Conditions: Metastatic Breast Cancer
Keywords: Oncology HER3 Antibody drug conjugate Developmental Phase I/II
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 182
Healthy volunteers: no

Brief summary:
This is an open-label, three-part, multiple-dose study to evaluate safety, tolerability, and efficacy of U3-1402 in patients with HER3-positive metastatic breast cancer. HER3 is a unique member of the human epidermal growth factor receptor, which defines a certain type of cancer.

The number of patients and treatment cycles are not fixed in this study. Subjects who continue to derive clinical benefit from the study treatment in the absence of withdrawal of consent, progressive disease (PD), unacceptable toxicity, or death may continue the study treatment until the end of the trial.

Detailed description:

Arms:
arm 1: Participants receive U3-1402 from 1.6 mg/kg to 8.0 mg/kg, administered via intravenous (IV) solution at 3-week intervals. arm 2: Participants receive 1 of 5 different U3-1402 dosing regimens, administered via IV solution at 2 or 3-week intervals at doses at or lower than those studied in the Dose Escalation Part. arm 3: Participants with HER3 high, HER2 negative, HR positive status receive 4.8 mg/kg or 6.4 mg/kg of U3-1402 administered via intravenous (IV) solution at 3-week intervals. Participants with HER3 low, HER2 negative, HR positive status receive 6.4 mg/kg of U3-1402 administered via intravenous (IV) solution at 3-week intervals. Participants with HER3 high, HER2 negative, HR negative status receive 6.4 mg/kg of U3-1402 administration via intravenous (IV) solution at 3-week intervals.

Interventions: intervention 1: Patritumab Deruxtecan
Intervention descriptions: intervention 1: U3-1402 consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a)

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
Page 1 
CLINICAL STUDY PROTOCOL 
 
PHASE 1/2, MULTICENTER, OPEN-LABEL, MULTIPLE 
DOSE, FIRST-IN-HUMAN STUDY OF U3-1402 IN 
SUBJECTS WITH HER3-POSITIVE METASTATIC 
BREAST CANCER 
 
U31402-A-J101 
VERSION 9.0, 8 NOV 2022 
VERSION 8.0, 25 MAY 2022 
VERSION 7.0, 28 OCT 2021 
VERSION 6.0, 15 SEP 2020 
VERSION 5.0, 05 SEP 2019 
VERSION 4.0, 29 MAR 2019 
VERSION 3.0, 26 JUN 2018 
VERSION 2.0, 06 FEB 2018 
VERSION 1.0, 10 AUG 2016 
 
DAIICHI SANKYO 
1-2-58, HIROMACHI 
SHINAGAWA-KU, TOKYO 
140-8710 JAPAN 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo.  The information is 
provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement.  Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 


U31402-A-J101 Clinical Study Protocol 
Version 9.0, 8 Nov 2022 
 
Proprietary and Confidential 
Page 2 
Disclosure Agreement) without the prior written permission of an authorized representative of 
Daiichi Sankyo. 


U31402-A-J101 Clinical Study Protocol 
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Proprietary and Confidential 
Page 3 
INVESTIGATOR AGREEMENT 
PHASE 1/2, MULTICENTER, OPEN-LABEL, MULTIPLE DOSE, 
FIRST-IN-HUMAN STUDY OF U3-1402 IN SUBJECTS WITH 
HER3-POSITIVE METASTATIC BREAST CANCER 
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by the Daiichi Sankyo 
representative listed below. 
 
Print Name 
Signature 
 Global Oncology 
Research and Development 
Title 
Date (DD MMM YYYY) 
Investigator’s Signature: 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that information contained in or pertaining to this protocol is confidential and should 
not be disclosed, other than to those directly involved in the execution or the ethical review of the 
study, without written authorization from the Sponsor.  It is, however, permissible to provide 
information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in accordance 
with the Declaration of Helsinki, International Council for Harmonisation guidelines on Good 
Clinical Practice (ICH E6), and applicable regional regulatory requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant regulatory 
authorities, my subjects’ study records in order to verify the data that I have entered into the case 
report forms.  I am aware of my responsibilities as a Principal Investigator as provided by the 
Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing.  Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the Sponsor. 
Print Name 
Signature 
Title 
Date (DD MMM YYYY) 
PPD
PPD


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SUMMARY OF CHANGES 
 
 
Amendment Rationale: 
The main purpose of this amendment is to revise the estimated study duration.. 
Changes to the Protocol: 
Please refer to the comparison document for protocol Version 9.0 (dated 8 Nov 2022) versus 
protocol Version 8.0 (dated 25 May 2022) for actual changes in-text.  The summary of changes 
below is a top-line summary and rationale of major changes in the U31402-A-J101 clinical study 
protocol (Version 9.0) by section. 
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 this Summary of Changes. 
Minor edits, such as updates to language that do not alter original meaning, update to version 
numbering, formatting, change in font color, corrections to typographical errors, use of abbreviations, 
moving verbiage within a section or table, change in style, or changes in case, are not noted in the table 
below. 
 
Section # and Title 
Description of Change 
Brief Rationale 
Section 3.1.1.3 Duration of 
the Study 
Section 17.2.2 Study Period 
Protocol Synopsis, Study 
Duration   
Study period was updated from 6 
years to 7 years (Nov 2016 to Dec 
2023). 
Study period was prolonged. 


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PROTOCOL SYNOPSIS 
EudraCT: 
NA 
IND Number: 
137503 
Protocol Number: 
U31402-A-J101 
Investigational Product: 
U3-1402 
Active Ingredient(s)/INN: 
U3-1402 consists of an antibody component (patritumab, U3-1287) 
covalently conjugated to a drug-linker (MAAA-1162a) containing a 
drug component (MAAA-1181a). 
Study Title: 
Phase 1/2, Multicenter, Open-label, Multiple Dose, First-in-human 
Study of U3-1402 in Subjects with HER3-Positive Metastatic Breast 
Cancer 
Study Phase: 
Phase 1/2 
Indication Under Investigation: 
U3-1402 will be evaluated in subjects with human epidermal growth 
factor receptor 3 (HER3)-positive, advanced/unresectable or 
metastatic breast cancer. 
Study Objectives: 
Primary Objectives: 
Dose Escalation Part 
1. To assess safety and tolerability of U3-1402. 
2. To determine the maximum tolerated dose (MTD) of U3-1402. 
Dose Finding Part 
1. To assess safety and evaluate efficacy of U3-1402. 
2. To assess the safety of alternative dosing schedule(s) of U3-1402. 
3. To determine the recommended dose(s) for expansion (RDEs) of 
U3-1402. 
Dose Expansion Part 
1. To assess safety and evaluate efficacy of U3-1402 at the RDEs in 
subjects with HER3-positive, human epidermal growth factor 
receptor 2 (HER2)-negative (including HR-positive and triple 
negative breast cancer [TNBC; HR-negative]) 
advanced/unresectable or metastatic breast cancers. 
Secondary Objectives: 
Dose Escalation Part 
1. To assess the pharmacokinetics (PK) profiles of U3-1402, total 
anti-HER3 antibody, and MAAA-1181a. 
2. To evaluate the efficacy of U3-1402. 
3. To assess the incidence of anti-drug antibodies (ADAs) against 
U3-1402. 
Dose Finding and Dose Expansion Parts 
1. To assess the PK profiles of U3-1402, total anti-HER3 antibody, 
and MAAA-1181a. 
2. To assess the incidence of ADA against U3-1402. 
Dose Expansion Part 
1. To determine the relationship between efficacy of U3-1402 and 
HER3 expression 


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Exploratory Objectives: 
1. To explore the concentration-corrected QT (QTc) relationships of 
U3-1402, total anti-HER3 antibody, and MAAA-1181a. 
2. To identify biomarkers that correlate with U3-1402 response or 
toxicity. 
Study Design: 
This is a Phase 1/2, multicenter, open-label, multiple dose, 
first-in-human study of U3-1402 in subjects with HER3-positive 
advanced/unresectable or metastatic breast cancer.  This study consists 
of 3 parts:  Dose Escalation, Dose Finding, and Dose Expansion. 
In the Dose Escalation Part, eligible subjects with HER3-high breast 
cancer who have been refractory to or intolerant to standard treatment, 
or for whom standard treatment is no longer available, will be 
enrolled. 
In the Dose Finding Part, eligible subjects with HER3-high breast 
cancer who have received ≥2 and ≤6 prior chemotherapy regimens 
(including ≥2 regimens given in the advanced disease setting) will be 
enrolled. 
In the Dose Expansion Part, eligible subjects with HER3-positive, 
HER2-negative, HR-positive breast cancer who have received ≥2 and 
≤6 prior chemotherapy regimens for breast cancer (including 
≥2 regimens administered for the treatment of advanced/unresectable 
or metastatic disease), and eligible subjects with HER3-high TNBC 
who have received 1 to 2 prior chemotherapy regimens in the 
advanced disease setting will be enrolled. 
Dose Escalation Part 
Beginning with Cycle 1, Day 1, U3-1402 will be administered via 
intravenous (IV) infusion once every 3 weeks (Q3W), in 21-day 
cycles. The treatment will continue until unacceptable toxicity, 
progressive disease (PD), or withdrawal of consent. The starting dose 
for the Dose Escalation Part will be 1.6 mg/kg. 
Dose escalation will be guided by the modified Continuous 
Reassessment Method (mCRM) using a Bayesian logistic regression 
model (BLRM) following the escalation with overdose control 
(EWOC) principle. In this method, a decision to escalate to the next 
dose cohort will be based on review of all subjects who have 
completed the dose-limiting toxicity (DLT) evaluation period. 
This DLT evaluation period is defined as the 21 days of Cycle 1. A 
DLT-evaluable subject is defined as any subject who has received at 
least one dose of U3-1402, with the exception of those subjects for 
whom DLT evaluation could not be adequately conducted. 
The second subject in each dosing level should receive dosing at least 
24 hours after the initial dosing of the first subject. This allows to 
check for acute toxicity such as an infusion-related reaction. 
The Dose Escalation Part will be conducted in Japan only. 
Dose Finding Part 
During the Dose Finding Part, subjects will be assigned into cohorts 
with multiple drug administration schedules, including up-titration of 
dose.  The objectives of the Dose Finding Part are to assess safety and 


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evaluate efficacy of U3-1402.  The Dose Finding Part will be 
conducted in Japan only. 
The following Dose Finding Cohorts may be evaluated. These cohorts 
are provisional, and may change based on emerging safety, 
tolerability, and efficacy data: 
Dose Finding Cohort 1  
 
U3-1402 at a dosage of 4.8 mg/kg administered via IV 
infusion Q3W in 21-day cycles. 
Dose Finding Cohort 2 
 
U3-1402 at a dosage of 6.4 mg/kg administered via IV 
infusion Q3W in 21-day cycles. 
Dose Finding Cohort 3  
 
U3-1402 administered via IV infusion Q3W in 21-day cycles 
with an up-titration of U3-1402 dose on Day 1 of the first 
3 cycles as described below: 
o Cycle 1, Day 1:  3.2 mg/kg 
o Cycle 2, Day 1:  4.8 mg/kg 
o Cycle 3, Day 1 and subsequent cycles:  6.4 mg/kg 
Dose Finding Cohort 4 
 
U3-1402 administered via IV infusion at a dosage of 
4.2 mg/kg Q2W in 14-day cycles for 3 cycles, followed by a 
dosage of 6.4 mg/kg administered via IV infusion Q3W 
thereafter. 
Dose Finding Cohort 5 
 
U3-1402 administered via IV infusion at a dosage of 
3.2 mg/kg Q2W in 14-day cycles for 3 cycles, followed by a 
dosage of 4.8 mg/kg administered via IV infusion Q3W 
thereafter. 
 
Additional Dose Finding Cohorts 
 
Additional dose levels equal to, or less than, the MTD (if 
attained or highest dose evaluated during the Dose Escalation 
Part) may be considered for the Dose Finding Part. 
 
