for the subject at 
screening, EOT, and as clinically indicated.  (Section 9.12).   
÷ Perform a 12-lead ECG.  Subjects should rest supine for at least 10 minutes prior to 
the ECG assessment.  The same test must be used for screening, EOT, and as 
clinically indicated (Section 9.10). 
÷ Ophthalmologic assessments include visual acuity test (ETDRS, Snellens, or 
Landolt), slit lamp examination, fundoscopy, and tonometry.  A 40 +7-Day F/U 
assessment is only required if an on-treatment assessment was abnormal at the time of 
discontinuation of study therapy, to confirm reversibility of the abnormality. 
÷ AEs/SAEs assessment and review concomitant medications (Section 9). 
6.5. 
40-day Post-treatment Follow-up 
Assessments to monitor ongoing safety, and immunogenicity in the follow-up period will be 
performed 40 days (+7 days) after the last dose of U3-1402 or before starting new anticancer 
treatment, whichever comes first.  For detailed explanations of the timing and nature of 
assessments performed, refer to the Schedule of Events (Table 13.1). 
÷ Perform tumor assessment by CT or MRI scans of the brain (if stable brain metastasis 
was present at baseline), chest, abdomen, pelvis, and any other sites of disease every 
6 weeks (± 7 days) from Cycle 1 Day 1 for the first 24 weeks then every 12 weeks 
(± 7 days) thereafter, independent of treatment cycle, until documented disease 
progression by BICR per RECIST v1.1, death, lost to follow-up, or withdrawal of 
consent.   
÷ Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential within 72 hours of enrollment for all female subjects of childbearing 
potential.  A positive urine pregnancy test result must immediately be confirmed 
using a serum test.   
÷ Complete physical examination and record weight (Section 9.11). 
÷ Vital signs (Section 9.9). Assessments will include systolic and diastolic blood 
pressure, pulse rate, respiratory rate, and body temperature.  Blood pressure and pulse 
rate should be measured after the subject has rested in a supine position for 5 minutes 
÷ Perform SpO2 (Section 9.12).  When CT/MRI is conducted, SpO2 should also be 
obtained per Investigator discretion. 
÷ Assess functional status using the ECOG PS Scale (Section 13.6).  
÷ Obtain blood samples for the safety laboratories (Section 9.8); 
÷ AEs/SAEs assessment and review medications (Section 9). 


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6.6. 
Every 3 Month Follow-up 
All subjects should be followed for survival at least every 3 months (±14 days) after 
discontinuing study drug.   
For detailed explanations of the timing and nature of assessments performed in the follow-up 
period refer to the Schedule of Events (Table 13.1). 
÷ For subjects with positive ADA, additional serum ADA samples should be collected 
every 3 months (± 30 days) for up to 1 year after the last dose of U3-1402, unless one 
or more of the following occurs sooner: the ADA becomes negative; the ADA titer 
falls below baseline if ADA was measurable prior to Cycle 1 Day 1; the subject starts 
another therapy for cancer, or the subject withdraws consent from the study 
(Section 8.4). 
÷ Obtain blood samples for the PK analysis per the cohort9s specifications in Table 13.1 
(see Section 8.1).  The PK assay can be performed on the ADA sample collected. 
÷ Survival monitoring will continue until death, withdrawal of consent by subject from 
the study (Note: this indicates that the subject withdraws consent and refuses to 
undergo any further study procedures or be followed for long-term survival), lost to 
follow-up, or study termination by Sponsor, whichever event occurs earlier. 
÷ Review new anticancer treatment. 


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7. 
EFFICACY ASSESSMENTS 
7.1. 
Tumor Assessments for Efficacy  
Clinical activity of U3-1402 will be assessed by evaluating tumor response. 
Tumor assessments will be conducted as indicated in the Schedule of Events (Table 13.1).  At 
screening, perform radiographic tumor assessments (CT/MRI) of the chest, abdomen, pelvis, 
brain, and all sites of disease.  Investigator determined tumor radiologic assessments of the brain 
(if stable brain metastasis was present at baseline), chest, abdomen, and pelvis and other relevant 
anatomic locations where imaging was performed at screening or newly suspected disease should 
be performed every 6 weeks (± 7 days) from Cycle 1 Day 1 for the first 24 weeks then every 
12 weeks (± 7 days) thereafter, independent of treatment cycle, and will continue to be 
performed until documented disease progression by BICR per RECIST v1.1 (Section 13.4), 
death, lost to follow-up, or withdrawal of consent (withdrawal by subject from the study as 
indicated on the end of study form: NOTE: This indicates that the subject withdraws consent and 
refuses to undergo any further study procedures or be followed for long-term survival).  Subjects 
who discontinue study treatment for any reason other than documented disease progression by 
BICR, death, lost to follow-up, or withdrawal of consent by the subject will continue to undergo 
tumor assessments at the same frequency of every 6 weeks (±7 days) from Cycle 1 Day 1 for the 
first 24 weeks then every 12 weeks (±7 days) during the Follow-up period. 
The same methodology (CT or MRI) and scan acquisition techniques (including use or nonuse of 
IV contrast unless medically infeasible, ie, newly developed AE or allergy to contrast agent) as 
were used for the screening assessments should be used throughout the study for all assessments 
for each subject unless prior approval is obtained from the Sponsor.  Unscheduled tumor 
assessments may be conducted if progression is suspected.  Tumor assessments should not be 
delayed by dose interruptions; they are timed relative to Cycle 1 Day 1.  Tumor assessments 
should be performed per RECIST v1.1 (Section 13.4).   
Objective responses must be confirmed at least 4 weeks later (eg, generally at the next tumor 
assessment time point).  Also, perform CT or MRI of the brain within a target of 1 week after a 
subject achieves a complete response (CR).   
7.2. 
Appropriateness of Selected Efficacy Assessment(s) 
Considerable medical need in advanced or metastatic CRC and lack of effective treatment 
options underpin the urgency for finding new effective therapeutic agents.   
ORR as assessed by BICR per RECIST v1.1 was selected as the primary endpoint for this study.  
Although OS is considered the most reliable efficacy endpoint for cancer trials, this endpoint 
requires a large sample size and long waiting times for an event to happen and is more 
appropriate for randomized controlled studies.  Replacing OS by a surrogate survival endpoint 
such as ORR or PFS allows determination of the effects of a new treatment in less time, using a 
smaller sample size and potentially with fewer confounding effects from prior lines of 
treatment.40,41   


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
8.1. 
Pharmacokinetic (PK) Assessment(s) 
Blood samples for U3-1402 PK analyses will be obtained at the time points specified in the 
Schedule of Events (Table 13.1).  Additionally, samples may be obtained at any time during the 
study if deemed clinically necessary.  At each time point, blood will be collected for U3-1402 
PK analysis.  Instructions for the collection and handling of blood samples and shipping of serum 
samples for U3-1402 PK analysis are included in the Laboratory Manual.  The actual time of 
U3-1402 administration (start of infusion and EOI) and the exact time of blood sampling for 
U3-1402 PK analysis must be recorded on the eCRF. 
If time points coincide for different blood samplings, the PK samples should be taken at the 
exact nominal time point, followed by serum chemistry, hematology, and then biomarker 
samples.  If time points of procedures coincide with blood sampling, ECG and vital signs should 
be taken immediately prior to PK sampling time. 
The U3-1402 PK samples will be shipped to a central laboratory for forwarding to a 
Sponsor-designated bioanalytical laboratory.  Serum concentrations of U3-1402 (ADC) and total 
anti-HER3 antibody (naked antibody plus ADC) will be measured with validated 
analyte-specific ligand binding assays.  Serum concentrations of the released payload 
MAAA-1181a will be measured with validated liquid chromatography/mass spectrometry assay. 
The serum PK parameters listed in Table 8.1 of U3-1402 (ADC, total anti-HER3 antibody and 
MAAA-1181a) will be estimated using standard noncompartmental methods: 
÷ Cmax = maximum serum concentration; 
÷ Tmax = time to reach maximum serum concentration; 
÷ Ctrough = trough serum concentration; 
÷ AUClast = area under the serum concentration-time curve up to the last quantifiable 
time;  
÷ AUCtau = area under the serum concentration-time curve during dosing interval. 
The other PK parameters (elimination rate constant associated with the terminal phase [Kel], 
terminal elimination half-life, total body clearance, volume of distribution based on the terminal 
phase, and volume of distribution at steady state) will be calculated if data permit.  
Initial 12 subjects in each cohort (12 subjects in Cohort 1 and 12 subjects in Cohort 2): 
Pharmacokinetic blood samples will be collected intensively prior to the interim futility analysis 
during Cycles 1 and 3 and sparsely in Cycles 2, 4, 6 and 8 (before and at EOI) (see the Schedule 
of Events in Table 13.1).  
PK samples from all other subjects, in each cohort, will be collected under a less-intensive 
schedule (see the Schedule of Events in Table 13.1). 


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Table 8.1: 
Pharmacokinetic Parameters 
Subject Population 
Analyte 
PK parameters 
Initial 12 subjects in Cohort 1 
and initial 12 subjects in 
Cohort 2 
U3-1402 (ADC, total anti-HER3 
antibody, and MAAA-1181a) 
Cmax, Tmax, Ctrough, AUClast, 
and AUCtau 
All other subjects 
U3-1402 (ADC, total anti-HER3 
antibody, and MAAA-1181a) 
Cmax, Tmax, Ctrough 
ADC = antibody drug conjugate; AUClast = area under the serum concentration-time curve up to the last 
quantifiable time; AUCtau = area under the serum concentration-time curve during dosing interval; Cmax = 
maximum serum concentration; Ctrough = trough serum concentration; HER3 = human epidermal growth factor 
receptor 3; Tmax = time to reach maximum serum concentration.  
8.2. 
Pharmacodynamic Assessment(s) 
Not applicable. 
8.3. 
Biomarker Assessment(s) 
Subjects will be requested to provide a tumor sample for assessing HER3 expression and other 
biomarkers at study entry, during the treatment period, and at EOT; see the Schedule of Events 
(Table 13.1) for details of assessments and timings.   
Detailed instructions for the collection, handling, and shipping of biomarker samples are outlined 
in the Laboratory Manual.  
All subjects will be asked to provide written consent to provide tumor tissue (archival tissue, 
pre-treatment tumor biopsy, and on-treatment tumor biopsy) and blood samples for research 
purposes prior to study entry.  The tumor biopsy will be performed if medically feasible.   
In addition, biomarker research including analysis of genes or DNA, RNA, proteins and 
metabolites may be conducted on blood/tumor tissue.  This research would extend the search for 
other potential biomarkers related to the effects of U3-1402 treatment.  See Section 8.4.1.3 for 
storage and disposal of specimens.  
8.3.1. 
HER3 Protein Expression 
The level of HER3 protein expression will be assessed using the archival and pre-treatment 
biopsy provided by the subject.  Subjects may be exempted from the requirement to provide a 
pre-treatment tumor biopsy if the archival tumor tissue was collected within 3 months of 
screening during or after treatment with the last prior cancer treatment and is of sufficient 
quantity (defined as 2 cores or 20 slides with adequate tumor tissue content).  An additional 
archival tissue sample collected greater than 3 months prior to screening must be available and of 
sufficient quantity, as defined above, at the time of screening.  If an archival tissue sample 
(collected greater than 3 months prior to screening) is not available, a subject may be included 
provided the pre-treatment tumor biopsy is obtained and after discussion and agreement from the 
Sponsor.  The level of HER3 expression in pre-study treatment, on-study treatment, and 
post-study treatment will be assessed with the tumor biopsy sample.  