Additional dose regimens, including up-titration of dose, may 
be considered for the Dose Finding Part based on emerging 
safety and efficacy data. 
Dose Expansion Part 
In the Dose Expansion Part, subjects will be assigned to cohorts as 
described below. The objectives of the Dose Expansion Part are to 
assess safety and evaluate efficacy of U3-1402 at the RDEs in subjects 
with HER3-positive, HER2-negative (including HR-positive and 
TNBC) advanced/unresectable or metastatic breast cancers.  The Dose 
Expansion Part may include subjects from any participating country, 
including the United States (US) and Japan. 
A total of approximately 110 subjects will be enrolled in the Dose 
Expansion Part among the following 4 cohorts: 


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HER3-High, HR-Positive Cohorts 
Approximately 60 eligible subjects with HER3-high, HER2-negative, 
HR-positive breast cancer will be randomized into 1 of 2 cohorts.  
Subjects will receive U3-1402 at a dosage of either 4.8 mg/kg or 
6.4 mg/kg administered via IV infusion Q3W. 
HER3-Low, HR-Positive Cohort 
Approximately 20 eligible subjects with HER3-low, HER2-negative, 
HR-positive breast cancer will be enrolled.  U3-1402 at a dosage of 
6.4 mg/kg will be administered via IV infusion Q3W. 
HER3-High, TNBC Cohort 
Approximately 30 eligible subjects with HER3-high, TNBC will be 
enrolled. U3-1402 at a dosage of 6.4 mg/kg will be administered via 
IV infusion Q3W. 
Additional Expansion Cohort(s) 
Additional cohorts may be considered for the Dose Expansion Part 
based on emerging safety and efficacy data. 
Study Duration: 
This study is expected to last approximately 7 years from the time the 
first subject is enrolled to the time the last subject is off the study. The 
end of the study is defined as the date of completion of the last visit or 
procedure shown in the Schedule of Events in the trial globally. 
Sponsor may terminate the study at any time due to administrative 
reason or at request from competent regulatory authorities. 
The number of treatment cycles is not limited in this study.  Subjects 
will continue the study treatment until withdrawal of consent, PD, 
unacceptable toxicity, death, or termination of the study by Sponsor. 
Study Sites and Location: 
Approximately 20 study sites in Japan and the United States are 
planned for this study.  
Subject Eligibility Criteria: 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the 
study: 
Common Inclusion Criteria for Dose Escalation Part and Dose 
Finding Part 
1. Has a pathologically documented advanced/unresectable or 
metastatic breast cancer. 
2. Has documented HER3-high expressing disease assessed using 
IHC testing by the central laboratory. 
3. Is refractory to or intolerant to standard treatment, or for whom 
standard treatment is no longer available. 
4. Male or female subjects aged 20 years in Japan. 
5. Has an Eastern Cooperative Oncology Group (ECOG) 
Performance Status (PS) 0-1, with no deterioration over the 
previous 2 weeks. 
6. Has left ventricular ejection fraction (LVEF)  50% by either 
echocardiography (ECHO) or multiple gated acquisition scan 
(MUGA) within 28 days prior to enrollment. 
7. Has adequate bone marrow reserve and organ function within 
7 days prior to enrollment, defined according to the following: 
 


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Item 
Laboratory value 
Platelet count 
100 000/mm3 
Hemoglobin (Hb) 
≥8.5 g/dL 
Absolute neutrophil 
count (ANC) 
1500/mm3 
Creatinine 
≤1.5  upper limit of normal (ULN), or 
creatinine clearance ≥60 mL/min as 
calculated using the Cockcroft-Gault 
equation 
Serum aspartate 
aminotransferase 
(AST)/Serum alanine 
aminotransferase (ALT) 
≤3  ULN (if liver metastases are 
present, ≤5  ULN) 
Total bilirubin 
≤1.5  ULN 
8. Has adequate treatment washout period before enrollment, defined 
according to the following: 
Treatment 
Washout period 
Major surgery 
3 weeks 
Radiation therapy 
≥3 weeks (or 2 weeks for palliative 
radiation for bone metastasis [excluding 
pelvic radiation] and brain metastasis, 
1 week for stereotactic radiotherapy) 
Hormonal therapy 
2 weeks 
Chemotherapy 
(including antibody drug 
therapy) 
3 weeks (2 weeks for 5-fluorouracil-
based agents, folinate agents, or weekly 
paclitaxel.  6 weeks for nitrosoureas or 
mitomycin C) 
Immunotherapy 
3 weeks 
Cytochrome P450 (CYP) 
3A4 strong inhibitor 
3 elimination half-lives of the inhibitor 
CYP3A4 strong inducer 
2 weeks 
QTc-prolonging 
medications 
3 elimination half-lives of the 
medications 
OATP1B inhibitor 
3 elimination half-lives of the inhibitor 
9. Has at least 1 measurable lesion based on Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 confirmed by the 
central laboratory. 
10. Male and female subjects of reproductive/childbearing potential 
must agree to use a highly effective form of contraception or 
avoid intercourse during the study and for at least 7 months after 
the last dose of study drug.  For the purpose of this protocol, 
methods considered as highly effective methods of contraception 
include: 
a. Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, or transdermal delivery). 


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b. Progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, or implantable 
delivery). 
c. Intrauterine device (IUD). 
d. Intrauterine hormone-releasing system (IUS). 
e. Bilateral tubal occlusion. 
f. Vasectomized partner. 
g. Complete sexual abstinence. 
Non-childbearing potential is defined as pre-menopausal with 
documented tubal ligation or hysterectomy; OR postmenopausal 
with documented ≥12 months of spontaneous amenorrhea (in 
questionable cases, a blood sample with simultaneous 
follicle-stimulating hormone [FSH] >40 mIU/mL and estradiol 
<40 pg/mL [<140 pmol/L] is confirmatory). 
Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to discontinue HRT 
and use 1 of the contraception methods outlined above for women 
of childbearing potential.  Otherwise, they must discontinue HRT 
to allow confirmation of post-menopausal status prior to study 
enrollment.  For most forms of HRT, at least 2 to 4 weeks must 
elapse between the cessation of therapy and the blood draw; this 
interval depends on the type and dosage of HRT.  Use of HRT is 
not allowed during the study.  Men who are fertile and sexually 
active should be willing to use highly effective methods of 
contraception if their partners are of reproductive potential. 
Male subjects must not freeze or donate sperm starting at 
Screening and throughout the study period, and at least 4 months 
after the final study drug administration. 
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 ≥7 months after the final dose of study drug. 
11. Is able to provide written informed consent.   
12. Has a life expectancy of ≥3 months. 
Additional Inclusion Criterion for Dose Finding Part 
13. Has received ≥2 and ≤6 prior chemotherapeutic regimens for 
breast cancer, ≥2 of which were administered for treatment of 
advanced/unresectable or metastatic disease.  At least 1 prior 
chemotherapeutic regimen must have included a taxane 
(eg, paclitaxel, docetaxel), administered in the neoadjuvant, 
adjuvant, or advanced setting. 
Inclusion Criteria for Dose Expansion Part 
1. Has a pathologically documented advanced/unresectable or 
metastatic breast cancer. 
2. Has documented HER3-positive (HER3-high or HER3-low) 
disease assessed by IHC assay by the central laboratory from 
archival tumor tissue or a screening tumor fresh biopsy sample. 
3. Is able to submit a fresh tumor biopsy sample prior to starting 
study treatment.  (If subjects have already submitted fresh tumor 


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biopsy sample for HER3 expression, resubmission is not 
necessary.) 
4. Has documented HER2-negative expression according to 
American Society of Clinical Oncology – College of American 
Pathologists (ASCO-CAP) guidelines. 
5. Has documented HR (estrogen and/or progesterone receptor) 
positive disease with exception of the TNBC cohort (see inclusion 
criterion #17 below). 
6. Is refractory to or intolerant to standard treatment, or for whom 
standard treatment is no longer available. 
7. With exception of the TNBC cohort (see inclusion criterion #18 
below), has received ≥2 and ≤6 prior chemotherapeutic regimens 
for breast cancer, ≥2 of which were administered for treatment of 
advanced/unresectable or metastatic disease. At least 1 prior 
chemotherapeutic regimen must have included a taxane 
(eg, paclitaxel, docetaxel), administered in the neoadjuvant, 
adjuvant, or advanced setting. 
8. Male or female subjects aged 20 years in Japan, 18 years in the 
United States. 
9. Has an ECOG PS 0-1, with no deterioration over the previous 
2 weeks. 
10. Has LVEF 50% by either ECHO or MUGA within 28 days prior 
to enrollment. 
11. Has adequate bone marrow reserve and organ function within 
7 days prior to enrollment, defined according to the following: 
Item 
Laboratory value 
Platelet count 
100 000/mm3 
Hemoglobin (Hb) 
≥9.0 g/dL 
Prothrombin time (PT) 
or PT-international 
normalized ratio (INR) 
and partial 
thromboplastin time 
(PTT) 
≤1.5 × 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. 
Absolute neutrophil 
count (ANC) 
1500/mm3 
Creatinine 
≤1.5  upper limit of normal (ULN), or 
creatinine clearance ≥50 mL/min as 
calculated using the Cockcroft-Gault 
equation 
Serum aspartate 
aminotransferase 
(AST)/Serum alanine 
aminotransferase (ALT) 
≤3  ULN (if liver metastases are 
present, ≤5  ULN) 
Total bilirubin 
≤1.5  ULN (<3 × ULN in the presence 
of documented Gilbert’s Syndrome 
[unconjugated hyperbilirubinemia] or 
liver metastases) 


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12. Has adequate treatment washout period before enrollment defined 
according to the following: 
Treatment 
Washout period 
Major surgery 
3 weeks 
Radiation therapy 
≥3 weeks (or 2 weeks for palliative 
radiation for bone metastasis [excluding 
pelvic radiation] and brain metastasis, 
1 week for stereotactic radiotherapy) 
Hormonal therapy 
2 weeks 
Chemotherapy 
(including antibody drug 
therapy) 
3 weeks (2 weeks for 5-fluorouracil-
based agents, folinate agents, or weekly 
paclitaxel.  6 weeks for nitrosoureas or 
mitomycin C) 
Immunotherapy 
3 weeks 
CYP3A4 strong inhibitor 
3 elimination half-lives of the inhibitor 
QTc-prolonging 
medications 
3 elimination half-lives of the 
medications 
OATP1B inhibitor 
3 elimination half-lives of the inhibitor 
13. Has at least 1 measurable lesion based on RECIST version 1.1 
confirmed by the central laboratory. 
14. Male and female subjects of reproductive/childbearing potential 
must agree to use a highly effective form of contraception or 
avoid intercourse during the study and for at least 7 months after 
the last dose of study drug.  For the purpose of this protocol, 
methods considered as highly effective methods of contraception 
include: 
a. Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, or transdermal delivery). 
b. Progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, or implantable 
delivery). 
c. Intrauterine device (IUD). 
d. Intrauterine hormone-releasing system (IUS). 
e. Bilateral tubal occlusion. 
f. Vasectomized partner. 
g. Complete sexual abstinence. 
Non-childbearing potential is defined as pre-menopausal with 
documented tubal ligation or hysterectomy; OR postmenopausal 
with documented ≥12 months of spontaneous amenorrhea (in 
questionable cases, a blood sample with simultaneous 
follicle-stimulating hormone [FSH] >40 mIU/mL and estradiol 
<40 pg/mL [<140 pmol/L] is confirmatory). 
Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to discontinue HRT 
and use 1 of the contraception methods outlined above for women 
of childbearing potential.  Otherwise, they must discontinue HRT 
to allow confirmation of post-menopausal status prior to study 


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enrollment.  For most forms of HRT, at least 2 to 4 weeks must 
elapse between the cessation of therapy and the blood draw; this 
interval depends on the type and dosage of HRT.  Use of HRT is 
not allowed during the study.  Men who are fertile and sexually 
active should be willing to use highly effective methods of 
contraception if their partners are of reproductive potential. 
Male subjects must not freeze or donate sperm starting at 
Screening and throughout the study period, and at least 4 months 
after the final study drug administration. 
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 ≥7 months after the final dose of study drug. 
15. Is able to provide written informed consent.   
16. Has a life expectancy of ≥3 months. 
Additional Inclusion Criteria for the HER3-high, TNBC 
Cohort 
17. Has a pathologically documented advanced/unresectable or 
metastatic breast cancer with HER3-high, HR- (estrogen and 
progesterone receptor) negative disease and HER2-negative 
expression according to American Society of Clinical Oncology – 
College of American Pathologists (ASCO-CAP) guidelines.  
18. Has progressed after receiving 1 to 2 prior chemotherapy 
regimens for advanced/unresectable or metastatic breast cancer.  
Exclusion Criteria 
Exclusion Criteria for Dose Escalation and Dose Finding Parts 
Subjects who meet any of the following criteria will be disqualified 
from entering the study in Dose Escalation and Dose Finding Parts: 
1. Prior treatment with an anti-HER3 antibody. 
2. Prior treatment with an antibody-drug conjugate (ADC) which 
consists of an exatecan derivative that is a topoisomerase I 
inhibitor (eg, DS-8201a). 
3. Has a medical history of symptomatic congestive heart failure 
(CHF) (New York Heart Association (NYHA) classes II-IV) or 
serious cardiac arrhythmia requiring treatment. 
4. Has a medical history of myocardial infarction or unstable angina 
within past 6 months prior to enrollment. 
5. Has a mean corrected QT by Fridericia’s formula (QTcF) 
prolongation to >450 milliseconds (ms) in males and >470 ms in 
females in 3 successive screening measurements as assessed by 
central laboratory. 
6. Has any history of interstitial lung disease (including pulmonary 
fibrosis or radiation pneumonitis), has current ILD/pneumonitis, 
or is suspected to have such disease by imaging during screening. 
7. Has clinically significant corneal disease. 
8. Has an uncontrolled infection requiring IV injection of antibiotics, 
antivirals, or antifungals. 
9. Has a positivity for human immunodeficiency virus (HIV), or 
active hepatitis B or C infection. 