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The slides from all subjects will be stained using an investigational device to measure HER3 
protein expression.  Subjects will be designated to each cohort based on the HER3 expression as 
(3+, 2+, 1+ or 0) using the algorithm that has been established for HER2 IHC testing in gastric 
cancer.42  
8.3.2. 
Tumor Sample Collection 
Refer to the Laboratory Manual for instructions regarding archival and pre-treatment tumor 
tissue handling and shipping. 
Study Entry 
All subjects are required to provide archival tumor tissue and a pre-treatment biopsy with 
adequate tumor tissue content, defined as 2 cores or 20 slides.  Biopsies will be taken from soft 
tissue.  Subjects may be exempted from the requirement to provide a pre-treatment tumor biopsy 
if the archival tumor tissue was collected within 3 months of screening during or after treatment 
with the last prior cancer treatment and is of sufficient quantity, as defined above.  An additional 
archival tissue sample collected greater than 3 months prior to screening should be submitted 
along with the mandatory pre-treatment tumor biopsy sample (or archival tumor tissue sample if 
collected within 3 months of screening).  If an archival tissue sample (collected greater than 
3 months prior to screening) is not available, a subject may be included provided the 
pre-treatment tumor biopsy is obtained and after discussion and agreement from Sponsor 
(Medical Monitor or designee). 
The pre-treatment biopsy and archival tissue will be analyzed for HER3 protein expression at the 
time of enrollment.  Tumor samples must be obtained after the date of informed consent for 
tumor screening.  The pre-treatment tumor biopsy should be obtained from a primary tumor or 
metastatic site, not previously irradiated, and preferably from a site of disease progression.  Any 
tumor material left after HER3 protein expression analysis will be used for exploratory 
biomarker assessment such as gene mutation analysis, gene expression as well as other immune 
marker analyses. 
On-treatment Biopsy  
All subjects will be required to consent to an on-treatment tumor biopsy to understand HER3 
expression dynamics and correlation of HER3 expression with MAAA-1181a delivery, and 
double-stranded-DNA damage.  The biopsy should be performed on Cycle 2, Day 3 (±1 day).  
Collection of the on-treatment biopsy is mandatory (if medically feasible) for all subjects unless 
communicated otherwise from the Sponsor.  Tumor tissue for this biopsy should be obtained 
from the primary tumor or metastatic site.  The on-treatment tumor biopsy samples will be 
analyzed for HER3 expression with IHC, other immune marker, and RNA expression profiling 
using NGS.  One core will be flash frozen for analysis of MAAA-1181a using validated assays at 
the bioanalytical laboratory.  Consent for this biopsy should be documented in the tissue consent 
portion of the ICF.  After at least 10 on-treatment tumor biopsies per cohort have been collected, 
sites will be notified of a change to the requirement.   
End-of-treatment Biopsy 
An optional EOT tumor biopsy may be performed at the time of progression or discontinuation 
from study treatment.  Consent for optional EOT biopsy should be documented in the tissue 


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consent portion of the ICF.  Tumor biopsy should be obtained from the primary tumor or a 
metastatic site, preferably from a site of recent radiographic progression, within 40 days of the 
date of discontinuation, and prior to starting any new anticancer treatment.  This sample will be 
tested for exploratory purpose such as gene mutation analysis, gene expression as well as other 
immune marker analysis. 
8.3.3. 
Biomarker Assessments in Tumor Tissue and Blood Samples  
Potential patient selection biomarkers (including HER3 expression using IHC) will be analyzed 
with the intent of identifying those subjects with advanced or metastatic CRC who will most 
likely derive clinical benefit from U3-1402, to support future subject selection strategies for 
advanced or metastatic CRC subjects. These potential biomarkers will be assessed in archival 
and pre-treatment tumor tissue.   
Further exploratory archival, pre-treatment, on-treatment, and end-of-treatment tissue (eg, RNA, 
DNA, and other immune marker IHC) or blood-based biomarkers (eg, soluble protein markers, 
circulating free DNA [cfDNA] and circulating free RNA [cfRNA]) will be analyzed based on 
emerging scientific knowledge to better understand the target disease and also to evaluate the 
effects of study treatment (pharmacodynamic effect and effects associated with U3-1402 clinical 
activity).  The exploratory biomarker analyses may be performed using methods other than IHC 
(eg, protein, RNA, or DNA analysis).  Blood for biomarkers assessment (eg, soluble protein, 
markers, cfDNA, cfRNA) should be collected as per the Schedule of Events (Table 13.1).  If 
consent is obtained to perform the mandatory on-treatment tumor biopsy, a tumor biopsy will be 
collected on Cycle 2 Day 3.  Blood sample for biomarkers will also be collected on Cycle 2 
Day 3.  If consent is not obtained to perform the mandatory on-treatment tumor biopsy, blood 
sample for biomarkers will be collected on Cycle 2 Day 1.  Moreover, blood samples may be 
used to measure soluble CRC markers, such as carcinoembryonic antigen, CA 19-9, and 
C-reactive protein, but not limited to these markers only. 
The results from exploratory biomarker research may be pooled with biomarker data from other 
studies with the investigational product to generate hypotheses to be verified in future studies. 
8.4. 
Immunogenicity 
Blood samples for ADA assessment will be obtained at the time points specified in the Schedule 
of Events (Table 13.1) and will be analyzed at the central laboratory.  The PK assay can be 
performed on the ADA sample collected.  The details on immunogenicity blood sample 
collection, handling and shipment are described in the Laboratory Manual.  The immunogenicity 
testing will be performed using a validated ADA assay comprised of tiered steps including 
screening, confirmatory, and titer determination.  ADA samples confirmed positive will be 
banked until availability of a neutralizing ADA assay.  Serum concentrations of U3-1402 may be 
measured using the same ADA samples collected for the purpose of ADA assessment at the EOT 
and the long-term follow-up visits that occur every 3 months.  
For subjects with positive ADA at the EOT visit, additional serum ADA samples should be 
collected every 3 months (±14 days) for up to 1 year after the last dose of U3-1402, unless 1 of 
the following occurs sooner:  the ADA becomes negative; the ADA titer falls below baseline if 


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ADA was measurable prior to Cycle 1 Day 1; the subject starts another therapy for cancer; or the 
subject withdraws consent from the study. 
8.4.1. 
Genomic or Genetic Banking and Analysis 
8.4.1.1. 
Sample Collection and Analysis 
An optional single blood sample for pharmacogenetics analysis should be collected on Cycle 1 
Day 1 or at any time during the study from subjects who provide consent. 
Pharmacogenomic samples may be analyzed for genes involved in absorption, distribution, 
metabolism, elimination, safety, and efficacy of the study drug.  Additionally, samples may be 
analyzed for genes involved in study drug-related signaling pathways, or to examine diseases or 
physiologic processes related to the study drug.  Subject samples will not be sold to anyone.  
This information may be useful in increasing the knowledge of differences among individuals in 
the way they respond to the study drug, as well as helping in the development of new drugs or 
improvement of existing drugs. 
8.4.1.2. 
Instructions for Collection of Specimens  
Instructions for collection of biospecimens are included in the Laboratory Manual. 
8.4.1.3. 
Storage and Disposal of Specimens 
Any remaining biosamples will be stored for a maximum of 15 years after the finalization of the 
clinical study report (CSR) for this protocol.  These specimens will be kept for analysis in case 
new genomic or genetic information is obtained in the future regarding the response (PK or 
pharmacodynamic) to U3-1402, or in case serious adverse drug reactions are noted in a clinical 
study and biomarker analysis is to be conducted for investigation into the cause. 
During the storage period, the samples will be coded with labels having no personal information 
and will not be immortalized or sold to anyone.  Subjects will have the right to withdraw consent 
and have their sample destroyed at any time.  However, the data will not be discarded if analysis 
has been completed before the subject withdraws consent.  
8.4.1.4. 
Disclosure of the Results  
Any data obtained from exploratory research will not be disclosed to the subject or Investigators. 


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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Assessment of Safety Endpoint(s) 
Safety endpoints will include SAEs, TEAEs, adverse events of special interest (AESIs), physical 
examination findings (including ECOG PS), vital sign measurements, and standard clinical 
laboratory parameters.  All AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  Adverse events and abnormal laboratory test results, if applicable, will be 
graded using NCI-CTCAE v5.0.   
9.2. 
Adverse Event Collection and Reporting 
All clinical AEs occurring after the subject signs the main study ICF and up to 47 days after the 
last dose of study drug (ie, the follow-up period), whether observed by the Investigator or 
reported by the subject, will be recorded on the AE eCRF.  When an AE of potential ILD 
(Section 9.3.1) is observed after 47 days since last dose of U3-1402, the AE (serious or 
non-serious) should be reported and recorded in AE eCRF if it is considered related to U3-1402.  
Medical conditions (including clinical laboratory values/vital signs that are out of range) that 
were diagnosed or known to exist prior to informed consent will be recorded as part of medical 
history.   
All AEs, AESIs, events of overdose, and SAEs are to be reported according to the procedures in 
Section 9.5. 
All clinical laboratory results, vital signs, and ECG results or findings should be appraised and 
documented by the Investigator to determine their clinical significance.  Isolated abnormal 
clinical laboratory results, vital sign findings, or ECG findings (ie, not part of a reported 
diagnosis) should be reported as AEs if they are symptomatic, lead to study drug discontinuation, 
dose reduction, require corrective treatment, or constitute an AE in the Investigator9s clinical 
judgment. 
At each time point, the Investigator will determine whether any AEs have occurred by evaluating 
the subject.  Adverse events may be directly observed, reported spontaneously by the subject or 
by questioning the subject (or, when appropriate, by a caregiver, surrogate, or the subject's 
legally authorized representative) at each time point.  Subjects should be questioned in a general 
way, without asking about the occurrence of any specific symptoms.  The Investigator must 
assess all AEs to determine seriousness, severity, and causality, in accordance with the 
definitions in Section 9.4.  The Investigator and any qualified designees are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE and 
remain responsible for following AEs that are serious, considered related to the study drug or 
study procedures, or that caused the subject to discontinue U3-1402.  The Investigator9s 
assessment must be clearly documented in the study site9s source documentation with the 
Investigator9s signature. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE. 


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For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization).  A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to signing the ICF) 
procedures or treatments requiring hospitalization for pre-existing conditions that do not worsen 
in severity should not be reported as SAEs (see Section 9.4.2 for definitions). 
All SAEs, potential ILD cases, overdoses, and hepatic events (both serious, non-serious, and 
clinical laboratory results) that meet the criteria of elevated (ALT or AST) g3 × upper limit of 
normal (ULN) and an elevated total bilirubin >2 × ULN should be reported within 24 hours of 
awareness (see Sections 9.3.1, 9.3.2, and  9.5.1 for definitions). 
For deaths, the underlying or immediate cause of death should always be reported as an SAE. 
Progressive disease is a study endpoint and, consequently, should not be reported as an AE/SAE.  
However, when a subject dies from PD with no other immediate causes, <Progressive disease= 
should be reported as an SAE.  In addition, any serious, untoward event that may occur 
subsequent to the reporting period that the Investigator assesses as related to study drug should 
also be reported and managed as an SAE.  The Investigator should follow subjects with AEs 
until the event has resolved or the condition has stabilized.  Unresolved AEs, including 
significant abnormal clinical laboratory values at the end of study assessment, will be followed 
until resolution or until they become clinically not relevant. 
9.3. 
Adverse Events of Special Interest 
9.3.1. 
Pulmonary Toxicity (Interstitial Lung Disease) 
Interstitial lung disease is considered an important identified risk based on a comprehensive 
cumulative review of the available safety data from the clinical development program as well as 
the results of potential ILD cases reviewed by the independent ILD Adjudication Committee 
(AC), available data from recent epidemiology/literature, biological plausibility, and safety 
information from drugs of similar class.  Refer to the current IB for a summary of preliminary 
clinical study data. 
If a subject develops an acute onset of new or worsening pulmonary or other related 
signs/symptoms such as dyspnea, cough or fever, rule out ILD.  If ILD is suspected, delay 
U3-1402 dosing pending further evaluation and start corticosteroid treatment promptly per 
consensus statement39 unless clinically contraindicated.  Refer to Table 5.2 for guidance on 
further evaluation and management of ILD. 
If a non-inflammatory/infectious etiology is confirmed by the Investigator, treat accordingly; 
resumption of U3-1402 may occur after discussion between the Investigator and Sponsor. 
All events of ILD regardless of severity or seriousness should be followed until resolution 
including after drug discontinuation. 
9.3.1.1. 
Interstitial Lung Disease Adjudication Committee 
An independent ILD AC for U3-1402 is responsible for reviewing all cases of potential ILD.  To 
ensure adequate and relevant independent evaluation, systematic additional data collection will 
be conducted for all cases that will be brought for adjudication.  This data collection will be 


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triggered for AEs reported using MedDRA preferred terms (PTs) from the current ILD Standard 
MedDRA Query (SMQ) and the PTs of acute respiratory failure and respiratory failure. 
9.3.2. 
Elevation of Aminotransferase(s) and Bilirubin: Hepatic Events  
Elevation of aminotransferase(s) and bilirubin in association with U3-1402 is considered to be an 
important potential risk based on a comprehensive cumulative review of the available safety data 
from the clinical development program, the available pre-clinical data, review of the cumulative 
literature and review of available information for products of the same class.  Refer to the current 
IB for a summary of preliminary clinical trial data. 
All hepatic events (serious, non-serious, and clinical laboratory results) that meet criteria of 
elevated ALT or AST g3 × ULN and an elevated total bilirubin >2 × ULN that may occur 
simultaneously or at different time points during the study, should be reported as an AE (serious 
or non-serious) and as an AESI to closely monitor potential Hy9s law, regardless of whether 
these hepatic events are symptomatic, lead to study drug discontinuation, dose reduction, or dose 
delay, require corrective treatment, constitute an AE in the Investigator9s clinical judgment, 
and/or are related to disease progression.  A detailed narrative and confirmations with repeated 
laboratory assessment(s) should also be provided.  Such events should be reported within 
24 hours of Investigator9s awareness of the event. 
9.4. 
Adverse Event 
9.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have to have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product (International Council for 
Harmonisation [ICH] E2A Guideline.  Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting, Oct 1994). 
It is the responsibility of Investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings which should be considered AEs. 
9.4.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
÷ Results in death, 
÷ Is life-threatening, 
÷ Requires inpatient hospitalization or prolongation of existing hospitalization, 
÷ Results in persistent or significant disability/incapacity, 
÷ Is a congenital anomaly/birth defect, or 
÷ Is an important medical event. 