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10. Is a lactating mother (women who are willing to temporarily 
interrupt breastfeeding will also be excluded), or pregnant as 
confirmed by pregnancy tests performed within 7 days prior to 
enrollment. 
11. Has clinically active spinal cord compression or brain metastases, 
defined as untreated and symptomatic, or requiring therapy with 
steroids or anticonvulsants to control associated symptoms.  
Subjects with treated brain metastases that are no longer 
symptomatic for 4 weeks before enrollment and who require no 
treatment with steroids may be included in the study if they have 
recovered from the acute toxic effect of radiotherapy. A minimum 
of 2 weeks must have elapsed between the end of whole brain 
radiotherapy and study enrollment (1 week for stereotactic 
radiotherapy). 
12. 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) version 5.0, grade ≤1 or baseline.  
Subjects with chronic grade 2 toxicities may be eligible per the 
discretion of the Investigator. 
13. Has a concomitant medical condition that would increase the risk 
of toxicity, in the opinion of the Investigator. 
14. Has known hypersensitivity to either the drug substances or 
inactive ingredients in the drug product. 
Additional Exclusion Criteria for Dose Finding Part 
15. Has multiple primary malignancies within 3 years, except 
adequately resected non-melanoma skin cancer, curatively treated 
in-situ disease, or other solid tumors curatively treated. 
Exclusion Criteria for Dose Expansion Part 
Subjects who meet any of the following criteria will be disqualified 
from entering the study in the Dose Expansion Part: 
1. Prior treatment with an anti-HER3 antibody. 
2. Prior treatment with an antibody-drug conjugate (ADC) which 
consists of a topoisomerase I inhibitor, exatecan derivative 
(eg, DS-8201a) or govitecan derivative (eg, IMMU-132). 
3. Has a medical history of symptomatic congestive heart failure 
(CHF) (New York Heart Association (NYHA) classes II-IV) or 
serious cardiac arrhythmia requiring treatment. 
4. Has a medical history of myocardial infarction or unstable angina 
within past 6 months prior to enrollment. 
5. Has any clinically important abnormalities in rhythm, conduction 
or morphology of resting ECG, eg, complete left bundle branch 
block, third-degree heart block, second-degree heart block, or PR 
interval >250 ms.   
6. Has a mean QTcF prolongation to >450 ms in males and >470 ms 
in females in 3 successive screening measurements as assessed by 
central laboratory. 
7. Has any factors that increase the risk of QTc prolongation or risk 
of arrhythmic events, such as congenital long QT syndrome, 


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family history of long QT syndrome or unexplained sudden death 
under 40 years of age in first-degree relatives. 
8. Has any history of interstitial lung disease (including pulmonary 
fibrosis or radiation pneumonitis), has current ILD/pneumonitis, 
or is suspected to have such disease by imaging during screening. 
9. Has clinically significant corneal disease. 
10. Has any evidence of severe or uncontrolled systemic diseases 
(including uncontrolled hypertension, and active bleeding 
diatheses or active infection including hepatitis B, hepatitis C, and 
HIV infection), psychiatric illness/social situations, substance 
abuse, or other factors which in the Investigator’s opinion makes 
it undesirable for the subject to participate in the study or which 
would jeopardize compliance with the protocol.  Screening for 
chronic conditions is not required. 
11. Is a lactating mother (women who are willing to temporarily 
interrupt breastfeeding will also be excluded), or pregnant as 
confirmed by pregnancy tests performed within 7 days prior to 
enrollment. 
12. Has clinically active spinal cord compression or brain metastases, 
defined as untreated and symptomatic, or requiring therapy with 
steroids or anticonvulsants to control associated symptoms.  
Subjects with treated brain metastases that are no longer 
symptomatic for 4 weeks before enrollment and who require no 
treatment with steroids may be included in the study if they have 
recovered from the acute toxic effect of radiotherapy.  A 
minimum of 2 weeks must have elapsed between the end of whole 
brain radiotherapy and study enrollment (1 week for stereotactic 
radiotherapy). 
13. Has unresolved toxicities from previous anticancer therapy, 
defined as toxicities (other than alopecia) not yet resolved to 
NCI-CTCAE version 5.0, grade ≤1 or baseline.  Subjects with 
chronic grade 2 toxicities may be eligible per the discretion of the 
Investigator. 
14. Has a concomitant medical condition that would increase the risk 
of toxicity, in the opinion of the Investigator. 
15. Has known hypersensitivity to either the drug substances or 
inactive ingredients in the drug product. 
16. Has multiple primary malignancies within 3 years, except 
adequately resected non-melanoma skin cancer, curatively treated 
in-situ disease, or other solid tumors curatively treated. 
Dosage Form, Dose and Route of 
Administration: 
U3-1402 will be provided as a sterile, 
 in an 
 
.  Each vial will contain 50 mg of U3-1402 in a 2.5 mL 
solution.  The selected dose of U3-1402 will be prepared by dilution 
of the required volume of the drug product (calculated from the 
subject’s body weight) into a volume of 250 mL of 5% dextrose in 
water.  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 
CCI
CCI


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each cycle.  An alternative drug administration schedule for dose 
finding may be considered upon review of human safety and PK 
parameters by the Investigators and Sponsor. 
Study Endpoints: 
Pharmacokinetic endpoints: 
Serum PK endpoints (area under the concentration-versus-time curve, 
from time 0 to the last measurable concentration as calculated by the 
linear-up log-down trapezoidal method [AUClast], AUC during 
dosing interval [AUCtau], maximum (peak) observed concentration 
[Cmax], time of maximum observed concentration [Tmax] and trough 
serum concentrations [Ctrough]) of U3-1402 for each subject will be 
estimated using standard noncompartmental methods.  For total anti-
HER3 antibody and MAAA-1181a, all parameters listed above will be 
estimated. 
Safety endpoints: 
Safety endpoints will include DLTs, serious adverse events (SAEs), 
treatment-emergent adverse events (TEAEs), adverse events of special 
interest (AESIs), physical examination findings (including ECOG PS), 
vital sign measurements, standard clinical laboratory parameters, ECG 
parameters, ECHO/MUGA findings, and ophthalmologic findings. 
Efficacy endpoints: 
Tumor response will be evaluated using RECIST version 1.1.  
Objective response rate (ORR) (the sum of CR rate and PR rate), 
disease control rate (DCR) (the sum of CR rate, PR rate, and stable 
disease [SD] rate), duration of response (DOR), clinical benefit rate 
(CBR; the proportion of subjects who achieved a best overall response 
of CR or PR or SD ≥ 6 months ), time to response (TTR), progression 
free survival (PFS), overall survival (OS), and percent change in target 
lesion(s). 
Planned Sample Size: 
The Dose Escalation Part of this study consists of mCRM with EWOC 
design with at least 3 DLT-evaluable subjects per dose level.  Sample 
size has been determined by practical considerations for the Dose 
Escalation Part. 
A total of approximately 12 subjects will be enrolled between Dose 
Escalation and Dose Finding for each of the Q3W Dosing Cohorts 
evaluated in Dose Finding.  For the alternative dosing cohorts 
evaluated in Dose Finding, a total of approximately 12 subjects will be 
enrolled into each cohort.  RDEs will be determined based on the risk 
and benefit assessment. 
For the Dose Expansion Part, there are 4 planned expansion cohorts: 
HER3-high, HR-positive (6.4 mg/kg), HER3-high, HR-positive 
(4.8 mg/kg), HER3-low, HR-positive (6.4 mg/kg) and HER3-high, 
TNBC (6.4 mg/kg): 
 
Approximately 60 eligible subjects with HER3-high, 
HER2-negative, HR-positive disease will be randomized 
into 1 of 2 cohorts:  4.8 mg/kg or 6.4 mg/kg. 
 
Subjects with HER3-low, HER2-negative, HR-positive 
breast cancer will not be randomized.  Approximately 
20 eligible subjects in this setting will be enrolled into a 
HER3-low, HR-positive (6.4 mg/kg) cohort. 


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 
Subjects with HER3-high, TNBC will not be randomized. 
Approximately 30 eligible subjects in this setting will be 
enrolled into a HER3-high, TNBC (6.4 mg/kg) cohort.  
A total of approximately 110 subjects will be enrolled into the Dose 
Expansion Part. 
In HER3-high, HR-positive cohorts of the Dose Expansion Part, if 
target ORR is more than 10% (null hypothesis: ORR 0.10, 
alternative hypothesis:  ORR >0.10), then the probability of no 
response out of 30 subjects will be less than 5%.  The probability that 
more than 6 responders out of 30 subjects (ORR >20%) are observed 
will be less than 5% under the null hypothesis with ORR 0.10 but 
more than 80% under alternative hypothesis with ORR = 0.30. 
In the HER3-low, HR-positive cohort of the Dose Expansion Part, if 
target ORR is more than 10% (null hypothesis: ORR 0.10, 
alternative hypothesis: ORR >0.10), then the probability of no 
response out of 20 subjects will be less than 15%.  The probability that 
more than 3 responders out of 20 subjects (ORR >15.0%) are 
observed will be less than 15% under the null hypothesis with ORR 
0.10 but more than 75% under alternative hypothesis with 
ORR = 0.25. 
In the HER3-high, TNBC cohort of the Dose Expansion Part, if target 
ORR is more than 20% (null hypothesis: ORR 0.20, alternative 
hypothesis: ORR >0.20), then the probability of no response out of 
30 subjects will be less than 5%. The probability that more than 
9 responders out of 30 subjects (ORR >30.0%) are observed will be 
less than 10% under the null hypothesis with ORR 0.20 but more 
than 80% under alternative hypothesis with ORR = 0.40. 
The probability values for the sample size are derived based on 
binomial distribution using SAS® version 9.4. 
Statistical Analyses: 
The data cutoff for the primary analysis will occur after all subjects 
have either discontinued from the study or have been followed for at 
least 9 months following the first dose of study treatment, whichever 
is earlier.  The primary analysis data cutoff may be extended if 
emerging data show responses are occurring later.  The final analysis 
of the study will occur after all subjects have discontinued the study. 
Data collected beyond the primary analysis cut-off time point will be 
presented as appropriate in a Clinical Study Report addendum. 
Data analyses will also be conducted during the Dose Escalation and 
Dose Finding Parts. 
Descriptive statistics will be provided for selected demographic, 
safety, and PK data by cohort and time as appropriate.  Descriptive 
statistics on continuous data will include means, medians, standard 
deviations, and ranges (as well as geometric means and geometric 
coefficient of variation for Cmax and AUC PK parameters), while 
categorical data will be summarized using frequency counts and 
percentages.  Graphical summaries of the data may be presented. 
Efficacy Analyses: 
Efficacy variables will include ORR, DCR, DOR, CBR, TTR, PFS, 
using RECIST version 1.1 and OS. 


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The efficacy variables will be listed and summarized.  For ORR and 
DCR, point estimates and 2-sided 95% exact binomial confidence 
intervals will be provided.  Time to event variables including DOR, 
TTR, PFS, and OS will be summarized descriptively using the 
Kaplan-Meier method.  PFS is defined as the time from the date of the 
first dose to the earlier of the dates of the first objective 
documentation of radiographic PD or death due to any cause.  
Censoring rules for the time-to-event endpoints such as PFS and OS 
analysis will be specified in the statistical analysis plan (SAP).   
Descriptive statistics for the best percent change in the sum of 
diameters of measurable tumors will be provided.  A waterfall plot of 
the best percent change from screening in the sum of diameters for 
each subject will be presented. 
Safety Analyses: 
The safety profile will be based on TEAEs, SAEs, AESIs, clinical 
laboratory measurements, vital sign measurements, ECG recordings, 
physical examination findings, ECHO/MUGA findings, and 
ophthalmologic findings.  In the Dose Escalation Part, the incidence of 
DLTs will also be evaluated. 
Safety analyses in general will be descriptive and will be presented in 
tabular format with the appropriate summary statistics.  In the Dose 
Escalation Part, the number of DLTs identified among the 
DLT-evaluable subjects in the DLT-evaluable set will be listed and 
summarized. 
Pharmacokinetic Analyses: 
PK analyses will be performed on the PK analysis set.  Serum 
concentration-time data for U3-1402, total anti-HER3 antibody and 
MAAA-1181a will be listed, plotted, and summarized using 
descriptive statistics at each point and in study period. 
PK parameters will be listed and summarized using descriptive 
statistics by dose and part. 
Biomarker and Exploratory Analyses: 
Exploratory analyses for biomarkers will be listed and summarized 
using descriptive statistics. 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................3 
SUMMARY OF CHANGES ...........................................................................................................4 
PROTOCOL SYNOPSIS ................................................................................................................5 
LIST OF ABBREVIATIONS ........................................................................................................30 
LIST OF PHARMACOKINETIC PARAMETERS ......................................................................34 
LIST OF DEFINITIONS OF TERMS ...........................................................................................35 
1. 
INTRODUCTION ...........................................................................................................36 
1.1. 
Background ......................................................................................................................36 
1.2. 
Data Summary .................................................................................................................37 
1.2.1. 
Physical, Chemical, Pharmaceutical Properties and Formulation ...................................37 
1.2.2. 
Nonclinical Studies ..........................................................................................................37 
1.2.2.1. Pharmacology ..................................................................................................................37 
1.2.2.2. Safety Pharmacology .......................................................................................................38 
1.2.2.3. Pharmacokinetics and Drug Metabolism .........................................................................38 
1.2.2.4. Toxicology .......................................................................................................................39 
1.2.3. 
Clinical Experience .........................................................................................................41 
1.3. 
Study Rationale ...............................................................................................................42 
1.4. 
Risks and Benefits for Study Subjects .............................................................................42 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ................................................................44 
2.1. 
Study Objectives ..............................................................................................................44 
2.1.1. 
Primary Objectives ..........................................................................................................44 
2.1.1.1. Dose Escalation Part ........................................................................................................44 
2.1.1.2. Dose Finding Part ............................................................................................................44 
2.1.1.3. Dose Expansion Part ........................................................................................................44 
2.1.2. 
Secondary Objectives ......................................................................................................44 
2.1.2.1. Dose Escalation Part ........................................................................................................44 
2.1.2.2. Dose Finding and Dose Expansion Parts .........................................................................44 
2.1.2.3. Dose Expansion Part ........................................................................................................44 
2.1.3. 
Exploratory Objectives ....................................................................................................45 
2.2. 
Study Hypotheses ............................................................................................................45 
2.3. 
Study Endpoints ...............................................................................................................45 


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3. 
STUDY DESIGN ............................................................................................................46 
3.1. 
Overall Design .................................................................................................................46 
3.1.1. 
Overview .........................................................................................................................46 
3.1.1.1. Study Type .......................................................................................................................46 
3.1.1.2. Treatment Groups ............................................................................................................46 
3.1.1.3. Duration of the Study ......................................................................................................46 
3.1.1.4. Duration of Subject Participation ....................................................................................47 
3.1.2. 
Dose Escalation Process and Dose Selection ..................................................................47 
3.1.3. 
Dose Escalation Part ........................................................................................................47 
3.1.4. 
Dose Finding Part ............................................................................................................49 
3.1.5. 
Dose Expansion Part ........................................................................................................50 
3.1.6. 
Study Stopping Criteria ...................................................................................................51 
3.1.7. 
Dose-limiting Toxicities ..................................................................................................51 
3.1.8. 
Maximum Tolerated Dose and Recommended Dose for Expansion Definition .............53 
3.1.9. 
Management of Subjects with Adverse Events ...............................................................53 
3.2. 
Discussion of Study Design .............................................................................................53 
3.2.1. 
Human Starting Dose ......................................................................................................53 
3.2.2. 
Treatment Schedule .........................................................................................................54 
4. 
STUDY POPULATION ..................................................................................................55 
4.1. 
Inclusion Criteria .............................................................................................................55 
4.1.1. 
Common Inclusion Criteria for Dose Escalation and Dose Finding Parts ......................55 
4.1.2. 
Additional Inclusion Criterion for Dose Finding Part .....................................................57 
4.1.3. 
Inclusion Criteria for Dose Expansion Part .....................................................................57 
4.1.4. 
Additional Inclusion Criteria for the HER3-high, TNBC Cohort ...................................59 
4.2. 
Exclusion Criteria ............................................................................................................59 
4.2.1. 
Exclusion Criteria for Dose Escalation and Dose Finding Parts .....................................59 
4.2.2. 
Additional Exclusion Criteria for Dose Finding Part ......................................................60 
4.2.3. 
Exclusion Criteria for Dose Expansion Part ....................................................................61 
5. 
STUDY TREATMENT(S) ..............................................................................................63 
5.1. 
Assigning Subjects to Treatment Group(s)/Sequences and Blinding ..............................63 
5.1.1. 
Treatment Group(s)/Sequences .......................................................................................63 
5.1.2. 
Method of Treatment Group(s)/Sequences Allocation ....................................................63 


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5.1.2.1. Enrollment .......................................................................................................................63 
5.1.3. 
Blinding ...........................................................................................................................64 
5.1.4. 
Emergency Unblinding Procedure ..................................................................................64 
5.2. 
Study Drug(s) ..................................................................................................................64 
5.2.1. 
Description ......................................................................................................................64 
5.2.2. 
Labeling and Packaging ..................................................................................................65 
5.2.3. 
Preparation .......................................................................................................................65 
5.2.4. 
Administration .................................................................................................................65 
5.2.5. 
Storage .............................................................................................................................65 
5.2.6. 
Drug Accountability ........................................................................................................65 
5.2.7. 
Retention Samples ...........................................................................................................66 
5.3. 
Control Treatment ...........................................................................................................66 
5.4. 
Dose Interruptions and Reductions .................................................................................66 
5.4.1. 
Dose Interruptions ...........................................................................................................66 
5.4.2. 
Dose Reductions ..............................................................................................................67 
5.5. 
Method of Assessing Treatment Compliance ..................................................................78 
5.6. 
Prior and Concomitant Medications ................................................................................79 
5.6.1. 
Prior Medications ............................................................................................................79 
5.6.2. 
Concomitant Medications ................................................................................................79 
5.6.3. 
Prohibited Concomitant Medications/Activities .............................................................79 
5.6.4. 
Dietary and Lifestyle Restrictions ...................................................................................80 
5.7. 
Subject Withdrawal/Discontinuation ...............................................................................81 
5.7.1. 
Reasons for Withdrawal ..................................................................................................81 
5.7.2. 
Withdrawal Procedures ...................................................................................................82 
5.7.3. 
Subject Replacement .......................................................................................................82 
5.7.4. 
Subject Re-screening Procedures ....................................................................................82 
5.8. 
Criteria for Suspending Study Treatment ........................................................................82 
6. 
STUDY PROCEDURES .................................................................................................83 
6.1. 
Screening .........................................................................................................................83 
6.2. 
Subject Management .......................................................................................................85 
6.3. 
Randomization .................................................................................................................85 
6.3.1. 
Dose Escalation Part ........................................................................................................85 


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6.3.2. 
Dose Finding Part ............................................................................................................85 
6.3.3. 
Dose Expansion Part ........................................................................................................85 
6.4. 
Treatment Period .............................................................................................................86 
6.4.1. 
Administration of U3-1402 .............................................................................................86 
6.4.2. 
Tumor Assessment ..........................................................................................................86 
6.4.3. 
ECG Measurement ..........................................................................................................86 
6.4.4. 
Cycle 1, Day 1 (All Parts) ...............................................................................................88 
6.4.5. 
Cycle 1, Day 2 (Dose Escalation, Dose Finding [Q3W Dosing Cohorts], and 
Dose Expansion Parts) .....................................................................................................89 
6.4.6. 
Cycle 1, Day 4 (Dose Escalation, Dose Finding [Q3W Dosing Cohorts and 
Q2W Dosing Cohorts], and Dose Expansion Parts) ........................................................89 
6.4.7. 
Cycle 1, Day 8 (All Parts) ...............................................................................................89 
6.4.8. 
Cycle 1, Day 15 (All Parts) .............................................................................................90 
6.4.9. 
Cycle 1, Day 22 (if Applicable; for Dose Escalation, Dose Finding [Q3W 
Dosing Cohorts and Q3W Dosing with Up-titration Cohorts], and Dose 
Expansion Parts) ..............................................................................................................90 
6.4.10. Cycle 2, Day 1 (All Parts) ...............................................................................................91 
6.4.11. Cycle 2, Day 3 (Dose Expansion Part Only) ...................................................................92 
6.4.12. Cycle 2, Day 8 (All Parts) ...............................................................................................92 
6.4.13. Cycle 2, Day 15 (± 2 days; Dose Escalation, Dose Finding [Q3W Dosing 
Cohorts, Q3W Dosing with Up-Titration Cohorts], and Dose Expansion Parts) ............92 
6.4.14. Cycle 2, Day 22 (if Applicable; for Dose Escalation and Dose Finding [Q3W 
Dosing with Up-titration] Parts ) .....................................................................................93 
6.4.15. Cycle 3, Day 1 (All Parts) ...............................................................................................93 
6.4.16. Cycle 3, Day 2 (Dose Escalation Part Only) ...................................................................94 
6.4.17. Cycle 3, Day 4 (Dose Escalation and Dose Finding [Q2W Dosing Cohort] 
Only) ................................................................................................................................94 
6.4.18. Cycle 3, Day 8 (All Parts) ...............................................................................................94 
6.4.19. Cycle 3, Day 15 (All Parts) .............................................................................................95 
6.4.20. Cycle 3, Day 22 (if Applicable; for Dose Escalation, Dose Finding [Q3W 
Dosing and Q3W Dosing with Up-titration], and Dose Expansion Parts) ......................95 
6.4.21. Cycle 4 and Subsequent Cycles, Day 1 (All Parts) .........................................................96 
6.4.22. Cycle 4, Day 8 (± 2 days) for Dose Finding (Q2W Dosing Cohort) Part .......................97 
6.4.23. Cycle 4, Day 15 (± 2 days) for Dose Finding (Q2W Dosing Cohort) Part .....................97 
6.4.24. Cycle 4, Day 22 (± 2 days) for Dose Finding (Q2W Dosing Cohort) Part .....................98 


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6.5. 
Washout ...........................................................................................................................98 
6.6. 
Check-out or Early Termination ......................................................................................98 
6.7. 
End of Treatment .............................................................................................................98 
6.8. 
Follow-up ........................................................................................................................99 
6.9. 
New Cancer Treatment and Survival Follow-up ...........................................................100 
6.10. 
Pharmacokinetics, Pharmacodynamics, Exploratory Biomarkers, and Anti-drug 
Antibodies ......................................................................................................................100 
6.10.1. Blood Sampling .............................................................................................................100 
6.10.2. Tumor Sampling ............................................................................................................100 
6.10.3. Pharmacokinetic ............................................................................................................101 
6.10.3.1. Dose Escalation Part Pharmacokinetic Sampling Time Points .....................................102 
6.10.3.2. Dose Finding Part Pharmacokinetic Sampling Time Points .........................................103 
6.10.3.3. Dose Expansion Part Pharmacokinetic Sampling Time Points .....................................106 
6.10.4. Pharmacodynamics ........................................................................................................106 
6.10.5. Exploratory Biomarkers ................................................................................................107 
6.10.6. Anti-Drug Antibodies ....................................................................................................108 
7. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS .........................110 
7.1. 
Pharmacokinetic Assessment(s) ....................................................................................110 
7.2. 
Pharmacodynamic Assessment(s) .................................................................................110 
7.3. 
Biomarker and Exploratory Assessment(s) ...................................................................110 
7.3.1. 
HER3 expression ...........................................................................................................110 
7.3.1.1. Tumor Sample Collection ..............................................................................................110 
7.3.2. 
Biomarker Assessments in Tumor Tissue and Blood Samples .....................................111 
7.4. 
Immunogenicity .............................................................................................................112 
7.5. 
Pharmacogenomic Analysis ..........................................................................................112 
7.5.1. 
Genomic or Genetic Banking and Analysis ..................................................................112 
7.5.1.1. Genomic or Genetic Banking and Analysis ..................................................................112 
7.5.1.2. Collection of Specimens for Genomic or Genetic Banking and Analysis ....................113 
7.5.1.3. Disclosure of the Results of Genomic or Genetic Analysis ..........................................113 
7.5.1.4. Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis .........................................................................................................................113 
8. 
SAFETY EVALUATION AND REPORTING ............................................................114 
8.1. 
Assessment of Safety Endpoint Event(s) ......................................................................114 


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8.2. 
Adverse Event Collection and Reporting ......................................................................114 
8.3. 
Adverse Events of Special Interest ................................................................................115 
8.3.1. 
Cardiotoxicity (Cardiac-related Events Including QT Prolongation and LVEF 
Decreased) .....................................................................................................................115 
8.3.2. 
Pulmonary Toxicity (Interstitial Lung Disease/Pneumonitis) .......................................115 
8.3.2.1. Interstitial Lung Disease Adjudication Committee .......................................................115 
8.3.3. 
Hepatotoxicity (Potential Hy’s Law) .............................................................................115 
8.4. 
Adverse Event ...............................................................................................................116 
8.4.1. 
Definition of Adverse Event ..........................................................................................116 
8.4.2. 
Serious Adverse Event ..................................................................................................116 
8.4.3. 
Severity Assessment ......................................................................................................116 
8.4.4. 
Causality Assessment ....................................................................................................117 
8.4.5. 
Action Taken Regarding Study Drug(s) ........................................................................117 
8.4.6. 
Other Action Taken for Event .......................................................................................118 
8.4.7. 
Adverse Event Outcome ................................................................................................118 
8.5. 
Serious Adverse Events Reporting – Procedure for Investigators ................................118 
8.6. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee ...............................................................................................119 
8.7. 
Exposure in Utero During Clinical Studies ...................................................................120 
8.8. 
Clinical Laboratory Evaluations ....................................................................................120 
8.9. 
Vital Signs .....................................................................................................................121 
8.10. 
Electrocardiograms ........................................................................................................121 
8.11. 
Physical Examinations ...................................................................................................121 
8.12. 
Other Examinations .......................................................................................................121 
9. 
EFFICACY ASSESSMENTS .......................................................................................122 
10. 
OTHER ASSESSMENTS .............................................................................................123 
11. 
STATISTICAL METHODS .........................................................................................124 
11.1. 
General Statistical Considerations .................................................................................124 
11.2. 
Analysis Sets .................................................................................................................124 
11.2.1. Full Analysis Set ............................................................................................................124 
11.2.1.1. Dose-Limiting Toxicity Evaluable Set ..........................................................................124 
11.2.1.2. Safety Analysis Set ........................................................................................................125 
11.2.1.3. Pharmacokinetic Analysis Set .......................................................................................125 


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11.3. 
Study Population Data ...................................................................................................125 
11.4. 
Statistical Analysis ........................................................................................................125 
11.4.1. Efficacy Analyses ..........................................................................................................125 
11.4.2. Pharmacokinetic Analyses .............................................................................................125 
11.4.3. Pharmacodynamic Analyses ..........................................................................................126 
11.4.4. Biomarker and Exploratory Analyses ...........................................................................126 
11.4.5. Safety Analyses .............................................................................................................126 
11.4.5.1. Adverse Event Analyses ................................................................................................126 
11.4.5.2. Clinical Laboratory Evaluation Analyses ......................................................................126 
11.4.5.3. Vital Sign Analyses .......................................................................................................127 
11.4.5.4. Electrocardiogram Analyses ..........................................................................................127 
11.4.5.5. Exploratory Safety Analyses .........................................................................................127 
11.4.5.6. Other Safety Analyses ...................................................................................................127 
11.5. 
Sample Size Determination ...........................................................................................127 
11.6. 
Statistical Analysis Process ...........................................................................................128 
11.7. 
Specification of Modified Continuous Reassessment Method with Escalation 
with Overdose Control ..................................................................................................129 
11.7.1. Bayesian Logistic Regression Model for Modified Continuous Reassessment 
Method ...........................................................................................................................129 
11.7.2. Prior Specification for Bayesian Logistic Regression Model Parameters .....................129 
11.7.3. Escalation with Overdose Control Principle .................................................................129 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ................................................131 
12.1. 
Monitoring and Inspections ...........................................................................................131 
12.2. 
Data Collection ..............................................................................................................131 
12.3. 
Data Management ..........................................................................................................132 
12.4. 
Study Documentation and Storage ................................................................................132 
12.5. 
Record Keeping .............................................................................................................133 
13. 
FINANCING AND INSURANCE ................................................................................134 
13.1. 
Finances .........................................................................................................................134 
13.2. 
Reimbursement, Indemnity, and Insurance ...................................................................134 
14. 
PUBLICATION POLICY .............................................................................................135 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION .................................136 
15.1. 
Compliance Statement, Ethics and Regulatory Compliance .........................................136 