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Note: The term <life-threatening= in the definition of <serious= refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe (ICH E2A Guideline.  Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting, Oct 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above.  Examples 
include allergic bronchospasm, convulsions, and blood dyscrasias or development of drug 
dependency or drug abuse. 
Note:  
÷ Procedures are not AEs or SAEs, but the reason for the procedure may be an AE or 
SAE.   
÷ Pre-planned (prior to signing the ICF) procedures or treatments requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are not 
SAEs. 
9.4.3. 
Severity Assessment 
All AEs will be graded according to the NCI-CTCAE v5.0: 
÷ Grade 1:  Mild AE 
÷ Grade 2:  Moderate AE 
÷ Grade 3:  Severe AE 
÷ Grade 4:  Life-threatening consequences; urgent intervention indicated 
÷ Grade 5:  Death related to AE 
Severity vs. Seriousness:  Severity is used to describe the intensity of a specific event while the 
event itself, however, may be of relatively minor medical significance (such as severe headache).  
This is not the same as "seriousness," which is based on subject/event outcome at the time of the 
event.  For example, the NCI-CTCAE Grade 4 (life-threatening consequences; urgent 
intervention indicated) is assessed based on unique clinical descriptions of severity for each AE, 
and these criteria may be different from those used for the assessment of AE seriousness.  An AE 
assessed as Grade 4 based on the NCI-CTCAE grades may or may not be assessed as serious 
based on the seriousness criteria. 
9.4.4. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the study drug on the basis 
of his/her clinical judgment and the following definitions.  The causality assessment must be 
made based on the available information and can be updated as new information becomes 
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÷ Related: 
ý The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the subject9s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
or 
ý The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its chemical group, or is 
predicted by known pharmacology. 
÷ Not Related: 
ý The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the subject9s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications).  
9.4.5. 
Action Taken Regarding Study Drug(s) 
÷ Dose not changed:  No change in study drug dosage was made. 
÷ Drug withdrawn:  The study drug was permanently stopped. 
÷ Dose reduced:  The dosage of study drug was reduced. 
÷ Drug interrupted:  The study drug was temporarily stopped. 
÷ Not applicable. 
9.4.6. 
Other Action Taken for Event 
÷ None:  No treatment was required. 
÷ Medication required:  Prescription and/or over-the-counter medication was required 
to treat the AE. 
÷ Other. 
9.4.7. 
Adverse Event Outcome 
÷ Recovered/Resolved:  The subject fully recovered from the AE with no residual effect 
observed. 
÷ Recovering/Resolving:  The AE improved but has not fully resolved. 
÷ Not Recovered/Not Resolved:  The AE itself is still present and observable. 
÷ Recovered/Resolved with Sequelae:  Sequelae/residual effects of the AE are still 
present and observable. 
÷ Fatal:  Death is a direct outcome of the AE. 
÷ Unknown 


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9.5. 
Serious Adverse Events Reporting Procedure For Investigators 
All AEs, AESIs, events of overdose, and SAEs will be reported in the eCRF.  Any SAEs after 
signing the appropriate ICF should be reported until 40 days (+7 days) after the last dose of the 
study drug.  Any SAEs directly related to a tumor biopsy procedure performed after signing the 
appropriate Tissue Screening ICF or Tissue Collection ICF should be reported according to the 
Adverse Event Reporting Requirements section.  Any serious, untoward event that may occur 
subsequent to the 40-day (+7 days) follow-up reporting period that the Investigator assesses as 
related to study drug should also be reported and managed as an SAE. 
Serious events that are also efficacy endpoints (disease progression) will be exempted from SAE 
processing and expedited reporting.  Disease progression should not be reported as an AE/SAE.  
However, if a subject dies from disease progression with no other immediate causes, <disease 
progression= should be reported as an SAE and captured on the AE eCRF. 
The following types of events should be reported by the Investigator in electronic data capture 
(EDC) within 24 hours of awareness: 
÷ SAEs (see Section 9.4.2 for definition) 
÷ All potential ILD cases should be reported within 24 hours; including both serious 
and non-serious potential ILD cases (potential ILD is defined by the Event 
Adjudication Site Manual List of PTs) (see Section 9.3.1 for details) 
÷ All hepatic events (both serious and non-serious, and clinical laboratory results) that 
meet criteria of elevated ALT or AST g3 × ULN and an elevated total bilirubin >2 × 
ULN that may occur simultaneously or at different time points during the study 
should be reported as an AE (serious or non-serious) and as an AESI, regardless of 
whether these hepatic events are symptomatic, lead to study drug discontinuation, 
dose reduction or dose delay, require corrective treatment, constitute an AE in the 
Investigator9s clinical judgment and/or are related to disease progression (see 
Section 9.3.2 for details). 
÷ Overdose (see Section 9.5.1 for a definition) 
All events (serious and non-serious) must be reported with Investigator9s assessment of the 
event9s seriousness, severity, and causality to the study drug.  A detailed narrative summarizing 
the course of the event, including its evaluation, treatment, and outcome should be provided for 
SAEs and AESIs.  Specific or estimated dates of event onset, treatment, and resolution should be 
included when available.  Medical history, concomitant medications, and laboratory data that are 
relevant to the event should also be summarized in the narrative.  For fatal events, the narrative 
should state whether an autopsy was or will be performed and include the results if available.  
Source documents (including medical reports) will be retained at the study center and should not 
be submitted to the Sponsor for SAE reporting purposes.  
Additional relevant information regarding the AESIs of ILD, and all hepatic events that meet the 
criteria of an elevated ALT or AST g 3 × ULN and an elevated total bilirubin > 2 × ULN that 
may occur simultaneously or at different time points during the study for the U3-1402 clinical 
program, regardless of seriousness, is to be collected through the targeted questionnaires within 
the clinical study database. 


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Urgent safety queries and follow-up information such as those upgraded to fatal/life threatening 
case must be followed up and addressed promptly.  The investigator will submit any updated 
SAE data to the sponsor and/or CRO within 24 hours of receipt of the information. Other 
follow-up information and response to non-urgent safety queries should be combined for 
reporting to provide the most complete data possible within each follow-up.  In the event that an 
eCRF is unavailable, report SAEs, overdoses, potential cases of ILD, and hepatic events that 
meet criteria of elevated ALT or AST g3 × ULN and an elevated total bilirubin >2 × ULN on a 
Serious Adverse Event Report (SAVER) form.  All completed SAVER forms must be signed by 
the Investigator and e-mailed or faxed to the Sponsor or the CRO using the provided fax 
transmittal form and the appropriate fax number provided for your country.  Once EDC becomes 
available, please enter events reported on the SAVER Form into the eCRF as soon as possible.  
Please refer to the eCRF Completion Guide for additional instructions. 
Please call the local SAE Hotline (see Study Manual) or your study monitor for any questions on 
SAE reporting. 
9.5.1. 
Overdose  
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important.  An <excessive and medically 
important= overdose includes any overdose in which an SAE, a non-serious AE, or no AE occurs 
and is considered by the Investigator as clinically relevant (ie, it poses an actual or potential risk 
to the subject).  All occurrences of overdose must be reported to the CRO or Sponsor within 
24 hours of awareness.  Overdose will be reported via the SAVER form or eCRF. 
9.6. 
Pregnancy 
The Sponsor must be notified of any female subject who becomes pregnant while receiving or 
within 7 months of the last dose of U3-1402.  The Sponsor must be notified of any male subject 
whose female partner becomes pregnant while the subject is receiving, or within 4 months of 
discontinuing, U3-1402. 
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome.  If a pregnancy is reported, the Investigator should inform the Sponsor 
within 24 hours of learning of the pregnancy. 
This information is important for both drug safety and public health concerns.  It is the 
responsibility of the Investigator, or designee, to report any pregnancy in a female subject or 
partner of a male subject using the Exposure In Utero (EIU) Reporting form.  Please contact your 
study monitor to receive the EIU Reporting Form upon learning of a pregnancy.  The 
Investigator should make every effort to follow the female subject or partner of a male subject 
(upon obtaining written consent from partner) until completion of the pregnancy and complete 
the EIU Reporting Form with complete pregnancy outcome information, including normal 
delivery or induced abortion.  Any adverse pregnancy outcome, either serious or non-serious, 
should be reported in accordance with study procedures.  If the outcome of the pregnancy meets 
the criteria for immediate classification as an SAE (ie, post-partum complications, spontaneous 
or induced abortion, stillbirth, neonatal death, or congenital anomaly, including that in an aborted 
fetus), the Investigator should follow the procedures for reporting SAEs. 


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Pregnancy Test 
For women of childbearing potential (as defined in Section 4.1): document the results of a 
negative serum pregnancy test.  For eligibility, if not performed as a part of routine care within 
72 hours prior to Cycle 1 Day 1, a serum pregnancy test must be performed with the results 
available (Table 13.1).  A positive urine pregnancy test must immediately be confirmed using a 
serum test.  Repeat pregnancy test (urine or serum per institutional guidelines) must be 
performed 72 hours before infusion at each cycle and at the EOT visit. 
A female is considered of childbearing potential following menarche and until becoming 
postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile 
(undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy) with surgery at 
least 1 month before the first dose or confirmed by FSH test (FSH >40 mIU/mL and estradiol 
<40 pg/mL [<147pmol/L] is confirmatory).  Females on hormone replacement therapy (HRT) 
and whose menopausal status is in doubt will be required to use 1 of the contraception methods 
outlined for women of childbearing potential if they wish to continue their HRT during the study.  
Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to 
the first dose of U3-1402 treatment. For most forms of HRT, at least 2 to 4 weeks must elapse 
between the cessation of therapy and the blood draw; this interval depends on the type and 
dosage of HRT.  Following confirmation of their post-menopausal status, they can resume use of 
HRT during the study without use of a contraceptive method. 
9.7. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee 
Daiichi Sankyo and/or CRO will inform Investigators and regulatory authorities of any suspected 
unexpected serious adverse reactions occurring in study sites or other studies of U3-1402, as 
appropriate per institutional and/or local reporting requirements. 
Daiichi Sankyo and/or CRO will comply with any additional local safety reporting requirements.  
The Investigator will assess if an AE is to be considered <unexpected= based on the <Reference 
Safety Information= section in the current IB.26  
9.8. 
Clinical Laboratory Evaluations 
Clinical laboratory measurements will be conducted at the local laboratory.  The following items 
will be measured.  For clinical laboratory parameters, the reference range of the institution that 
performs the measurements will be used.  Refer to the Schedule of Events (Table 13.1) for 
timing of these assessments.  


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Table 9.1: 
Clinical Laboratory Tests 
Laboratory tests 
Parameters 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, white blood 
cell count, mean platelet volume (if available), reticulated platelet fraction 
(if available), and differential white blood cell count (absolute and 
percent) (ie, neutrophils, lymphocytes, monocytes, eosinophils, basophils) 
Blood Chemistry 
Total protein, albumin, ALP, ALT, AST, bicarbonate, TBL, direct 
bilirubin, indirect bilirubin, BUN/urea, calcium, chloride, creatinine, 
LDH, magnesium, potassium, sodium, CEAa, CA19-9a, and CRPa 
Coagulation (only at 
screening) 
Prothrombin time or prothrombin time-international normalized ratio, and 
activated partial thromboplastin time/partial thromboplastin time 
Urinalysis 
Protein, glucose, blood, bilirubin, glucose, ketone bodies, leukocyte 
esterase, occult blood, pH, urobilinogen, microscopic assessment of urine 
sediment (casts, RBC, WBC), and specific gravity 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; CA 19-9 = cancer antigen 19-9; CEA = carcinoembryonic antigen; CRP = C-reactive protein; LDH = 
lactate dehydrogenase; RBC = red blood cell; TBL = total bilirubin; WBC = white blood cell 
a Assessed at the central laboratory 
In addition, a pregnancy test (serum) for all female subjects of childbearing potential must be 
performed during the Screening Period and at the visits (serum or urine) indicated in the 
Schedule of Events.  A positive urine pregnancy test result must be confirmed immediately using 
a serum test. 
All laboratory values must be appraised by the Investigator as to clinical significance and used to 
take appropriate clinical management measures.  All abnormal laboratory values considered 
clinically significant by the Investigator should be recorded on the AE eCRF.  If the abnormal 
laboratory value constitutes an SAE, it should be reported by the Investigator with a targeted 
questionnaire that is in-built as an eCRF or a SAVER form within 24 hours of awareness and 
other relevant procedures must be followed (see Section 9.5).  Abnormal laboratory values 
(NCI-CTCAE Grade 3 or 4) occurring during the clinical study will be followed until repeat test 
results return to normal (or baseline), stabilize, or are no longer clinically significant. 
9.9. 
Vital Signs 
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, respiratory 
rate, and body temperature.  
Blood pressure and pulse rate should be measured after the subject has rested in a supine position 
for 5 minutes.  
9.10. 
Electrocardiograms 
Standard supine/semi-recumbent 12-lead ECG prior to blood draws and will be performed as 
described in the Schedule of Events (Table 13.1).  The ECG will be measured after the subject 
has rested supine for at least 10 minutes prior to the ECG assessment.  ECGs must be recorded 


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on an ECG machine and reviewed by the Investigator or delegated physician for the presence of 
abnormalities.  The same test must be used for Screening, EOT, and as clinically indicated. 
Abnormal, clinically relevant findings occurring post-baseline will be reported as AEs.  Whether 
or not the measurement is performed, the date the ECG is to be performed, heart rate, PR 
interval, RR interval, QRS duration, QT interval, QTcF interval, and results will be recorded in 
the eCRF. 
9.11. 
Physical Examinations 
Physical examination findings including ECOG PS will evaluate the following body 
systems/organs: general appearance; dermatological; head and eyes; ears, nose, mouth, and 
throat; pulmonary; cardiovascular; abdominal; genitourinary (optional); lymphatic; 
musculoskeletal/extremities; and neurological.  Weight and height will also be recorded in 
kilograms and centimeters, respectively. 
9.12. 
Other Safety Assessments 
Cardiac assessments: 
÷ LVEF 
ý LVEF will be measured by either ECHO or MUGA, as described in the Schedule 
of Events (Table 13.1).  All ECHO/MUGA assessments must be evaluated by the 
Investigator or delegate.  The same modality (ECHO or MUGA) should be used 
for the subject throughout the study. 
ý Refer to Section 13.5 for the NYHA Functional Capacity and Objective 
Assessment. 
Ophthalmologic assessments: 
÷ Ophthalmologic assessments will include a visual acuity test (ETDRS, Snellens, or 
Landolt), slit lamp examination, fundoscopy, and tonometry as indicated in the 
Schedule of Events (Section 13.1).  All ophthalmologic assessments must be 
evaluated by an ophthalmologist or other qualified practitioner.  More frequent 
examinations may be performed at the discretion of the Investigator and if indicated.  
Pulmonary assessments: 
÷ SpO2 should be measured along with tumor assessments per Investigator discretion 
and as indicated in the Schedule of Events (Section 13.1).  Additional testing to 
investigate pulmonary disorders may be performed, eg, chest radiograph, 
functional/blood-gas examination, pulmonary function testing, or serological 
examinations, at the Investigator9s discretion as described in Table 5.2.  An ILD AC 
has been set up for this study.  Additional details regarding the ILD AC are available 
in Section 9.3.1.1. 


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10. 
OTHER ASSESSMENTS 
10.1. 
Patient Reported Outcomes 
Not applicable. 
10.2. 
Pharmacoeconomic Assessments 
Not applicable. 


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11. 
STATISTICAL CONSIDERATIONS 
11.1. 
General Statistical Considerations 
The primary analysis DCO will occur when all subjects have either a minimum of 9 months 
follow-up or have discontinued from the study earlier.  The DCO may be shifted if emerging 
data indicate responses are occurring at a different time.  The final analysis will occur when all 
subjects have discontinued from the study for any reason.  The primary analysis will be included 
in the CSR.   
Descriptive statistics on continuous data will include mean, median, standard deviation, and 
range (as well as geometric means and geometric coefficient of variation for PK parameters), 
while categorical data will be summarized using frequency counts and percentages.  Graphical 
summaries of the data may be presented. 
Assessments of change from baseline to post-treatment or the ratio of post-treatment to baseline 
will include only those subjects with both baseline and post-treatment measurements.  The last 
non-missing value of a variable taken before start of study treatment will be used as the baseline 
value, unless otherwise specified.  In general, missing or dropout data will not be imputed for the 
purpose of data analysis, unless otherwise specified. 
A detailed Statistical Analysis Plan (SAP) describing the methodology to be used in the final 
analysis will be prepared and finalized before database lock.   
11.2. 
Statistical Hypothesis 
No statistical testing is planned for this study. 
11.3. 
Sample Size Determination 
In Part 1 of the study, approximately 36 subjects will be evaluated in the two cohorts. If both 
Cohort 1 and Cohort 2 advance to Part 2 of the study, approximately 44 additional subjects will 
be enrolled in Part 2 (regardless of HER3 IHC status). In such a circumstance, approximately 
80 subjects will be enrolled in total. If only Cohort 1 advances to Part 2 of the study, 
approximately 44 additional subjects will be enrolled in Part 2. In such circumstance, 
approximately 80 subjects will be enrolled in total (68 of 80 subjects will have HER3 high 
expressing tumors).  
The total sample size is shown in Table 11.1. 


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Table 11.1: 
Total Sample Size Pre- and Post-futility Analysis  
 
Scenario 1 
Enrollment continues in both 
Cohorts 
Scenario 2 
Enrollment continues in Cohort 
1 only 
Cohort 1 
Cohort 2 
Cohort 1 
Cohort 2 
Futility decision per cohort 
Go 
Go 
Go 
Stop 
Sample size up to futility 
24 
12 
24 
12 
Additional sample size after 
futility  
44a 
44 
NA 
Cohort sample size  
80 a 
68 
12 
Total sample size for the study 
80 a 
80 
HER3 = human epidermal growth factor receptor 3; IHC = immunohistochemistry; NA = not applicable 
a All comers will be enrolled regardless of HER3 IHC status 
If the criteria to continue enrollment are not met at interim futility analysis in either cohort, 
further enrollment will be stopped.  In this scenario, the total sample size for the study will be 
approximately 36 subjects (Cohort 1: 24 subjects, Cohort 2: 12 subjects). 
Table 11.2 presents the minimum number of responders at various sample sizes for the 95% 
exact CIs lower bound to be above 5%.   
The clinically meaningful ORR is considered as 20% and the ORR based on historical data is 
considered as 5%.9,10  
With a sample size of 68 subjects, if 8 responses are observed, the observed ORR will be 11.8% 
with a 95% exact confidence interval (CI) of (5.2%, 21.9%).  The probability of observing 8 or 
more responders in 68 subjects is approximately 97.4% when the true ORR is 20%.  If the true 
ORR is 5%, the probability of observing 8 or more responders in 68 subjects is approximately 
2%. 
With a sample size of 80 subjects, if 9 responses are observed, the observed ORR will be 11.25% 
with a 95% exact CI of (5.3%, 20.3%).  The probability of observing 9 or more responders in 
80 subjects is approximately 98.7% when the true ORR is 20%.  If the true ORR is 5%, the 
probability of observing 9 or more responders in 80 subjects is approximately 1.8%. 
Table 11.2: 
Statistical Properties for Different Sample Sizes 
N 
Number of 
Responders 
(x) 
Observed 
ORR 
95% Exact CI 
P (X g x | p = 0.2) 
P (X g x| p = 0.05) 
68 
8 
11.8% 
(5.2%, 21.9%) 
97.4% 
2.0% 
80 
9 
11.25% 
(5.3%, 20.3%) 
98.7% 
1.8% 
CI = confidence interval; ORR = objective response rate.  
Table 11.3 summarizes the exact two-sided 95% CIs for the observed ORR ranging from 5% to 
20% approximately (with an increment of approximately 5%) at various sample sizes.   


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Table 11.3: 
Exact Confidence Interval for Different Observed Objective Response Rates 
N=68 
N=80 
Number of Responders 
(Observed ORR) 
95% Exact CI 
Number of Responders 
(Observed ORR) 
95% Exact CI 
4 (5.9%) 
(1.6%, 14.4%) 
4 (5%) 
(1.4%, 12.3%) 
7 (10.3%) 
(4.2%, 20.1%) 
8 (10%) 
(4.4%, 18.8%) 
11 (16.2%) 
(8.4%, 27.1%) 
12 (15%) 
(8%, 24.7%) 
14 (20.6%) 
(11.7%, 32.1%) 
16 (20%) 
(11.9%, 30.4%) 
CI = confidence interval; ORR = objective response rate.  
All calculations were performed using the SAS 9.4 software. 
11.4. 
Population for Analysis Sets 
FAS will include all subjects who received at least one dose of study drug. Efficacy analyses will 
be performed using FAS.  
Safety Analysis Set will include all subjects who received at least one dose of study drug.  
PK Analysis Set will include all subjects in the Safety Analysis Set who have at least one PK 
sample with measurable concentration for U3-1402 (ADC, total anti-HER3 Ab, or 
MAAA-1181). 
11.5. 
Statistical Analyses 
11.5.1. 
Efficacy Analyses 
11.5.1.1. Primary Efficacy Analyses 
The primary efficacy endpoint is ORR (the proportion of subjects with a best overall response 
[BOR] of CR or PR) as assessed by BICR per RECIST v1.1.  CR/PR will be confirmed with a 
follow-up tumor assessment at least 4 weeks apart.  
ORR will be summarized with the 2-sided 95% CI using the Clopper-Pearson method in the 
FAS.  For the computation of ORR, subjects with BOR of <not evaluable (NE)= will be included 
in the FAS and will be considered non-responders. Data will be summarized by cohort if 
applicable.  No formal comparison between the 2 cohorts is planned.   
11.5.1.2. Secondary Efficacy Analyses 
The key secondary efficacy endpoint is duration of response (DoR), defined as the time from the 
date of the first documentation of objective response (CR or PR) to the date of the first 
documentation of disease progression or death due to any cause, as assessed by BICR per 
RECIST v1.1.  DoR will be calculated for responding subjects (PR or CR) only.  Subjects who 
are progression-free at the time of the analyses will be censored on the date of the last adequate 
tumor assessment (CR, PR, or stable disease [SD]). 
Other secondary efficacy endpoints include: 


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÷ ORR as assessed by Investigator per RECIST v1.1 will be analyzed in the same 
manner as the primary efficacy endpoint. 
÷ DoR as assessed by Investigator per RECIST v1.1 will be analyzed in the same 
manner as the key secondary efficacy endpoint. 
÷ DCR is defined as the proportion of subjects who achieved a confirmed BOR of CR, 
PR, or SD as assessed by BICR and Investigator per RECIST v1.1.  It will be 
analyzed in the same manner as the primary efficacy endpoint. 
÷ Time to response (TTR) is defined as the time between the start of study treatment to 
the date of the first documentation of objective response (CR or PR) that is 
subsequently confirmed.  TTR will be assessed by BICR and Investigator per 
RECIST v1.1.  TTR will be calculated for responding subjects (BOR of PR or CR) 
only. 
÷ PFS is defined as the time from start of study treatment to the first objective 
documentation of radiological disease progression or death due to any cause. Subjects 
who are progression-free at the time of the analyses will be censored on the date of 
the last adequate tumor assessment (CR, PR, or SD). 
÷ OS is defined as the time from the start of study treatment to the date of death due to 
any cause.  Subjects who are alive at the time of the analyses will be censored on the 
last contact date at which the subject is known to be alive. 
Distribution of time-to-event endpoints (DoR, PFS, and OS) will be estimated using the 
Kaplan-Meier method and results will be presented graphically.  Median DoR and its 2-sided 
95% CIs will be calculated using Brookmeyer and Crowley methods.  In addition, the event-free 
probability at different time points (eg, 3, 6, 9, 12 months) will be estimated with corresponding 
2-sided 95% CIs using the Greenwood formula for variance derivation.  TTR will be 
summarized using descriptive statistics.  Censoring rules for the time-to-event endpoints (DoR, 
PFS and OS) will be specified in the SAP.   
No formal comparison between the two cohorts is planned. 
Descriptive statistics for the best percent change from baseline in the SoD will be provided by 
cohort, if applicable.  A waterfall plot of the best percent change in the SoD and a swimmer9s 
plot for response over time will also be prepared.  
The correlation between HER3 protein expression level (as determined by HER3 IHC assay) and 
efficacy will be assessed.   
11.5.1.3. Exploratory Efficacy Analyses 
Analyses to explore the relationship between exposure and efficacy may be conducted using data 
from this study, or may be conducted using pooled data with other studies.  If conducted, such 
analyses will be reported separately and will therefore not be part of the CSR.  
11.5.1.4. Multiplicity Adjustment 
Not applicable.  