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15.2. 
Subject Confidentiality ..................................................................................................136 
15.3. 
Informed Consent ..........................................................................................................136 
15.4. 
Regulatory Compliance .................................................................................................137 
15.5. 
Protocol Deviations .......................................................................................................138 
15.6. 
Supply of New Information Affecting the Conduct of the Study .................................138 
15.7. 
Protocol Amendments ...................................................................................................139 
15.8. 
Study Termination .........................................................................................................139 
15.9. 
Data and Safety Monitoring Board ................................................................................139 
15.10. 
Address List ...................................................................................................................139 
16. 
REFERENCES ..............................................................................................................140 
17. 
APPENDICES ...............................................................................................................142 
17.1. 
Blood Collection Volume by Category and Total .........................................................142 
17.2. 
Additional Information (for Japanese Study Sites Only) ..............................................147 
17.2.1. GCP compliance ............................................................................................................147 
17.2.2. Study Period ..................................................................................................................147 
17.2.3. Payment for Participation, Compensation for Study-Related Injuries, and 
Insurance ........................................................................................................................147 
17.2.3.1. Payment for Participation ..............................................................................................147 
17.2.3.2. Compensation and Insurance .........................................................................................147 
17.3. 
Eastern Cooperative Oncology Group Performance Status Scale .................................148 
17.4. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 .........................................148 
17.4.1. Measurability of Tumor at Baseline ..............................................................................148 
17.4.1.1. Definitions .....................................................................................................................148 
17.4.1.2. Specifications by Methods of Measurements ................................................................149 
17.4.2. Tumor Response Evaluation ..........................................................................................150 
17.4.2.1. Assessment of Overall Tumor Burden and Measurable Disease ..................................150 
17.4.2.2. Baseline Documentation of “Target” and “Non-target” Lesions ..................................150 
17.4.2.3. Response Criteria ...........................................................................................................151 
17.4.2.4. Evaluation of Best Overall Response ............................................................................153 
17.4.2.5. Frequency of Tumor Re-evaluation ...............................................................................155 
17.5. 
New York Heart Association Functional Classification ...............................................156 
17.6. 
Electronic Data Capture System ....................................................................................156 
17.7. 
Supplement List .............................................................................................................157 


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17.8. 
Schedule of Events ........................................................................................................158 
17.9. 
Instructions Related to Coronavirus Disease 2019 (COVID-19) ..................................170 
 


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LIST OF TABLES 
Table 3.1: Dose Escalation Cohorts .............................................................................................48 
Table 3.2: Dose Finding Cohort 3 Dosing Schedule ...................................................................50 
Table 3.3: Dose Finding Cohort 4 Dosing Schedule ...................................................................50 
Table 3.4: Dose Finding Cohort 5 Dosing Schedule ...................................................................50 
Table 5.1: Dose Levels for U3-1402 ............................................................................................67 
Table 5.2: Dose Delay Criteria and Dose Reduction for U3-1402 ..............................................68 
Table 6.1: ECG Measurement Time Points .................................................................................87 
Table 6.2: Pharmacokinetic Sampling Time Points (Dose Escalation Part) ..............................102 
Table 6.3: Q3W Dosing Cohorts ...............................................................................................103 
Table 6.4: Q3W Dosing with Up-titration Cohorts ...................................................................104 
Table 6.5: Q2W Dosing Cohorts ...............................................................................................105 
Table 6.6: Pharmacokinetic Sampling Time Points (Dose Expansion Part) .............................106 
Table 6.7: HER3ECD Sampling Time Points ............................................................................107 
Table 6.8: cfDNA and cfRNA Sampling Time Points ..............................................................108 
Table 6.9: cTnI Sampling Time Points ......................................................................................108 
Table 6.10: ADA Sampling Time Points .....................................................................................109 
Table 7.1: Pharmacokinetic Parameters .....................................................................................110 
Table 17.1: Blood Collection in Dose Escalation Part ................................................................142 
Table 17.2: Blood Collection in Dose Finding (Q3W Dosing Schedule) and Dose 
Expansion Parts ........................................................................................................143 
Table 17.3: Blood Collection in Dose Finding Part (Q2W Dosing Schedule) ............................145 
Table 17.4: Blood Collection in Dose Finding Part (Q3W Dosing Schedule with 
Up-titration) ..............................................................................................................146 
Table 17.5: Overall Response: Subjects with Target (± Non-target) Disease .............................154 
Table 17.6: Overall Response: Subjects with Non-target Disease Only .....................................154 
Table 17.7: Schedule of Events (Dose Escalation Part) ..............................................................158 
Table 17.8: Schedule of Events (Dose Finding [Q3W Dosing Cohorts] and Dose 
Expansion Parts) .......................................................................................................161 
Table 17.9: Schedule of Events (Dose Finding Part [Q2W Dosing Cohorts]) ............................164 
Table 17.10: Schedule of Events (Dose Finding Part [Q3W with Up-titration Cohorts]) ........167 
Table 17.11: COVID-19 Dose Modification Criteria ...............................................................170 
 


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LIST OF FIGURES 
Figure 1.1: Tumor Growth of MDA-MB-453 Tumors Xenografted in Nude Mice .....................37 
Figure 5.1: Subject Enrollment Process ........................................................................................63 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ADA 
anti-drug antibodies 
ADC 
antibody-drug conjugate 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
serum alkaline phosphatase 
ALT 
serum alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
serum aspartate aminotransferase 
BI 
before infusion 
BLRM 
Bayesian logistic regression model 
CBR 
clinical benefit rate 
CDISC 
Clinical Data Interchange Standards Consortium 
cfDNA 
cell-free DNA 
CFR 
Code of Federal Regulations 
cfRNA 
cell-free RNA 
CHF 
congestive heart failure 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CSF 
colony stimulating factor 
CT 
computed tomography 
cTnI 
cardiac troponin I 
cTnT 
cardiac troponin T 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
EC 
ethics committee 
ECD 
extracellular domain 


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ABBREVIATION 
DEFINITION 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EIU 
exposure in utero 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EOI 
end of infusion 
EOT 
end of treatment 
EWOC 
escalation with overdose control 
FDA 
Food and Drug Administration 
F/U 
follow-up 
GCP 
Good Clinical Practice 
Hb 
hemoglobin 
HED 
human equivalent dose 
HER2 
human epidermal growth factor receptor 2 
HER3 
human epidermal growth factor receptor 3 
HER3ECD 
human epidermal growth factor receptor 3 extracellular domain 
hERG 
human ether-a-go-go-related gene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
HR 
hormone receptor 
HSD 
human starting dose  
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IgG1 
immunoglobulin G1 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
INN 
International Non-proprietary Name 
IO 
immuno-oncology 
IRB 
institutional review board 


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ABBREVIATION 
DEFINITION 
IRT 
interactive response technology 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
mCRM 
modified continuous reassessment method 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
ms 
millisecond 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition scan 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOAEL 
no observed adverse effect level 
NRU 
neutral red uptake 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease  
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
PS 
performance status 
Q2W 
once every 2 weeks 
Q3W 
once every 3 weeks 
QTc 
corrected QT 
QTcF 
corrected QT by Fridericia’s formula 
QW 
once every week 
RDEs 
recommended doses for expansion 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAE 
serious adverse event 
SAP 
statistical analysis plan 


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ABBREVIATION 
DEFINITION 
SAVER 
serious adverse event report 
SD 
stable disease 
SOP 
standard operating procedure 
SpO2 
oxygen saturation of peripheral artery 
STD10 
severely toxic dose in 10% of the animals 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TK 
toxicokinetic 
TNBC 
triple-negative breast cancer 
TTR 
time to response 
ULN 
upper limit of normal 
US 
United States 


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LIST OF PHARMACOKINETIC PARAMETERS 
ABBREVIATION 
DEFINITION 
AUC 
area under the plasma/serum concentration-time curve 
AUClast 
area under the plasma/serum concentration-time curve up to the last 
quantifiable time 
AUCtau 
AUC during dosing interval 
CL 
total body clearance 
Cmax 
maximum plasma/serum concentration 
Ctrough 
trough plasma/serum concentration 
C0 
estimated plasma/serum concentration at time 0 
Kel 
elimination rate constant associated with the terminal phase 
MRTinf 
mean residence time to infinity 
Tmax 
time to reach maximum plasma/serum concentration 
T1/2 
terminal elimination half-life 
Vss 
steady-state volume of distribution 
Vz 
volume of distribution based on the terminal phase 




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1. 
INTRODUCTION 
1.1. 
Background 
Globally, breast cancer is the most frequently diagnosed cancer in women, with 1.5 million 
women impacted each year.1  In the United States (US), in 2016, there were an estimated 
61,000 new cases of in situ disease, 246,660 cases of invasive disease, and 40,450 deaths due to 
breast cancer in women.2 
In Japan, there were 89,400 estimated cases of breast cancer in 2015. Additionally, breast cancer 
represents 21% of all female cancers in Japan.3  The number of cases is increasing every year. 
Breast cancer is a heterogeneous disease with respect to molecular alterations, cellular 
composition, and clinical outcome.  This diversity presents a challenge in developing tumor 
classifications that are clinically useful with respect to prognosis or prediction.  Diagnosis by 
intrinsic subtype (eg, hormone receptor [HR] or human epidermal growth factor receptor 
2 [HER2] status) adds significant prognostic and predictive information in breast cancer, 
particularly concerning the risk of relapse.4  Among all breast cancer subtypes, HR-positive and 
HER2-negative tumors make up the majority of breast cancer patients.  With regard to metastatic 
and relapsing breast cancer, the survival of patients with metastasis or relapse has gradually 
improved since the introduction of newer chemotherapeutic agents.5, 6,7  However, despite these 
modest improvements, there is no single standard of care in late-line treatment for patients with 
metastatic/relapsing breast cancer and prognosis remains poor in this group.8,9  In general, 
chemotherapies, which were not used in prior cancer treatments, are selected for treatment in late 
line, such as eribulin, capecitabine, vinorelbine, and so on.  According to the Phase 3 study of 
eribulin in patients with metastatic breast cancer who received 2 to 5 previous chemotherapy 
regimens, including anthracyclines and taxanes, median progression-free survival (PFS) was 
3.7 months and median overall survival (OS) was 13.1 months.10  
In patients with advanced/unresectable or metastatic breast cancer classified as triple-negative 
breast cancer (TNBC; HER2-negative/HR-negative) chemotherapy remains the mainstay of 
treatment. While many drugs, including taxanes, anthracyclines, capecitabine, eribulin, S-1, and 
irinotecan, have shown activity, no standard of care has been established.11, 12  Despite the 
treatment options presented by these agents, the prognosis for TNBC remains poor, with an 
estimated median overall survival of 10 to 18 months and post-progression survival of 6 months 
after first-line therapy.13, 14  There is still an unmet medical need in advanced TNBC with disease 
progression after chemotherapy.  
Considering the unmet medical need in breast cancer described here, an urgent need for the 
development of new therapy for advanced/unresectable or metastatic breast cancer is justified. 
Preliminary data from Study U31402-A-J101 in patients with human epidermal growth factor 
receptor 3 (HER3)-positive, advanced/unresectable or metastatic breast cancer (N=42, total), 
including 10 subjects with TNBC, showed a persistent U3-1402 antitumor effect with a 
confirmed ORR of 42.9%, a DCR of 90.5%, and a median (range) PFS of 8.3 (1.2, 16.8) months 
(median follow-up of 10.5 months). 


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1.2. 
Data Summary 
1.2.1. 
Physical, Chemical, Pharmaceutical Properties and Formulation 
The U3-1402 drug product is an 
sterile solution in 
and is provided 
as a 
  U3-1402 is an antibody-drug conjugate (ADC) comprised of a recombinant 
fully human anti-human epidermal growth factor receptor 3 (HER3) immunoglobulin G1 (IgG1) 
monoclonal antibody covalently conjugated to a drug-linker, MAAA-1162a.  The released drug 
is MAAA-1181a. 
1.2.2. 
Nonclinical Studies 
Additional information describing the U3-1402 nonclinical studies are available in the current 
Investigator’s Brochure. 
1.2.2.1. 
Pharmacology 
U3-1402 bound specifically to human HER3 recombinant protein but did not bind to the other 
human HER family recombinant proteins.  U3-1402 bound against human, cynomolgus monkey, 
rat, and mouse HER3.  Cynomolgus monkey, rat, and mouse are therefore considered 
appropriate for the nonclinical pharmacokinetic (PK) and toxicological studies of U3-1402. 
Significant dose-dependent antitumor activity of U3-1402 was shown in the MDA-MB-453 
xenograft mouse model (Figure 1.1). 
Figure 1.1: 
Tumor Growth of MDA-MB-453 Tumors Xenografted in Nude Mice 
 
U3-1402 produced significant tumor regression in nude mice in HCC1569 (HER3 3+) and 
MDA-MB-453 (HER3 2+) human breast cancer xenograft models.  U3-1402 showed inhibition 
of tumor proliferation in the NIBIO-G016 (HER3 1+) gastric cancer patient-derived xenograft 
model but did not show any anti-tumor effect in the MDA-MB-231 (HER3 0) human breast 
CCI
CCI
CCI


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cancer model.  In conclusion, U3-1402 showed tumor regression in HER3 2+ and 3+ tumors, 
inhibition in HER3 1+ gastric tumour and no activity in HER3 0 tumors. 
In addition, U3-1402 did not show antibody-dependent cellular cytotoxicity (ADCC) activity 
against HER3-expressing human breast cancer cell line. U3-1402 exerted specific cytotoxic 
activity against HER3-expressing cells, but did not exert cytotoxic activity against 
HER3-negative cells. 
1.2.2.2. 
Safety Pharmacology 
In telemetered male cynomolgus monkeys treated with single intravenous (IV) doses of 
U3-1402, no effects on the cardiovascular system, the respiratory system, or the central nervous 
system were observed at dose levels up to 30 mg/kg, the highest dose level tested.  In addition, in 
human ether-a-go-go-related gene (hERG) studies of MAAA-1181a, the drug component, 
MAAA-1181a did not inhibit the hERG channel current at concentrations of up to 10 μmol/L 
(approximately 5000 ng/mL), the highest concentration level tested. 
1.2.2.3. 
Pharmacokinetics and Drug Metabolism 
In a single dose IV administration PK study of U3-1402 of 21 days duration in female nude 
mice, estimated plasma concentration at time 0 [C0], area under the plasma concentration-time 
curve [AUC] and terminal elimination half-life [T1/2] increased with increasing dose, and total 
body clearance [CL] decreased with increasing dose. 
In a single dose IV administration PK study of 21 days duration in cynomolgus monkeys, plasma 
concentrations of U3-1402 were determined up until Day 7.  The AUC for U3-1402 had more 
than a dose proportional increase from 0.1 to 1 mg/kg.  The T1/2 and mean residence time to 
infinity [MRTinf] values increased at 1 mg/kg, and the CL value trended towards a decrease with 
increasing dose.  Anti-U3-1402 antibodies were detected in all animals on Days 14 and 21 after 
the dosing.  MAAA-1181a was detected at low concentrations at 0.3 mg/kg (1 animal) and 
1 mg/kg (3 animals) within 24 h after dosing. 
The steady-state volume of distribution [Vss] value showed no apparent change with dose in 
mice and monkeys. 
The plasma protein binding ratios of MAAA-1181a (10 ng/mL to 100 ng/mL) were 90.3% to 
92.5% in mice, 94.2% to 96.7% in rats, 86.5% to 89.1% in monkeys, and 96.8% to 98.0% in 
humans. 
The in vitro release rates of MAAA-1181a from U3-1402 in mouse, rat, monkey and human 
plasma, for 3 weeks were 5.9% or less. 
MAAA-1181a was metabolized by cytochrome P450 (CYP) enzymes.  CYP3A4 was the 
primary CYP isoform in the metabolism; however, CYP3A5 and CYP2D6 were also involved in 
the metabolism. 
In rats, excretion of radioactivity from administered 14C-labeled MAAA-1181a 
(14C-MAAA-1181a) into feces via bile was predominant.  Unchanged MAAA-1181a was the 
predominant component being excreted into urine, feces, and bile of the rat. 


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MAAA-1181a did not exhibit any potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, and CYP3A (50% inhibitory concentration [IC50] >50 μmol/L).  
MAAA-1181a did not exhibit any potential to induce CYP3A4, CYP1A2, and CYP2B6 up to 
30 μmol/L.  MAAA-1181a did not inhibit organic anion transporter (OAT) 3, organic cation 
transporter (OCT) 1, OCT2, organic anion transporting polypeptide (OATP) 1B3, multidrug and 
toxin extrusion (MATE) 1, MATE2-K, P-glycoprotein (P-gp), breast cancer resistance protein 
(BCRP), and bile salt export pump (BSEP) (IC50 >30 μmol/L). MAAA-1181a was a substrate for 
organic anion transporting polypeptide (OATP) 1B1, OATP1B3, multidrug and toxin extrusion 
(MATE) 2-K, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug 
resistance-associated protein (MRP) 1 (but not MRP2 or MRP3). MAAA-1181a inhibited OAT1 
and OATP1B1 with the IC50 values of 12.7 and 14.4 μmol/L, respectively, although the values 
were much higher than the observed plasma concentrations of MAAA-1181a in all the 
nonclinical in vivo studies.  In addition, OATPs appeared to contribute to the human hepatic 
uptake of MAAA-1181a. 
In the toxicokinetics (TK) evaluation of U3-1402 in rats (20, 60, and 194.3 mg/kg of U3-1402) 
and cynomolgus monkeys (3, 10, and 30 mg/kg of U3-1402), C0, maximum plasma 
concentration [Cmax] and AUC values of U3-1402, or MAAA-1181a generally increased with 
increasing dose after the first dose.  There were no clear sex differences.  In rats, no apparent 
changes in TK parameters were noted after repeated dosing.  In monkeys after the 4th dose, 
plasma concentrations of U3-1402 showed decreases in C0 and AUC values.  However, plasma 
concentrations of MAAA-1181a showed increases in the Cmax and AUC values in the 3 and 
10 mg/kg groups. 
Animals in which anti-U3-1402 antibody was detected tended to have lower AUC and T1/2 
values of U3-1402, and higher Cmax of MAAA-1181a on Day 64 compared to the 
corresponding animals on Day 1.  Anti-U3-1402 antibody was not detected in rats given 20 and 
60 mg/kg on Day 64.  Anti-U3-1402 antibodies were detected in serum samples from several 
U3-1402-treated rats, and from 11 out of 12 of U3-1402-treated monkeys at 3 and 10 mg/kg.  No 
marked differences were observed in PK and TK parameters in animals between U3-1402 and 
total antibody (drug conjugated and unconjugated antibody) before the occurrence of a positive 
reaction to anti-U3-1402 antibody.  These in vivo and in vitro results indicate that U3-1402 is 
stable in plasma. 
1.2.2.4. 
Toxicology 
The binding profile of U3-1402 using an enzyme-linked immunosorbent assay (ELISA) showed 
that U3-1402 bound to the extracellular domain of HER3 in rats and cynomolgus monkeys. 
Therefore, for safety assessment, intermittent IV dosing studies were conducted in these 
2 cross-reactive species for U3-1402.  In a 12-week intermittent dose toxicity study of U3-1402 
in rats, the animals received 20, 60, or 194.3 mg/kg of U3-1402 Q3W.  The highest dose level 
selected for this study was the maximum feasible level, considering the tolerable range of dosing 
volume for rats and formulation concentration.  In a 12-week intermittent dose toxicity study of 
U3-1402 in the monkey, the animals received 3, 10, or 30 mg/kg of U3-1402 Q3W based upon 
the results of a preliminary intermittent dose toxicity study (once every week [QW] dosing, 
2 weeks).  In the latter study, 30 mg/kg of U3-1402 and greater induced cardiotoxic changes and 
80 mg/kg of U3-1402 induced moribundity.  An in vitro tissue cross-reactivity study was 


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conducted using human, cynomolgus monkey, and rat tissues.  No test-article related effects 
were observed in the 1- or 6-month intermittent dose toxicity study of U3-1287 in cynomolgus 
monkeys.  A 4-week intermittent IV dosing study of MAAA-1181a was conducted in rats and 
cynomolgus monkeys to clarify the toxicity of MAAA-1181a.  In addition, an in vitro 3T3 
neutral red uptake (NRU) phototoxicity study was also conducted because MAAA-1181a has 
demonstrated photoabsorption in the UV-visible light range.  No phototoxic reaction was noted 
in a single dose phototoxicity study of MAAA-1181a in pigmented rats at doses up to 3 mg/kg 
(the highest dose administered). 
In the study of intermittent IV dosing of U3-1402 in the rat (Q3W dosing for 12 weeks at 20, 60, 
or 194.3 mg/kg), 1 male given 194.3 mg/kg in the toxicity evaluation group died and 1 female 
given 194.3 mg/kg in the TK evaluation group became moribund due to severe liver injury and 
severe suppression of lymphatic/hematopoietic systems.  Myocardial necrosis was seen in the 
animal found dead and single cell necrosis of corneal epithelium was seen in the moribund 
animal.  In the surviving animals, the major findings were hepatobiliary, thymic, gastrointestinal, 
reproductive organ, skin, and dental toxicity at dose levels of 20 mg/kg and greater, and renal, 
lymphatic/hematopoietic, pulmonary, and mammary gland toxicity at dose levels of 60 mg/kg 
and greater.  At 194.3 mg/kg, treatment-related changes were observed in the mesenteric lymph 
node, urinary bladder (female only), accessory reproductive gland, tongue, harderian gland, 
salivary gland, and skeletal muscle.  Except for the testicular changes, these changes showed 
recovery or a tendency of recovery after 6-week recovery period.  Therefore, the severely toxic 
dose in 10% of the animals (STD10) in the rat intermittent IV dosing study of U3-1402 was found 
to be 194.3 mg/kg because no severe or irreversible toxicity was seen in the surviving animals 
except for that in the testis and an incidence of death was substantially low. 
In a 2-week preliminary intermittent IV dosing study of U3-1402 in cynomolgus monkeys 
(QW dosing), 1 male died and 1 female was sacrificed due to moribundity at 80 mg/kg, the 
highest dose level tested.  The cause of the death or moribundity appeared to be sustained 
deterioration of the animals’ physical conditions.  The major findings of toxicity in the surviving 
animals in the 30 mg/kg and greater group were observed in the lymphatic/hematopoietic 
systems, digestive system, and heart.  In the 80 mg/kg group, hepatotoxicity, renal, pancreas, and 
skin toxicity were also observed. 
In the intermittent IV dosing study of U3-1402 in cynomolgus monkeys (Q3W, 12 weeks at 0, 3, 
10, or 30 mg/kg), there were no deaths or moribund animals.  The major findings of toxicity 
were observed in the thymus and ovary at 10 mg/kg and greater, and in the bone marrow leading 
to suppression of hematopoiesis and in the skin at 30 mg/kg.  Emetic action, immunogenicity 
including anti-U3-1402 antibody production, and increased inflammatory parameters were also 
observed at 3 mg/kg and greater.  By the end of the 6-week recovery period, all the treatment-
related changes observed during the dosing period had disappeared or shown a trend of 
reversibility.  Therefore, the highest non-severely toxic dose (HNSTD) was considered to be 
30 mg/kg in the Q3W dosing regimen because no severe or irreversible toxicity was seen at up to 
30 mg/kg. 
An intermittent dose toxicity study of U3-1402 for cardiotoxic assessment was additionally 
conducted in cynomolgus monkeys at 30 mg/kg in the QW dosing regimen for 2 weeks.  One 
male out of 4 monkeys was sacrificed moribund with severe deterioration of physical conditions 
6 days after the second dose.  This animal had necrosis of cardiac myocytes with notable 


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increase in plasma cardiac troponin I (cTnI) concentration detected just before autopsy.  Higher 
MAAA-1181a concentration in the heart tissue was also observed in this animal in comparison 
with those of the other 3 animals.  Plasma cTnI was increased transiently in the other 2 out of 
3 monkeys after the first dosing; however, no histopathological changes in their heart were 
observed at the end of 2-week dosing period. 
In the intermittent IV dose toxicity studies of U3-1287 in cynomolgus monkeys (QW dosing for 
1 or 6 months), the no observed adverse effect level (NOAEL) was 200 mg/kg, the highest dose 
tested, because of no significant changes in any examination. 
In an intermittent IV dose toxicity study of MAAA-1181a (QW dosing for 4 weeks) in the rat, 
there was no death or moribundity at up to 30 mg/kg.  Toxicity findings in the 
lymphatic/hematopoietic system, intestinal tract, and the cornea of the eye were observed at 
3 mg/kg and greater.  Findings similar to those in rats were observed in cynomolgus monkeys at 
dose levels of 1 mg/kg and greater in a toxicity study of MAAA-1181a with the same dose 
regimen.  In addition, 1 female died and 1 male was sacrificed moribund at 12 mg/kg.  Although 
effects on the heart (focal myocardial cell degeneration/necrosis) were found in the moribund 
male, there were no abnormal heart findings in the female found dead.  Both animals exhibited 
worsening clinical conditions associated with sustained decreases in food consumption, bone 
marrow toxicity, and intestinal toxicity.  These changes were considered to be the cause of the 
death and moribundity. 
The common target organs of toxicity of U3-1402 and MAAA-1181a were the 
lymphatic/hematopoietic systems, intestine, cornea, liver and heart.  For U3-1402 treatment, 
there were treatment-related toxicities in the lung, kidney, reproductive organ, skin, thymus, 
pancreas, mesenteric lymph node, urinary bladder, accessory reproductive gland, harderian 
gland, salivary gland, and skeletal muscle. 
Tissue-cross reactivity studies of U3-1402 with human and monkey tissue panels showed no 
U3-1402-specific immunoreactivity in any tissues.  In rats, there was U3-1402 specific staining 
in red blood cells, bone marrow, and spleen, with staining of mast cells in a variety of tissues. 
In an in vitro 3T3 NRU phototoxicity study, MAAA-1181a was found to be phototoxic to Balb/c 
3T3 mouse fibroblasts.  However, in an in vivo single dose phototoxicity study of MAAA-1181a 
in pigmented rats, no phototoxic reaction was noted at 3 mg/kg, the highest dose tested. 
1.2.3. 
Clinical Experience 
This is a first-in-human study of U3-1402. 
As of the 25 Aug 2018 data cut-off, 56 subjects had received U3-1402 as part of 
Study U31402-A-J101: 34 subjects in the Dose Escalation Part, 8 subjects in the Dose Finding 
Part, and 14 subjects in the Dose Expansion Part.  At the time of the data cut-off, 41 subjects 
were receiving treatment, 13 subjects had discontinued treatment due to disease progression, 
1 subject had discontinued treatment due to Grade 2 pneumonitis, and 1 subject had withdrawn 
consent. 
Fifty-four (96.4%) of the 56 treated subjects had experienced at least 1 TEAE.  All 54 subjects 
had also experienced at least 1 TEAE considered by the investigator as related to study drug.  
Among all treated subjects, the most frequent (>20%) TEAEs, all grades, regardless of causality 