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11.5.2. 
Safety Analyses 
Safety analyses will be performed using the Safety Analysis Set and in general will be 
descriptive.  Additional details regarding safety analyses will be described in the SAP. 
The overall study period will be divided into three mutually exclusive segments: 
÷ Pre-treatment period: from date of study informed consent (inclusive) to the start date 
of study treatment 3 1; 
÷ On-treatment period: from the start date of study treatment (inclusive) to 47 days after 
the end date of study treatment (inclusive); 
÷ Post-treatment period: starting from 48 days after the end date of study treatment. 
Safety summaries will include assessments collected during the on-treatment period unless 
otherwise specified. Data will be summarized by cohort if applicable. All assessments will be 
listed.  
11.5.2.1. Adverse Event Analyses 
TEAEs are defined as those AEs with a start or worsening date during the on-treatment period.  
AEs will be coded using MedDRA and graded based on v5.0 of NCI-CTCAE. 
The number and percentage of subjects with TEAEs will be summarized by system organ class 
(SOC), and/or PT.  Additional summaries will be provided by the worst CTCAE grade, 
relationship to the study treatment (ie, regardless of relationship to study drug, study drug 
related), seriousness, actions taken with study treatment (ie, associated with dose reduction, dose 
interruption, study treatment discontinuation), and fatality. 
AESIs will also be summarized. 
All deaths and on-treatment deaths will be summarized by primary cause of death.  All deaths 
will be listed. 
A by-subject AE (including TEAE) data listing will be provided including, but not limited to, 
verbatim term, PT, SOC, NCI-CTCAE grade, and relationship to study drug.  SAEs, AESIs and 
TEAEs associated with treatment discontinuation will be listed. 
SAEs starting or worsening after the on-treatment period, if reported as related to study 
treatment, will be listed separately. 
11.5.2.2. Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for clinical laboratory test results (hematology and 
chemistry) and changes from baseline by scheduled time of evaluation, including EOT.  The 
baseline value is defined as the last non-missing value before the start of study treatment.   
Abnormal laboratory results will be graded according to NCI-CTCAE v5.0, if applicable.  A 
shift table, presenting the 2-way frequency tabulation for baseline and the worst post-treatment 
value according to the NCI-CTCAE grade, will be provided.  Abnormal clinical laboratory test 
results that are deemed of clinical significance or of Grade 3 or 4 will be listed. 


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11.5.2.3. ECG 
A listing of ECG data will be generated. 
11.5.2.4. Vital Signs 
Descriptive statistics will be provided for the vital sign measurements and the change from 
baseline by scheduled time of evaluation, including EOT.  The baseline value is defined as the 
last non-missing value before the start of study treatment.  A listing of vital sign data will be 
generated. 
11.5.2.5. Other  
Listings of all other safety endpoints (eg, physical examination findings including ECOG PS, 
ECHO/MUGA, and ophthalmologic findings) will be generated. 
Immunogenicity (Anti-Drug Antibody) Analyses 
Immunogenicity will be assessed through characterization of prevalence, incidence, and titer of 
ADA.  The number and percentage of subjects with treatment-emergent ADA will be calculated.  
Treatment-emergent ADA positive is defined as subjects who were ADA negative at baseline 
and became ADA positive (ie, confirmed positive ADA) post-treatment or ADA positive at 
baseline and post-treatment and had an increase in ADA titer from baseline to post-treatment that 
meets the cut-off value of fold change or had missing ADA data at baseline and became ADA 
positive post-treatment.  Concentrations and PK parameters of total anti-HER3 antibody, intact 
U3-1402 ADC, and released payload MAAA-1181a may be summarized by status of ADA, if 
data allow.  ADA titer will be determined for samples confirmed ADA positive.  When 
neutralizing antibody assay becomes available, confirmed ADA-positive samples may be 
analyzed for neutralizing activity.   
11.5.3. 
Other Analyses 
11.5.3.1. Pharmacokinetics 
Data will be summarized by cohort if applicable. 
PK Analyses as Secondary Objective 
PK parameters will be listed and summarized using descriptive statistics. 
Serum concentration-time data for U3-1402 (ADC, total anti-HER3 antibody and MAAA-1181a) 
will be listed, plotted, and summarized using descriptive statistics at each time point. 
Exploratory PK Analyses 
Serum concentration data may be used to perform a population PK modeling.  The influences of 
intrinsic or extrinsic factor will be assessed in the population PK analysis.  Population PK and 
exposure-response analyses for U3-1402 (ADC, total anti-HER3 antibody, and MAAA-1181a) 
may be performed to characterize the relationship between dose and exposure and between 
exposure and efficacy and/or safety endpoints.  If performed, results of population PK analyses 
will be reported separately (ie, not in the CSR). 


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11.5.3.2. Pharmacodynamics 
Not applicable.  
11.5.3.3. Biomarker Analyses 
HER3 protein expression in tumor tissue (as determined by IHC) may be summarized 
descriptively, and the correlation with efficacy parameters may be analyzed if data permits. 
11.6. 
Interim Analyses 
For each study cohort, review of the preliminary data from Part 1 will be used to determine 
whether to open Part 2.  The decision to advance from Part 1 to Part 2 will be made separately in 
Cohort 1 and Cohort 2; the interim futility analysis will be conducted with approximately 
24 subjects in Cohort 1 and approximately 12 subjects in Cohort 2 after all subjects have had the 
opportunity to complete two tumor assessments.  The tumor assessment period may be extended 
if emerging data show responses are occurring later, or if the tumor assessment for the final 
evaluated subject in each cohort is delayed.  At the time of the interim analysis for each cohort, 
enrollment into the respective cohort will be paused until the determination that criteria for 
advancement to Part 2 has been achieved.  Note it is possible for the futility criterion to be 
passed before the above specified analysis timing.  These analyses will be conducted based on 
BICR assessment in the FAS. 
Cohort 1 Decision Criteria at Interim: 
1. If at least 3 responders out of 24 subjects in Cohort 1 are observed, then further 
enrollment in this cohort may proceed.   
2. If 0 or 1 responder out of 24 subjects in Cohort 1 is observed at the interim, then further 
enrollment in this cohort may stop.  
3.  If 2 responders out of 24 subjects in Cohort 1 are observed, then a decision will be made, 
after further review of the data, to either continue or stop further enrollment in this 
cohort.   
Cohort 2 Decision Criteria at Interim: 
1. If at least 2 responders out of 12 subjects in Cohort 2 are observed, further enrollment in 
this cohort may proceed after submission of a protocol amendment which includes the 
preliminary data from Cohort 2 Part 1.  
2. If 0 responder out of 12 subjects in Cohort 2 is observed at the interim, then further 
enrollment in this cohort may stop.  
3. If 1 responder out of 12 subjects in Cohort 2 is observed, then a decision will be made, 
after further review of the data, to either continue or stop further enrollment in this 
cohort.  Further enrollment will be contingent upon submission of a protocol amendment 
which includes the preliminary data from Cohort 2 Part 1. 
The exact decision rules will depend on the actual number of subjects at the respective interim 
analysis.  


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If the criterion to pass futility is met at interim for Cohort 2 but not Cohort 1, all data will be 
reviewed thoroughly to decide the next step for the study. 
The criterion for interim analysis is constructed as follows: based on the interim data, if in a 
cohort there is less than 10% probability for the true ORR to be above 20% (clinically 
meaningful ORR), then U3-1402 is considered futile in this cohort and further enrollment may 
not be warranted.  If there is at least 10% probability for the true ORR to be above 20% and at 
least 80% probability for the true ORR to be above 5% (ORR based on historical data)9,10 then 
promising efficacy is demonstrated in this cohort and further enrollment in this cohort may 
proceed. 
If the true ORR is 20%, then the probability of observing at least 3 responders out of 24 subjects 
in Cohort 1 at the interim analysis will be 88.5% and the probability of observing at least 
2 responders out of 12 subjects in Cohort 2 at the interim analysis will be 72.5%.  If the true 
ORR is 5%, then the probability of observing 0 or 1 responder out of 24 subjects in Cohort 1 at 
the interim analysis will be 66.1% and the probability of observing 0 responders out of 
12 subjects in Cohort 2 at the interim analysis will be 54%. 
The determination of whether to advance a cohort to Part 2 of the study may also take into 
consideration the PK properties of U3-1402 among subjects enrolled in this study, and the 
subject or disease characteristics of enrolled subjects, among others. The decision to advance the 
study to Part 2 might be deferred based on the collective evaluation of such information. If 
indicated, the Sponsor may amend the protocol to evaluate other doses, dose regimens, or 
selected subject populations with advanced or metastatic CRC prior to advancing the study to 
Part 2. 
11.7. 
Statistical Analysis Process 
Data from the clinical study will be analyzed by the Sponsor and/or its agent/CRO. 
The SAP will provide the statistical methods and definitions for the analysis of the efficacy, 
safety, PK, and other data, as well as describe the approaches to be taken for summarizing other 
clinical study information such as subject disposition, demographic and baseline characteristics, 
study drug exposure, and prior and concomitant medications.  The SAP will also include a 
description of how missing and spurious data will be addressed. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP will be 
finalized prior to database lock. 
All statistical analyses will be performed using SAS® Version 9.2 or higher (SAS Institute, 
Cary, NC 27513). 