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and noted in descending order of frequency, included nausea (47 subjects [83.9%]), decreased 
appetite (36 subjects [64.3%]), platelet count decreased (36 subjects [64.3%]), white blood cell 
count decreased (30 subjects [53.6%]), neutrophil count decreased (29 subjects [51.8%]), 
vomiting (25 subjects [44.6%]), aspartate aminotransferase (AST) increased (23 subjects 
[41.1%]), alanine aminotransferase (ALT) increased (22 subjects [39.3%]), anemia (19 subjects 
[33.9%]), stomatitis (17 subjects [30.4%]), alopecia (15 subjects [26.8%]), diarrhea (15 subjects 
[26.8%]), fatigue (12 subjects [21.4%]), and malaise (12 subjects [21.4%]). 
Eighteen (32.1%) of the 56 treated subjects had developed treatment-emergent SAEs, including 
12 subjects (21.4%) with study drug-related SAEs.  The treatment-emergent SAEs, in 
descending order of frequency, included platelet count decreased (6 subjects [10.7%]); decreased 
appetite (3 subjects [5.4%]); and atelectasis, cellulitis, cholecystitis acute, dehydration, dyspnea, 
implant site infection, malaise, myalgia, pneumonia, pneumothorax, pseudomembranous colitis, 
thrombocytopenia, and urinary tract infection (1 subject [1.8%] each). 
Additional data describing the clinical experience of U3-1402 are available in the current 
Investigator’s Brochure. 
1.3. 
Study Rationale 
U3-1402 is an ADC that targets HER3 and is comprised of a fully human anti-HER3 monoclonal 
IgG1 antibody (U3-1287) covalently linked to MAAA-1162a (
 linker and a 
topoisomerase I inhibitor [MAAA-1181a]). The drug MAAA-1181a, a derivative of 
exatecan,15,16,17 is released after internalization of U3-1402 and leads to apoptosis of the target 
tumor cells by inhibition of topoisomerase I. 
In nonclinical studies, the fact that U3-1402 binds specifically to the HER3 extracellular domain 
(ECD) and does not bind to other HER family proteins has been confirmed.  In vivo studies 
indicate that U3-1402 exhibits HER3 expression-dependent cell growth inhibition activity, 
moreover, no growth inhibition was observed in HER3-negative cells, thus confirming the HER3 
specificity of U3-1402.  U3-1402 showed significant tumor regression in human breast cancer 
xenograft models. 
In summary, U3-1402 is hypothesized to show anticancer activity with a manageable safety 
profile in HER3-positive cancer. 
High HER3 expression was reported in breast cancer patients.18,19,20  Therefore, U3-1402 is 
being developed as an ADC targeting HER3-positive breast cancer, NSCLC and potentially 
other solid tumors expressing HER3. 
1.4. 
Risks and Benefits for Study Subjects 
U3-1402 is being developed for the treatment of HER3-expressing malignant tumors. The 
product is in the early stages of development. 
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 HER3-expressing 
tumors in patients. 
In nonclinical toxicology studies, toxicity of intestinal, lymphatic/hematopoietic, skin, 
pulmonary, reproductive and accessory organ, hepatic, cardiovascular, and renal systems were 
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found in association with the administration of U3-1402. As with any therapeutic antibodies, 
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 potential risks of QT prolongation, left ventricular ejection fraction (LVEF) decreased, 
potential Hy’s Law, ILD, pneumonitis, infusion-related reaction, dry eye, keratitis, 
photosensitivity, stomatitis, alopecia, dry skin, rash, rash maculopapular, and skin pigmentation 
in humans from exposure to U3-1402 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, nausea, 
decreased appetite, platelet count decreased/thrombocytopenia, white blood cell count 
decreased/leukopenia, neutrophil count decreased/neutropenia, vomiting, anemia, diarrhea and 
interstitial lung disease/pneumonitis are identified risks and will continue to be closely monitored 
and evaluated in the U3-1402 clinical development program. 
In conclusion, based on the efficacy and safety data from the nonclinical studies and the 
preliminary clinical efficacy and safety data from the ongoing studies, the benefit/risk balance 
supports continued clinical development of U3-1402. 


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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
2.1.1.1. 
Dose Escalation Part 
The primary objectives are as follows: 
1. To assess safety and tolerability of U3-1402. 
2. To determine the maximum tolerated dose (MTD) of U3-1402. 
2.1.1.2. 
Dose Finding Part 
The primary objectives are as follows: 
1. To assess safety and evaluate efficacy of U3-1402. 
2. To assess safety of alternative dosing schedule(s) of U3-1402. 
3. To determine the recommended dose(s) for expansion (RDEs) of U3-1402. 
2.1.1.3. 
Dose Expansion Part 
The primary objective is as follows: 
1. To assess safety and evaluate efficacy of U3-1402 at the RDEs in subjects with 
HER3-positive, HER2-negative (including HR-positive and TNBC) 
advanced/unresectable or metastatic breast cancers. 
2.1.2. 
Secondary Objectives 
2.1.2.1. 
Dose Escalation Part 
The secondary objectives are as follows: 
1. To assess the PK profiles of U3-1402, total anti-HER3 antibody, and MAAA-1181a. 
2. To evaluate efficacy of U3-1402. 
3. To assess the incidence of human anti-drug antibodies (ADAs) against U3-1402. 
2.1.2.2. 
Dose Finding and Dose Expansion Parts 
The secondary objective is as follows: 
1. To assess the PK profiles of U3-1402, total anti-HER3 antibody, and MAAA-1181a. 
2. To assess the incidence of ADA against U3-1402. 
2.1.2.3. 
Dose Expansion Part 
1. To determine the relationship between efficacy of U3-1402 and HER3 expression. 


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2.1.3. 
Exploratory Objectives 
The exploratory objectives for the Dose Escalation Part, Dose Finding Part, and Dose Expansion 
Part are as follows: 
1. To explore the concentration-corrected QT (QTc) relationships of U3-1402, total 
anti-HER3 antibody, and MAAA-1181a. 
2. To identify biomarkers that correlate with U3-1402 response or toxicity. 
2.2. 
Study Hypotheses 
U3-1402 will have anticancer activity in breast cancer patients whose tumors express HER3 and 
will be well-tolerated with acceptable PK properties.   
2.3. 
Study Endpoints 
The endpoints for the study include the following: 
 Pharmacokinetic endpoints: 
Serum PK endpoints (area under the concentration-versus-time curve, from time 0 to the 
last measurable concentration as calculated by the linear-up log-down trapezoidal method 
[AUClast], AUC during dosing interval [AUCtau], Cmax, time of maximum observed 
concentration [Tmax] and trough serum concentrations [Ctrough]) of U3-1402 for each 
subject will be estimated using standard noncompartmental methods.  For total anti-
HER3 antibody and MAAA-1181a, all parameters listed above will be estimated. 
 Safety endpoints: 
Safety endpoints will include dose-limiting toxicities (DLTs), serious adverse events 
(SAEs), treatment-emergent adverse events (TEAEs), adverse events of special interest 
(AESIs), physical examination findings (including ECOG PS), vital sign measurements, 
standard clinical laboratory parameters, electrocardiogram (ECG) parameters, 
echocardiography (ECHO)/multiple gated acquisition scan (MUGA) findings and 
ophthalmologic findings. 
 Efficacy endpoints: 
Tumor response will be evaluated using Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1.  Objective response rate (ORR) (the sum of complete response 
[CR] rate and partial response [PR] rate), disease control rate (DCR) (the sum of CR rate, 
PR rate, and stable disease [SD] rate), duration of response (DOR), clinical benefit rate 
(CBR; the proportion of subjects who achieved a best overall response of CR or PR or 
SD ≥ 6 months), time to response (TTR), PFS, OS, and percent change in target lesion(s). 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
3.1.1. 
Overview 
3.1.1.1. 
Study Type 
This 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 Dose Escalation and Dose Finding 
Parts will be conducted in Japan only.  The Dose Expansion Part may include subjects from any 
participating country, including the US and Japan. 
3.1.1.2. 
Treatment Groups 
Dose Escalation Part 
In the Dose Escalation Part, eligible subjects with HER3-high breast cancer who have been 
refractory to or intolerant to standard treatment, or for whom standard treatment is no longer 
available, will be enrolled.  Subjects will receive U3-1402 at varying dose levels based on their 
assigned cohort to identify the MTD of U3-1402. Refer to Section 3.1.3 for further details. 
Dose Finding Part 
In the Dose Finding Part, eligible subjects with HER3-high breast cancer will be enrolled. 
Cohorts with multiple drug doses and/or administration schedules, including up-titration of dose, 
will be selected by the Sponsor for further evaluation.  Doses evaluated for alternative 
administration schedules, including up-titration of dose, will be equal to or less than the MTD (or 
highest dose evaluated) of U3-1402 administered via IV infusion Q3W. Refer to Section 3.1.4 
for details. 
Dose Expansion Part 
In the Dose Expansion Part, eligible subjects with HER3-positive (HER3-high or HER3-low), 
HER2-negative, HR-positive breast cancer who have received ≥2 and ≤6 prior chemotherapy 
regimens for breast cancer (including ≥2 regimens administered for the treatment of 
advanced/unresectable or metastatic disease) and those with HER3-high, TNBC who have 
received 1 to 2 prior chemotherapy regimens in the advanced disease setting will be enrolled to 
evaluate safety and efficacy of U3-1402 at the RDEs.  In the Dose Expansion Part, multiple 
expansion cohorts will be evaluated as described in Section 3.1.5.  
3.1.1.3. 
Duration of the Study 
This study is expected to last approximately 7 years from the time the first subject is enrolled to 
the time the last subject is off the study. The end of the study is defined as the date of completion 
of the last visit or procedure shown in the Schedule of Events (Section 17.8) in the trial globally. 
Sponsor may terminate the study at any time due to administrative reason or at request from 
competent regulatory authorities. 


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3.1.1.4. 
Duration of Subject Participation 
The number of treatment cycles is not limited in this study. Subjects will continue study 
treatment until withdrawal of consent, progressive disease (PD), unacceptable toxicity, death, or 
termination of the study by Sponsor. 
There is an end-of-treatment (EOT) Visit which occurs within 7 days after the date of 
discontinuation. A 28-Day F/U Visit (- 7 days) takes place 28 days after the last U3-1402 
administration. If the subject begins another anticancer therapy before the end of the 28 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 Section 6.7 and Section 6.8, respectively.  
For subjects with positive ADA at F/U visit (or EOT visit if F/U visit was not performed), 
additional serum ADA samples should be collected every 3 months (± 1 month) for up to 1 year 
after the last dose of U3-1402, unless one of the following occurs sooner; the ADA becomes 
negative; the ADA titer falls below baseline if ADA was measurable prior to first dose of 
U3-1402; the subject starts another therapy for cancer; or the subject withdraws consent from the 
study. 
After discontinuation from study treatment, follow-up information for survival and subsequent 
anticancer therapy, if available, should be collected approximately every 3 months; refer to 
Section 6.9 for details. 
3.1.2. 
Dose Escalation Process and Dose Selection 
The study will enroll subjects into cohorts during dose escalation by modified continuous 
reassessment method (mCRM) with escalation with overdose control (EWOC) principle as 
outlined in Section 3.1.3).  The starting dose will be 1.6 mg/kg (see Section 3.2.1 for justification 
of the human starting dose). 
In the Dose Escalation Part, the second subject in each dosing level should start dosing at least 
24 hours after the initial dosing of the first subject to check the acute toxicity such as 
infusion-related reaction. 
In the Dose Finding Part, subjects will be enrolled to multiple Dose Finding cohorts equal to or 
less than the MTD (if attained, or the highest dose evaluated) to determine the RDEs 
(Section 3.1.4).  Doses evaluated for alternative administration schedules, including up-titration 
of dose, will be equal to or less than the MTD (or highest dose evaluated) of U3-1402 
administered via IV infusion Q3W. 
In the Dose Expansion Part, subjects will be enrolled to multiple Dose Expansion cohorts as 
described in Section 3.1.5. 
3.1.3. 
Dose Escalation Part 
Dose escalation of U3-1402 to determine the MTD will be guided by the mCRM using a 
Bayesian logistic regression model (BLRM) following EWOC principle.  The proposed human 
starting dose of U3-1402 is 1.6 mg/kg, based on 1/6 human equivalent dose (HED) of HNSTD in 
monkey (30 mg/kg).  The following planned dose levels will be assessed in the Dose Escalation 
Part (Table 3.1).  U3-1402 will be administered via IV infusion Q3W in 21-day cycles in the 
Dose Escalation Part. 