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41. Aprile G, Fontanella C, Bonotto M, et al. Timing and extent of response in colorectal 
cancer: critical review of current data and implication for future trials. Oncotarget. 
2015;6:28716-28730. 
42. Bartley AN, Washington MK, Ventura CB, et al. HER2 testing and clinical decision 
making in gastroesophageal adenocarcinoma: guideline from the College of American 
Pathologists, American Society for Clinical Pathology, and American Society of Clinical 
Oncology. Arch Pathol Lab Med. 2016;140(12):1345-63. 
43. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16:31-41. 
44. American Heart Association. Classification of Functional Capacity and Objective 
Assessment [Internet]. [cited 2019 Nov 18]. Available from: 
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/Previ
ousYears/Classification-of-Functional-Capacity-and-Objective-
Assessment_UCM_423811_Article.jsp. 
45. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649-56. 
46. Heads of Medicines Agencies. Clinical Trial Facilitation Group (CTFG). 
Recommendations related to contraception and pregnancy testing in clinical trials. 
September 2014. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 


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13. 
APPENDICES 
13.1. 
Schedule of Events 
 








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b 40 days (+ 7 days) after the last study drug administration or before starting new anticancer treatment, whichever comes first.  If the EOT Visit occurs g40 days after the final dose of U3-1402, the 40-
Day F/U Visit does not need to be conducted. 
c Archival tumor tissue is required with minimal 2 cores or 20 slides with adequate tumor tissue content. FFPE block is preferred.  An additional archival tissue sample collected greater than 3 months 
prior to screening must be available and of sufficient quantity, as defined above, at the time of screening.  If an archival tissue sample (collected greater than 3 months prior to screening) is not 
available, a subject may be included provided the pre-treatment tumor biopsy is obtained and after discussion and agreement from Sponsor (Medical Monitor or designee). 
d Pre-treatment tumor biopsy is required and should be obtained from a primary tumor or metastatic site, and not previously irradiated. Exception: Pre-treatment tumor biopsy may not be required if the 
archival tumor tissue was collected within 3 months of screening during or after treatment with the last prior cancer treatment and is of sufficient quantity, defined as 2 cores or 20 slides with adequate 
tumor tissue content.  
e An on-treatment tumor biopsy is required to be performed on Cycle 2 Day 3 (± 1 day). On-treatment tumor biopsy sample (with minimum of 2 cores) will be analyzed for HER3 protein expression 
using IHC and RNA expression profiling and genomic alteration using NGS. One core will be flash frozen for analysis of MAAA-1181a using fit-for-purpose qualified assay at the bioanalytical 
laboratory. Consent for this biopsy should be documented in the tissue consent portion of the appropriate ICF. Soft tissue tumor biopsy should be obtained from the primary tumor or metastatic site. A 
blood for hematology must be obtained within 2 days of the tumor biopsy and results must be reviewed by the Investigator prior to obtaining a tumor biopsy. After approximately 10 on-treatment 
tumor biopsies per cohort have been collected, the Sponsor will notify the Investigator of a change in this requirement. If the subject does not consent to the mandatory on-treatment tumor biopsy, a 
blood sample for biomarkers will be collected on Cycle 2 Day 1. 
f An optional EOT on-treatment tumor biopsy will also be performed at the time of progression or discontinuation from study treatment with minimal 2 cores or 20 slides (if provided as slides). Consent 
for this biopsy should be documented in the tissue consent portion of the appropriate ICF. Tumor biopsy should be obtained from primary tumor or metastatic site, preferably from a site of recent 
radiographic progression, within 40 days of the last dose of U3-1402, and prior to starting any new anticancer treatment. 
g Perform Hepatitis B (HBsAg), Hepatitis C (HCV Ab), and HIV viral load assessments (if indicated) as described in the eligibility criteria within 28 days prior to Cycle 1 Day 1 (see Section 4.2)  
h Urinalysis assessment should be performed within 72 hours prior to Cycle 1 Day 1.  Assessments may be repeated as clinically indicated as part of a scheduled or unscheduled visit and should include 
microscopic evaluation as indicated. 
i Within 72 hours of enrollment for all female subjects of childbearing potential. A positive urine pregnancy test result must immediately be confirmed using a serum test. Perform repeat pregnancy 
tests (urine or serum test per institutional guideline) 72 hours BI of each cycle.  
j Screening: Within 28 days prior to Cycle 1 Day 1. 
jk Screening assessment should be peformed within 28 days prior to Cycle 1 Day 1.  Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature. Blood pressure and pulse rate should be measured after the subject has rested in a supine position for 5 minutes. When CT/MRI is conducted, SpO2 should also be obtained per 
Investigator discretion. 
k Screening: Within 14 days prior to Cycle 1 Day 1. 
l Should be performed f 2 days of scheduled visit. Results are required prior to study treatment. 
m Screening assessment should be peformed within 14 days prior to Cycle 1 Day 1.  Subjects taking warfarin should be monitored regularly for changes in prothrombin time or international normalized 
ratio. 
n Screening assessment should be peformed within 28 days prior to Cycle 1 Day 1.  ECG: Subjects should rest supine for at least 10 minutes prior to the ECG assessment. The same test must be used for 
screening, EOT, and as clinically indicated. Assessment for EOT visit may be performed with a window up to 7 days.  
o Screening assessment should be peformed within 28 days prior to Cycle 1 Day 1.  ECHO or MUGA: The same test must be used for the subject at screening, EOT, and as clinically indicated. 
Assessment for EOT Visit may be performed with a window up to 7 days.  
p If subject provides consent, samples should be collected prior to study drug infusion.  For subjects with suspected or confirmed COVID-19 infections, follow the dose modifications in Section 13.9.  
q Ophthalmologic assessments (2 7 days) include visual acuity test (ETDRS, Snellens, or Landolt), slit lamp examination, fundoscopy, and tonometry. Assessment may be repeated as clinically 
indicated as part of an unscheduled visit. 
r Ophthalmologic assessments: A 40 +7-Day F/U assessment is only required if an on-treatment assessment was abnormal at the time of discontinuation of study therapy, to confirm reversibility of the 
abnormality. 
s The subject9s weight at Screening (baseline) will be used to calculate the initial dose. The subject9s weight will be determined at the beginning of each cycle.  If during Cycle 1 Day 1 or throughout the 
course of treatment, the subject9s weight changes g ± 10% from the baseline weight, the dose will be recalculated using this new weight and will be considered the new baseline weight for all 
subsequent dosing calculations.  U3-1402 will be infused as a continuous IV infusion over approximately 90 minutes on Day 1 of Cycle 1.  If there are no infusion-related reactions after the initial 
dose, subsequent doses of U3-1402 will be infused over approximately 30 minutes on Day 1 of each subsequent cycle Q3W. Refer to Table 5.2 for additional information on drug administration 
following infusion-related reactions. Refer to the Pharmacy Manual for information on storage and preparation of U3-1402. 
t Blood samples will be drawn to derive serum for HER3 extracellular domain or plasma for liquid biopsy, such as cfDNA and cfRNA  
u If consent is not obtained to perform the mandatory on-treatment tumor biopsy, a blood sample for biomarkers will be collected on Cycle 2 Day1. If consent is obtained to perform the mandatory on-
treatment tumor biopsy, a blood sample for biomarkers will be collected on Cycle 2 Day 3. 
v An optional single blood sample for PGx analysis should be collected on Cycle 1 Day 1 or at any time during the study. 


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w For subjects with positive ADA, additional serum ADA samples should be collected every 3 months (± 30 days) for up to 1 year after the last dose of U3-1402, unless one or more of the following 
occurs sooner: the ADA becomes negative; the ADA titer falls below baseline if ADA was measurable prior to Cycle 1 Day 1; the subject starts another therapy for cancer, or the subject withdraws 
consent from the study. 
x 2 8 to 0 hours BI on Day 1 of Cycles 1, 2, 3, 4, 6, and 8. 
y Within 15 minutes of EOI, then 1,2, 4, 8 hours (± 15 minutes) after the EOI. 
z Within 15 minutes of the EOI only. 
aa If consent is not obtained to perform the mandatory on-treatment tumor biopsy, the PK sample at C2D3 is not needed. 
bb PK assay can be performed on the ADA sample collected. 
cc Within 15 minutes of EOI, then 4 hours (± 15 minutes) after the EOI. 
dd If subject provides consent, samples should be collected. A washout period of no less than 14 days is required before restarting U3-1402. 
ee Screening assessment should be peformed within 28 days prior to Cycle 1 Day 1.  The same methodology (CT or MRI) and scan acquisition techniques (including use or nonuse of IV contrast unless 
medically infeasible, ie, newly developed AE or allergy to contrast agent) as were used for the screening assessments should be used throughout the study for all assessments for each subject unless 
prior approval is obtained from the Sponsor.  Unscheduled tumor assessments may be conducted if progression is suspected.  Tumor assessments should not be delayed by dose interruptions; they are 
timed relative to Cycle 1 Day 1.  Tumor assessments should be performed per RECIST v1.1 (Section 13.4) and submitted for BICR. 
ff CT or MRI of the brain should be performed for all subjects as well as the abdomen, pelvis, chest and any other sites of disease. 
gg Perform radiographic tumor assessments (CT/MRI) of the chest, abdomen, pelvis, CT or MRI of the brain (required at baseline), all sites of disease, and other areas where scans were performed at 
screening or newly suspected disease as per RECIST v1.1 (Section 13.4).  Objective responses must be confirmed at least 4 weeks later (eg, generally at the next tumor assessment time point). Also, 
perform CT or MRI of the brain within a target of 1 week after a subject achieves a CR.   
hh Any SAEs after signing the appropriate ICF should be reported until 47 days after the last dose of the study drug. Any SAEs directly related to a tumor biopsy procedure performed after signing the 
appropriate the Tissue Screening ICF or Tissue Collection ICF should be reported according to the Adverse Event Reporting Requirements section. Any serious, untoward event that may occur 
subsequent to the 40-day (+ 7 days) follow-up reporting period that the Investigator assesses as related to study drug should also be reported and managed as an SAE. 
ii Any AEs after signing of the main ICF until 47 days after the last dose of the study drug should be followed until resolution or stabilized. 
jj Survival F/U contact can occur via telephone contact or unscheduled visit and will continue until death or withdrawal of consent. 


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13.2. 
Regulatory and Ethical Considerations 
13.2.1. 
Regulatory Compliance 
The study protocol, the Investigator9s Brochure, available safety information, recruitment 
procedures (eg, advertisements), subject information and consent form, any subject written 
instructions to be given to the subject, information about payments and compensation available 
to the subjects, and documentation evidencing the Investigator9s qualifications should be 
submitted to the independent IRB or IEC for ethical review and approval according to local 
regulations, prior to the study start.  The written approval should identify all documents reviewed 
by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP.  Written approval of all protocol amendments and changes to any of 
the above listed documents must be obtained from the IRB or IEC. 
The Investigator should notify the IRB or IEC of deviations from the protocol or SAEs occurring 
at the study site and other AE reports received from the Sponsor/CRO, in accordance with local 
procedures. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the International Council for Harmonisation (ICH) 
consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and 
applicable regulatory requirement(s) including the following: 
÷ European Commission Directive (2001/20/EC Apr 2001) and/or; 
÷ European Commission Directive (2005/28/EC Apr 2005) and/or; 
÷ United States (US) Food and Drug Administration GCP Regulations: Code of Federal 
Regulations (CFR) Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or; 
÷ Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 (27 Mar 1997) 
and/or; 
÷ The Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical 
Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and 
Cosmetics No. 1 (25 Nov 2014); 
÷ Other applicable local regulations. 
In addition, the Investigator will inform the Sponsor in writing within 24 hours of any urgent 
safety measures taken by the Investigator to protect the study subjects against any immediate 
hazard, and of any suspected/actual serious GCP non-compliance that the Investigator becomes 
aware of. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects or the 
conduct of the study, the Sponsor will inform all Investigators involved in the clinical study, 


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IECs/IRBs, and regulatory authorities of such information, and when needed, will amend the 
protocol and/or subject information. 
The Investigator should immediately inform the subject whenever new information becomes 
available that may be relevant to the subject9s consent or may influence the subject9s willingness 
to continue participation in the study.  The communication should be documented on medical 
records, for example, and it should be confirmed whether the subject is willing to remain in the 
study. 
If the subject information is revised, it must be re-approved by the IEC/IRB.  The Investigator 
should obtain written informed consent to continue participation with the revised written 
information even if subjects were already informed of the relevant information.  The Investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised ICF. 
13.2.2. 
Informed Consent 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  The ICF and any revision(s) should be approved 
by the IEC/IRB prior to being provided to potential subjects. 
The subject9s written informed consent should be documented in the subject9s medical records.  
The ICF should be signed and personally dated by the subject and by the person who conducted 
the informed consent discussion (not necessarily the Investigator).  The original signed ICF 
should be retained in accordance with institutional policy, and a copy of the signed ICF should 
be provided to the subject.  The date and time (if applicable) that informed consent was given 
must be recorded in the eCRF. 
If the subject cannot read, then according to ICH GCP Guideline, Section 4.8.9, an impartial 
witness should be present during the entire informed consent discussion.  This witness should 
sign the ICF after the subject has consented to their participation.  By signing the ICF, the 
witness attests that the information in the ICF and any other written information was adequately 
explained to and apparently understood by the subject and that informed consent was freely 
given by the subject. 
A separate special consent for inherited genetic analysis will be obtained from subjects in 
accordance with health authorities in their particular region/country. 
Suggested model text for the ICF for the study and any applicable subparts (PK, 
pharmacodynamic, etc) is provided in the Sponsor9s ICF template for the Investigator to prepare 
the documents to be used at his or her study site.  Updates to applicable forms will be 
communicated via letter from the Sponsor. 
For study sites in the US, an additional consent is required for the Health Insurance Portability 
and Accountability Act (HIPAA). 
13.2.3. 
Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in accordance with GCP and local regulations. 


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For European Union (EU) study sites, the Sponsor will observe the rules laid down in the EU 
Regulation 2016/679/General Data Protection Regulation on the protection of individuals with 
regard to the processing of personal data and the free movement of such data. 
The Investigator must ensure that the subject9s anonymity is maintained.  On the eCRFs or other 
documents submitted to the Sponsor or the CRO, subjects should be identified by a unique 
subject identification as designated by the Sponsor.  Documents that are not for submission to the 
Sponsor or the CRO (eg, signed ICF) should be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the 
independent IRB/EC direct access to review the subject9s original medical records for 
verification of study-related procedures and data.  The Investigator is obligated to inform the 
subject that his/her study-related records will be reviewed by the above named representatives 
without violating the confidentiality of the subject. 
13.2.4. 
Data Integrity and Quality Assurance 
Monitoring and Inspections 
The Sponsor monitor and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the study (eg, eCRFs, source data, and other pertinent documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to ICH GCP and local regulations on the conduct of clinical research will be 
accomplished through a combination of onsite visits by the monitor and review of study data 
remotely.  The frequency of the monitoring visit will vary based on the activity at each study 
site.  The monitor is responsible for inspecting the eCRFs and ensuring completeness of the 
study essential documents.  The monitor should have access to subject medical records and other 
study-related records needed to verify the entries on the eCRFs.  Detailed information is 
provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, SOPs, GCP and applicable 
regulations to the Investigator and will ensure that appropriate action (s) designed to prevent 
recurrence of the detected deviations is taken and documented. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are addressed to the satisfaction of the Sponsor and 
documented. 
In accordance with ICH GCP and the Sponsor9s audit plans, this study may be selected for audit 
by representatives from the Sponsor.  Audit of study site facilities (eg, pharmacy, drug storage 
areas, laboratories) and review of study related records will occur in order to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory requirements.  
The Investigator should respond to audit findings. 
In the event that a regulatory authority informs the Investigator that it intends to conduct an 
inspection, the Sponsor shall be notified immediately. 


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Data Collection 
An eCRF must be completed for each subject who signs an ICF and undergoes any screening 
procedure.  If a subject is not treated, the reason must be recorded on the eCRF.  All data 
collected during the study will be recorded in this individual, subject-specific eCRF.  Instructions 
will be provided for the completion of the eCRF and any corrections made will be automatically 
documented via an <audit trail.= 
The eCRF should be kept current to enable the study monitor to review the subject9s status 
throughout the course of the study.  Upon completion of the subject9s eCRF, it will be reviewed 
and signed off by the Investigator via the EDC system9s electronic signature.  This signature will 
indicate that the Investigator inspected or reviewed the data in the subject-specific eCRF, the 
data queries, and the site notifications and agrees with the eCRF content. 
Data Management 
Each subject will be identified in the database by a unique subject identification. 
To ensure the quality of clinical data across all subjects and study sites, a Sponsor/CRO Clinical 
and Data Management review will be performed on subject data according to specifications 
developed by the Sponsor.  Data will be vetted both electronically by programmed data rules 
within the application and manually.  Queries generated by rules and raised by reviewers will be 
generated within the EDC application.  During this review, subject data will be checked for 
consistency, completeness and any apparent discrepancies. 
Data received from external sources such as central laboratories will be reconciled to the clinical 
database. 
All AEs will be coded using MedDRA.  Serious adverse events in the clinical database will be 
reconciled with the safety database. 
All concomitant medications and prior cancer therapies will be coded using the World Health 
Organization Drug Reference (WHO-DD) Dictionary. 
13.2.5. 
Committees 
Interstitial Lung Disease Adjudication Committee 
An external ILD AC will be used for this study.  Details on the membership, responsibilities, and 
working procedures of the external ILD AC will be described in its own charter, provided as a 
separate document.  The ILD AC will adjudicate all cases of potential ILD on an ongoing basis.  
Adjudication of ILD cases will be based on evaluation of eCRFs and source documents 
including, but not limited to, chest high-resolution CT, arterial blood gases, and carbon 
monoxide diffusing capacity.  The ILD AC will review ongoing cases of ILD to make the final 
determination of ILD diagnoses to guide Sponsor decisions regarding trial suspension or trial 
discontinuation and to provide assessment of ILD prevalence at the end of the study.  Findings of 
the ILD AC with its recommendations will be provided to the Sponsor. 


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13.2.6. 
Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties.  All persons authorized to obtain informed consent and make 
entries and/or corrections on eCRFs will be included on the Signature List. 
Investigators will maintain a confidential screening log of all potential study candidates that 
includes limited information of the subjects, date and outcome of the screening process. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study number. 
Investigators will maintain a confidential subject identification code list.  This confidential list of 
names of all subjects allocated to study numbers on enrolling in the study allows the Investigator 
to reveal the identity of any subject when necessary. 
Source documents are original documents, data, and records from which the subject9s eCRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, X-rays, and correspondence. 
Records of subjects, source documents, monitoring visit logs, data correction forms, eCRFs, 
inventory of study drug, regulatory documents (eg, protocol and amendments, IEC/IRB 
correspondence and approvals, approved and signed ICFs, Investigator9s Agreement, clinical 
supplies receipts, distribution and return records), and other Sponsor correspondence pertaining 
to the study must be kept in appropriate study files at the study site (site specific Trial Master 
File).  Source documents include all recordings and observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of the 
clinical study.  These records will be retained in a secure file for the period required by local 
laws or regulations or study site policy.  Prior to transfer or destruction of these records, the 
Sponsor must be notified in writing and be given the opportunity to provide further instruction. 
Record Keeping 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (site specific Trial Master File) of all study-related (essential) documentation, 
suitable for inspection at any time by representatives from the Sponsor and/or applicable 
regulatory authorities.  Essential documents include: 
÷ Subject files containing completed eCRFs, ICFs, and supporting source 
documentation (if kept). 
÷ Study files containing the protocol with all amendments, Investigator9s Brochure, 
copies of relevant essential documents required prior to commencing a clinical study, 
and all correspondence to and from the independent IRB/EC and the Sponsor. 
÷ Records related to the study drug(s) including acknowledgment of receipt at study 
site, accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
All essential documentation will be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 


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contemplated marketing applications in an ICH region or at least 2 years have lapsed since the 
formal discontinuation of clinical development of the investigational drug.  These documents 
should be retained for a longer period, however, if required by the applicable laws or regulatory 
requirements or by an agreement with the Sponsor.  It is the responsibility of the Sponsor to 
inform the Investigator/Institution as to when these documents no longer need to be retained. 
Subjects9 medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice.  
No study document should be destroyed without prior written agreement between the Sponsor 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor in writing of the new responsible 
person and/or the new location. 
13.2.7. 
Finances 
Prior to starting the study, the Principal Investigator and/or Institution will sign a clinical study 
agreement with the Sponsor.  This agreement will include the financial information agreed upon 
by the parties. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 
13.2.8. 
Publication and Public Disclosure Policy 
The Sponsor is committed to meeting the highest standards of publication and public disclosure 
of information arising from clinical studies sponsored by the company.  The Sponsor will 
comply with US, EU, and Japanese policies for public disclosure of the clinical study protocol 
and clinical study results, and for sharing of clinical study data.  The Sponsor will follow the 
principles set forward in <Good Publication Practice for Communicating Company-Sponsored 
Medical Research (GPP3)=, and publications will adhere to the <Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals= 
established by the International Council of Medical Journal Editors (ICMJE). 
In order to ensure compliance with the public disclosure policies and the ICMJE 
recommendations, and to protect proprietary information generated during the study, all 
publications (manuscripts, abstracts, or other public disclosure) based on data generated in this 
study must be reviewed and approved in writing by the Sponsor prior to submission. 
13.2.9. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by the 
Sponsor and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the IECs/IRBs. 


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A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the subject. 
The Sponsor must be notified in writing of all intended or unintended deviations to the protocol 
(eg, inclusion/exclusion criteria, dosing, missed study visits) within 24 hours and in accordance 
with the clinical study agreement between the parties. 
The Investigator, or person designated by the Investigator, should document and explain any 
deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or study treatment, and had at least one 
administration of study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the IEC/IRB of deviations from the protocol in 
accordance with local procedures. 
13.2.10. 
Study and Site Closure 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor.  Study sites will be closed upon study completion.  A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
÷ Failure of the Investigator to comply with the protocol, the requirements of the 
IEC/IRB or local health authorities, the Sponsor's procedures, or GCP guidelines 
÷ Inadequate recruitment of subjects by the Investigator 
÷ Discontinuation of further study intervention development 
Study termination may also be requested by a competent authority. 
At the time of study closure, any subjects who are continuing treatment with U3-1402 and who 
are judged by the Investigator to have ongoing benefit may continue to receive treatment with 
U3-1402 through a rollover protocol or another mechanism consistent with local requirements. 
13.2.11. 
Product Complaints 
A product complaint is any dissatisfaction with a product that may be attributed to the identity, 
quality, durability, reliability, or safety of the product.  Individuals who identify a potential 
product complaint situation should immediately report the event.  Whenever possible, the 
associated product should be maintained in accordance with the label instructions pending 
further guidance from a quality representative from the Sponsor. 
For product complaints, refer to the Pharmacy Manual for instructions and details. 


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13.3. 
Cockcroft-Gault Equation  
The estimated creatinine clearance rate (CrCl; mL/min) will be calculated using the 
Cockcroft-Gault equation based on actual weight, where weight is lean body mass in kilograms 
(1 kilogram = 2.2 pounds)43: 
Conventional: serum creatinine in mg/dL: 
Male: 
CrCl (mL/min) = 
 
Female: 
CrCl (mL/min) = 
72
 
 
mg/dL)
 
(in
 
creatinine
 
serum
kg)
 
(in
 weight 
 
 years)]
(in
 
age
 - 
[140
ô
ô
 ô 0.85 
International System of Units (SI): serum creatinine in ¿mol/L: 
Male: 
CrCl (mL/min) = 
 
Female: 
CrCl (mL/min) = 
0.0113
 
 
72
 
 
mol/L)
 
(in
 
creatinine
 
serum
kg)
 
(in
 weight 
 
 years)]
(in
 
age
 - 
[140
ô
ô
ô
ý
 ô 0.85 
13.4. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
13.4.1. 
Measurability of Tumor at Baseline 
13.4.1.1. Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
13.4.1.1.1. Measurable 
÷ Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of: 
ý 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
ý 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
ý 20 mm by chest X-ray 
÷ Measurable malignant lymph nodes:  To be considered pathologically enlarged and 
measurable, a lymph node must be ó15 mm in short axis when assessed by CT scan 
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(CT scan slice thickness recommended to be no greater than 5 mm).  At baseline and 
in F/U, only the short axis will be measured and followed.  See also notes below on 
<Baseline documentation of target and non-target lesions= for information on lymph 
node measurement. 
13.4.1.1.2. Non-measurable 
All other lesions, including small lesions (longest diameter ü10 mm or pathological lymph nodes 
with ó10 to ü15 mm short axis), as well as truly non-measurable lesions.  Lesions considered 
truly non-measurable include:  leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
13.4.1.1.3. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment. 
13.4.1.1.3.1. Bone Lesions 
÷ Bone scan, positron emission tomography scan or plain films are not considered 
adequate imaging techniques to measure bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions. 
÷ Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
÷ Blastic bone lesions are non-measurable. 
13.4.1.1.3.2. Cystic Lesions 
÷ Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
÷ <Cystic lesions= thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if noncystic lesions are present in the same subject, these are preferred for 
selection as target lesions. 
13.4.1.1.3.3. Lesions with Prior Local Treatment 
÷ Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion. 


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13.4.1.2. Specifications by Methods of Measurements 
13.4.1.2.1. Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and NEVER 
more than 30 days before the first dose of U3-1402. 
13.4.1.2.2. Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation should 
always be performed rather than clinical examination unless the lesion(s) being followed cannot 
be imaged but are assessable by clinical exam. 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (eg, for body scans). 
13.4.2. 
Tumor Response Evaluation 
13.4.2.1. Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. 
Only subjects with measurable disease at baseline should be included in the study. 
13.4.2.2. Baseline Documentation of <Target= and <Non-target= Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (representative of all involved organs) should be identified as target lesions and 
will be recorded and measured at baseline (this means in instances where subjects have only 1 or 
2 organ sites involved a maximum of 2 and 4 lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  As noted above, pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of ó15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor.  Nodal size is normally reported as 2 dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
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For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ó10 mm 
but ü15 mm) should be considered non-target lesions.  Nodes that have a short axis ü10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required, and 
these lesions should be followed as <present,= <absent,= or in rare cases <unequivocal 
progression.=  In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg, <multiple enlarged pelvic lymph nodes= or 
<multiple liver metastases=). 
13.4.2.3. Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
13.4.2.3.1. Evaluation of Target Lesions 
CR:  Disappearance of all target lesions.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to ü10 mm. 
PR:  At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
Progressive disease:  At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also considered 
progression). 
SD:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
progressive disease, taking as reference the smallest sum diameters while on study. 
13.4.2.3.2. Special Notes on the Assessment of Target Lesions 
Lymph nodes:  Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that when lymph 
nodes are included as target lesions, the <sum= of lesions may not be 0 even if CR criteria are 
met, since a normal lymph node is defined as having a short axis of ü10 mm.  For PR, SD, and 
progressive disease, the actual short axis measurement of the nodes is to be included in the sum 
of target lesions. 


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Target lesions that become <too small to measure=:  While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes lesions or lymph 
nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
<too small to measure.=  When this occurs, it is important that a value be recorded on the eCRF.  
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned (Note:  It is less likely that this rule 
will be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well).  This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness).  The 
measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error.  To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if 
it is below 5 mm. 
Lesions that split or coalesce on treatment:  When non-nodal lesions <fragment,= the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum.  
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the <coalesced lesion.= 
13.4.2.3.3. Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
CR:  Disappearance of all non-target lesions and normalization of tumor marker level.  All 
lymph nodes must be non-pathological in size (ü10 mm short axis). 
Non-CR/Non-progressive disease:  Persistence of 1 or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive disease:  Unequivocal progression (see comments below) of existing non-target 
lesions (Note:  The appearance of 1 or more new lesions is also considered progression). 
13.4.2.3.4. Special Notes on Assessment of Progression of Non-target Disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the subject also has measurable disease:  In this setting, to achieve <unequivocal 
progression= on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A modest 


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<increase= in the size of 1 or more non-target lesions is usually not sufficient to quality for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the subject has only non-measurable disease:  The same general concepts apply here as 
noted above, however, in this instance there is no measurable disease assessment to factor into 
the interpretation of an increase in non-measurable disease burden.  Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable) a useful test that can be applied when assessing subjects for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare progressive disease for measurable disease (ie, an increase in tumor burden representing 
an additional 73% increase in <volume= [which is equivalent to a 20% increase diameter in a 
measurable lesion]).  If <unequivocal progression= is seen, the subject should be considered to 
have had overall progressive disease at that point.  While it would be ideal to have objective 
criteria to apply to non-measurable disease, the very nature of that disease makes it impossible to 
do so, therefore the increase must be substantial. 
13.4.2.3.5. New Lesions 
The appearance of new malignant lesions denotes disease progression.  There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal:  ie, not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, 
some <new= bone lesions may be simply healing or flare of preexisting lesions).  This is 
particularly important when the subject9s baseline lesions show PR or CR.  For example, 
necrosis of a liver lesion may be reported on a CT scan report as a <new= cystic lesion, which it 
is not. 
A lesion identified on an F/U study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression.  An example of this is the subject 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases.  The subject9s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and F/U 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
13.4.2.4. Evaluation of Overall Response 
13.4.2.4.1. Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 13.2 provides a summary of the overall response status calculation at each time point for 
subjects who have measurable disease at baseline. 


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Table 13.2: 
Overall Response: Subjects with Target (± Non-target) Disease 
Time Point Response: Subjects with Target (± Non-target) Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial response;  
SD = stable disease. 
13.4.2.4.2. Missing Assessments and Inevaluable Designation 
When no imaging/measurement is performed at all at a particular time point, the subject is not 
evaluable (NE) at that time point.  If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response.  This would be most likely to happen in the case of progressive 
disease.  For example, if a subject had a baseline sum of 50 mm with 3 measured lesions and at 
follow-up only 2 lesions were assessed, but those gave a sum of 80 mm, the subject will have 
achieved progressive disease status, regardless of the contribution of the missing lesion. 
13.4.2.4.3. Best Overall Response: All Time Points 
Best response determination in trials where confirmation of complete or partial response is 
required:  when SD is believed to be best response, it must also meet the protocol-specified 
minimum time from baseline, 6 weeks (21 week).  If the minimum time is not met when SD is 
otherwise the best time point response, the subject9s best response depends on the subsequent 
assessments.  Complete or partial responses may be claimed only if the criteria for each are met 
at a subsequent time point as specified in the protocol.  In this circumstance, the best overall 
response can be interpreted as in Table 13.3. 


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Table 13.3: 
Best Overall Response when Confirmation of CR and PR Required 
Overall Response 3 
First Time Point 
Overall Response 3 
Subsequent Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, NE 
NE 
NE 
NE 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  
Best response would depend on whether minimum duration for SD (6 weeks) was met.  However, sometimes 8CR9 
may be claimed when subsequent scans suggest small lesions were likely still present and in fact the subject had 
PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR and the 
best response is PR. 
13.4.2.4.4. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to <normal= 
size (ü10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that subjects with CR may 
not have a total sum of <zero= on the eCRF. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
<symptomatic deterioration.=  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such subjects is to be determined by evaluation of target and non-target disease. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 


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the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
13.5. 
New York Heart Association 
The ninth edition, revised by the Criteria Committee of the American Heart Association, New 
York City Affiliate, was released 14 Mar 1994.44  The new classifications are summarized below 
for the many physicians and scientists who use them to describe the status of individual patients. 
Functional Capacity  
Objective Assessment  
Class I.  Patients with cardiac disease but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
A.  No objective evidence 
of cardiovascular disease. 
Class II.  Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
B.  Objective evidence of 
minimal cardiovascular 
disease. 
Class III.  Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
C.  Objective evidence of 
moderately severe 
cardiovascular disease. 
Class IV.  Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased. 
D.  Objective evidence of 
severe cardiovascular 
disease. 
13.6. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
The Eastern Cooperative Oncology Group performance status scale45 is summarized in 
Table 13.4. 
Table 13.4: 
Eastern Cooperative Oncology Group Performance Status Scale Grade 
Description 
GRADE 
DESCRIPTION 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work). 
2 
In bed ü50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead. 


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13.7. 
National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0 
1. Toxicity Grade should reflect the most severe degree occurring during the evaluated 
period, not an average. 
2. When 2 different criteria Grades might be applicable for rating a particular toxicity, or 
similar toxicities, the more severe Grade should be used. 
3. Any toxicity resulting in death is defined as Grade 5. 
4. The evaluator must attempt to discriminate between disease/treatment and related 
signs/symptoms. 
5. For links to the NCI-CTCAE v5.0, please refer to 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40  
13.8. 
Highly Effective Contraception 
Male and female subjects of reproductive/childbearing potential must agree to use a highly 
effective form of contraception or avoid intercourse during and upon completion of the study for 
at least 4 months for male and for at least 7 months for female after the last dose of study drug.  
Methods considered to be highly effective contraception include:46   
÷ Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
ý Oral 
ý Intravaginal 
ý Transdermal 
÷ Progestogen-only hormonal contraception associated with inhibition of ovulation: 
ý Oral 
ý Injectable 
ý Implantable 
÷ Intrauterine device 
÷ Intrauterine hormone-releasing system 
÷ Bilateral tubal occlusion 
÷ Vasectomized partner 
÷ Complete sexual abstinence 
 


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13.9. 
Instructions Related to Coronavirus Disease 2019 (COVID-19) 
Due to the potential impact of coronavirus disease 2019 (COVID-19, due to severe acute 
respiratory syndrome coronavirus 2 [SARS CoV-2]), on subject safety, the Sponsor recommends 
the following dose modification and management plan for subjects with confirmed or suspected 
COVID-19 while being treated with U3-1402.  Dose modifications will be based on the worst 
CTCAE grade.  Use CTCAE version 5.0 general grading criteria to evaluate COVID-19.  All 
dose modifications (discontinuation, interruptions or reductions) must be recorded on the AE and 
drug administration eCRFs. 
Dose Modification Criteria for Suspected or Confirmed COVID-19 
If COVID-19 infection is suspected, interrupt U3-1402 and rule out SARS-CoV-2 per local 
guidance. 
÷ If COVID-19 is ruled out, follow dose modification and management guidance as 
outlined in Table 5.2. 
÷ If COVID-19 is confirmed or is still suspected after evaluation, follow dose 
modification as outlined in Table 13.5 below and manage COVID-19 per local 
guidance until recovery of COVID-19.  COVID-19 recovery is defined as no 
signs/symptoms of COVID-19, at least 1 negative real-time reverse transcription 
polymerase chain reaction (RT-PCR) test result, and nearly or completely resolved 
chest CT findings. 
Table 13.5: 
COVID-19 Dose Modification Criteria 
COVID-19 Worst Toxicity NCI-CTCAE 
(Version 5.0 Grade unless otherwise specified) 
Schedule Modification for U3-1402 
Grade 1 
Resume study drug at the same dosea 
Grade 2 
Resume study drug at the same dose if chest CT 
findings are completely resolveda 
Reduce by 1 dose level if chest CT findings are 
nearly resolveda 
Grade 3 
Reduce by 1 dose level if chest CT findings are 
completely resolveda 
Discontinue study drug if chest CT findings are 
not completely resolved 
Grade 4 
Discontinue study drug 
CT = computed tomography; COVID-19 = coronavirus 2019; NCI-CTCAE = National Cancer Institute Common 
Terminology Criteria for Adverse Events;  
a Closely monitor signs/symptoms after resuming U3-1402, initially with a phone call every 3 days for the first 
week, and then with a weekly phone call thereafter, for a total of 6 weeks. 
In addition to the recommendations outlined in Table 13.5, Investigators may consider dose 
modifications of the study drug according to the subject9s condition and after discussion with the 
study Medical Monitor or designee. 


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If an event is suspected to be drug-related ILD/pneumonitis, manage per protocol 
ILD/pneumonitis management guideline (Table 5.2). 
Prior and Concomitant Medications - Prohibited Therapies/Products 
÷ Chloroquine or hydroxychloroquine; 
ý Concomitant treatment is not allowed during the study treatment (Section 4.2). 
ý If treatment is absolutely required for COVID-19, U3-1402 must be interrupted. 
ý If administered, then a washout period of no less than 14 days is required before 
resumption of U3-1402. 
PK Assessment(s) if Chloroquine or Hydroxychloroquine is Administered 
Additional PK serum samples should be collected from each subject who provides consent, if 
chloroquine or hydroxychloroquine is administered for COVID-19 infection, at the time points 
specified in the Schedule of Events (Table 13.1). 
The chloroquine or hydroxychloroquine administration time and the exact time of blood sample 
collection for PK analysis must be recorded on the eCRF. 
COVID-19 Assessment(s) 
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF.  If a 
subject presents to the clinic with symptoms suggestive of COVID-19, but the real-time RT-PCR 
test is not available at the site (the participant must not have any signs or symptoms of 
COVID-19 infection for at least 2 weeks and nearly or completely resolved chest CT findings) a 
sample kit will be provided for sample collection to be tested at a central laboratory.  The results 
will be provided to the site from the central laboratory. 
Serum samples will be used for COVID-19 testing from each subject who provides 
consent.  Samples will be collected prior to the study drug infusion, at the time points specified 
in the Schedule of Events (Table 13.1), shipped to a central laboratory, and stored there until the 
tests become available. 
If the subject consents, the remaining serum samples will also be stored for future analysis. 
Sample collection, preparation, handling, storage, and shipping instructions are provided in the 
Study Laboratory Manual. 
Statistical Analysis - Assessment of the Impact of COVID-19 
If deemed appropriate, analyses will be performed to explore the impact of COVID-19 on the 
safety, efficacy, and any other endpoints, as appropriate, reported for the study. 
As a result of the impact of COVID-19 on study conduct, adjustments to the statistical analysis 
and interpretation will be made, if required.  These will be described in the statistical analysis 
plan. 
13.10. 
Membrane Transport Inhibitors 
A list of membrane transport inhibitors is available at the link provided: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers#table5-2.