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subject in the new cohort will be based on an updated BLRM using DLT outcome data from all 
assessed doses.  Subject ongoing will continue treatment at their assigned dose level. 
Subjects can be backfilled (added) to lower doses previously proven to be safe at any point 
during dose escalation. 
To better understand the safety, tolerability, PK or preliminary activity of U3-1402, additional 
patients may be enrolled to preceding dose levels, or to intermediate dose level before or while 
proceeding with further dose escalation. 
The Dose Escalation Part will be stopped according to the following rules: 
i. 
at least 6 evaluable subjects have been enrolled at the MTD level with at least 
18 evaluable subjects in total enrolled in the Dose Escalation Part 
ii. 
at least 9 evaluable subjects have been enrolled at a particular dose level, the model 
recommends continuing at the same dose level, and the posterior probability of the 
DLT rate falling within the target DLT interval is ≥50%.  The target DLT interval is 
defined as 16% <DLT rate ≤33% 
iii. 
DLT assessment with at least 3 evaluable subjects at the maximum possible dose 
level with upper limit of 95% credible interval for posterior probability of DLT rate is 
lower than 33% 
iv. 
the initial dose level is too toxic. 
Cohorts may be expanded at any dose level or at the MTD for further elaboration of safety, or 
PK parameters as required. 
3.1.4. 
Dose Finding Part 
In the Dose Finding Part, subjects will be enrolled into cohorts with multiple drug doses and/or 
administration schedules, including up-titration of dose.  Doses evaluated for alternative 
administration schedules, including up-titration of dose, will be equal to or less than the MTD (or 
highest dose evaluated) of U3-1402 administered via IV infusion Q3W.  The objectives of the 
Dose Finding Part are to assess the safety and evaluate the efficacy of U3-1402 and determine 
the RDEs for the Dose Expansion Part.  A total of approximately 12 subjects will be enrolled 
between Dose Escalation and Dose Finding for each of the Q3W Dosing Cohorts evaluated in 
Dose Finding.  For the alternative dosing cohorts evaluated in Dose Finding, a total of 
approximately 12 subjects will be enrolled into each cohort. 
Dose Finding Cohorts 
The following cohorts may be evaluated during the Dose Finding Part.  These cohorts are 
provisional and may change based on emerging safety, tolerability, and efficacy data. 
Dose Finding Cohort 1 (Q3W Dosing) 
U3-1402 at a dosage of 4.8 mg/kg administered via IV infusion Q3W in 21-day cycles. 
Dose Finding Cohort 2 (Q3W Dosing) 
U3-1402 at a dosage of 6.4 mg/kg administered via IV infusion Q3W in 21-day cycles. 
Dose Finding Cohort 3 (Q3W Dosing with Up-titration) 
U3-1402 administered via IV infusion Q3W in 21-day cycles with an up-titration of U3-1402 
dose on Day 1 of the first 3 cycles as described below. 


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Table 3.2: 
Dose Finding Cohort 3 Dosing Schedule 
Cycle 
U3-1402 Dosage 
1 
3.2 mg/kg IV infusion Q3W 
2 
4.8 mg/kg IV infusion Q3W 
3 
6.4 mg/kg IV infusion Q3W 
Subsequent cycles 
6.4 mg/kg IV infusion Q3W 
IV = intravenous; Q3W = once every 3 weeks. 
Dose Finding Cohort 4 (Q2W Dosing) 
U3-1402 at a dosage of 4.2 mg/kg administered via IV infusion once every 2 weeks (Q2W) in 
14-day cycles for the first 3 cycles of treatment, followed by a dosage of 6.4 mg/kg administered 
via IV infusion Q3W thereafter. 
Table 3.3: 
Dose Finding Cohort 4 Dosing Schedule 
Cycle 
U3-1402 Dosage 
Cycle 1, 2, and 3 
4.2 mg/kg IV infusion Q2W 
Subsequent cycles 
6.4 mg/kg IV infusion Q3W 
IV = intravenous; Q2W = once every 2 weeks; Q3W = once every 3 weeks.  
Dose Finding Cohort 5 (Q2W Dosing) 
U3-1402 at a dosage of 3.2 mg/kg administered via IV infusion Q2W in 14-day cycles for the 
first 3 cycles of treatment, followed by a dosage of 4.8 mg/kg administered via IV infusion Q3W 
thereafter.  
Table 3.4: 
Dose Finding Cohort 5 Dosing Schedule 
Cycle 
U3-1402 Dosage 
Cycle 1, 2, and 3 
3.2 mg/kg IV infusion Q2W 
Subsequent cycles 
4.8 mg/kg IV infusion Q3W 
IV = intravenous; Q2W = once every 2 weeks; Q3W = once every 3 weeks. 
Additional Dose Finding Cohorts 
 Additional dose levels equal to, or less than, the MTD (if attained or highest dose 
evaluated during the Dose Escalation Part) may be considered for the Dose Finding 
Part. 
 Additional dose regimens, including up-titration of dose, may be considered for the 
Dose Finding Part based on emerging safety and efficacy data. 
3.1.5. 
Dose Expansion Part 
In the Dose Expansion Part, subjects will be enrolled into cohorts as described below based on 
HER3 status and breast cancer molecular subtype. The primary objective of the Dose Expansion 
Part is to assess safety and evaluate efficacy of U3-1402 at the RDE in subjects with 


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HER3-positive, HER2-negative (including HR-positive and TNBC) advanced/unresectable or 
metastatic breast cancer.  The Dose Expansion Part may include subjects from any participating 
country, including the US and Japan. 
A total of approximately 110 subjects will be enrolled in the Dose Expansion Part. 
HER3-High, HR-Positive Cohorts  
Approximately 60 eligible subjects with HER3-high, HER2-negative, HR-positive breast cancer 
will be randomized into 1 of 2 cohorts.  U3-1402 at a dosage of either 4.8 mg/kg or 6.4 mg/kg 
will be administered via IV infusion Q3W in 21-day cycles. 
HER3-Low, HR-Positive Cohort 
Approximately 20 eligible subjects with HER3-low, HER2-negative, HR-positive breast cancer 
will be enrolled.  U3-1402 at a dosage of 6.4 mg/kg will be administered via IV infusion Q3W in 
21-day cycles. 
HER3-High, TNBC Cohort 
Approximately 30 eligible subjects with HER3-high, TNBC will be enrolled. U3-1402 at a 
dosage of 6.4 mg/kg will be administered via IV infusion Q3W. 
Additional Expansion Cohort(s) 
Additional cohorts may be considered for the Dose Expansion Part based on emerging safety and 
efficacy data. 
3.1.6. 
Study Stopping Criteria 
The study treatment will be continued according to the dosing criteria to derive clinical benefit in 
the absence of withdrawal of subject consent, PD, unacceptable toxicity, or death.  If the study 
treatment is delayed more than 4 weeks from the planned date of administration (ie, 49 days 
from the last infusion date), the subject may be withdrawn from the study (see Sections 5.4 and 
5.7). 
The study may be terminated any time at the Sponsor’s discretion. 
3.1.7. 
Dose-limiting Toxicities 
A DLT is defined as any TEAE not attributable to disease or disease-related processes that 
occurs during the DLT evaluation period (Day 1 to Day 21 in Cycle 1 of Dose Escalation Part) 
and is Grade 3 or above according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) version 5.0, with the exceptions as defined below: 
For hematological toxicities, a DLT is defined as follows: 
 Grade 4 neutrophil count decreased lasting >7 days, neutrophil count decreased that 
requires standard therapies, such as colony stimulating factor (CSF) 
 Grade ≥3 febrile neutropenia 
 Grade 4 anemia 
 Grade 4 platelet count decreased 


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 Grade ≥3 platelet count decreased lasting >7 days 
 Grade ≥3 platelet count decreased with clinically significant hemorrhage 
 Grade 4 lymphocyte count decreased lasting ≥14 days 
For hepatic organ toxicities, a DLT is defined as follows: 
 Serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT) >20  
upper limit of normal (ULN) 
 AST or ALT >5  ULN, if accompanied by blood bilirubin >1.5  ULN 
 In subjects without liver metastases, AST or ALT >5  ULN lasting >3 days 
 In subjects with liver metastases, AST or ALT >5  ULN lasting >3 days, if the baseline 
level was ≤3  ULN 
 In subjects with liver metastases, AST or ALT >8  ULN lasting >3 days, if the baseline 
level was >3  ULN 
For non-hematological, non-hepatic major organ toxicities, a DLT is defined as follows: 
 Symptomatic congestive heart failure (CHF) 
 Left ventricular ejection fraction (LVEF) decline to <40% or >20% drop from baseline 
 Other Grade ≥3 non-hematological, non-hepatic major organ toxicities 
The following TEAEs are NOT considered DLTs: 
 Grade 3 fatigue lasting <7 days 
 Grade 3 nausea, vomiting, diarrhea, or anorexia that has resolved to Grade ≤2 within 
3 days 
 Isolated laboratory findings not associated with signs or symptoms including Grade 3/4 
serum alkaline phosphatase (ALP) increased, hyperuricemia, serum amylase increased, 
and lipase increased, and Grade 3 hyponatremia lasting <72 hours developed from 
Grade 1 at baseline 
 Grade 3 lymphocyte count decreased 
If any of the above toxicities is observed during the DLT evaluation period, whether the toxicity 
is regarded as DLT will be determined based on consultation between the Investigator and 
Sponsor. 
In addition, with regard to other toxicities that impact the conduct of the scheduled study 
treatment, anemia with blood transfusion, or platelet count decreased with platelet transfusion, 
whether they are regarded as DLT will be determined based on consultation between the 
Investigator and Sponsor. 
The premedication, which is a treatment before study drug administration to avoid adverse event 
(AE), is prohibited during the DLT evaluation period. 
However, the supportive therapy for the treatment is permitted after study drug administration: 


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For example: 
 Nausea, vomiting:  Antiemetics 
3.1.8. 
Maximum Tolerated Dose and Recommended Dose for Expansion Definition 
Once the dose escalation stopping criteria are met, the MTD estimated by mCRM + EWOC will 
be the dose with the highest posterior probability of the DLT rate in the target DLT rate interval 
of 16% <DLT rate ≤33% among all doses fulfilling the overdose control constraint: there is less 
than 25% probability of a DLT rate 33% (probability for excessive or unacceptable toxicity) 
(Section 3.1.3).  The final MTD for each dosing schedule will be decided based on 
considerations of the respective MTDs estimated by the mCRM and on an overall assessment of 
safety data from subsequent cycles and PK information collected at all different doses tested. 
Multiple drug doses less than the MTD (if attained, or the highest dose evaluated) and/or 
administration schedules, including up-titration of dose, will be selected by the Sponsor for 
further evaluation in the Dose Finding Part.  Doses evaluated for alternative administration 
schedules, including up-titration of dose, will be equal to or less than the MTD (or highest dose 
evaluated) of U3-1402 administered via IV infusion Q3W.  Based on the safety, PK, and efficacy 
profiles of U3-1402 obtained from the Dose Escalation and Dose Finding Parts, multiple dosing 
regimens may be selected by the Sponsor for further evaluation in the Dose Expansion Part. 
The study team will actively monitor all safety data within the EDC database on a regular basis.  
Study drug interruption and modification guidelines are in place for this study and described here 
in the protocol (Section 5.4). During the Dose Expansion Part, Safety Review Meetings will 
occur as needed to assess safety and tolerability of the selected RDEs. 
3.1.9. 
Management of Subjects with Adverse Events 
See Section 5.4. 
3.2. 
Discussion of Study Design 
3.2.1. 
Human Starting Dose 
For the first in human, dose escalation clinical trial with U3-1402, the proposed human starting 
dose (HSD) is 1.6 mg/kg.  This dose was selected based on the following rationale: 
In the 12-week intermittent dose toxicity study in rats, no severe and irreversible toxicity was 
seen in surviving males and females except for testis effects at 194.3 mg/kg, although 1 of 
15 males died in the 194.3 mg/kg group after the 4th administration.  Therefore, under the 
conditions of this study, the STD10 of the animals was considered to be 194.3 mg/kg, which was 
also the highest (maximum feasible) dose level tested.  By determining 1/10 of the STD10 and 
taking the HED of this conversion results in a HSD of 3.1 mg/kg. 
In the 12-week intermittent dose toxicity study in monkeys, the HNSTD was 30 mg/kg, which 
was the highest dose level tested.  By determining 1/6 of the HNSTD and taking the HED of this 
conversion results in a HSD of 1.6 mg/kg. 
With regard to the interests of patients for considering the safety, 1.6 mg/kg was determined as 
the HSD, which was also the maximum recommended starting dose.  At the proposed HSD, 


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estimated human U3-1402 AUC (<43.7 μg·d/mL), which was calculated based on the hypothesis 
that human PK is the same as monkey, is greater than mouse AUC at 1.5 mg/kg (27.8 μg·d/mL), 
which showed the regression of tumor size from the initiation of dosing in a subcutaneous 
xenograft model using the MDA-MB-453 cell line (HER3-expressing).  In case that the efficacy 
in human is expected to the same as that to the xenograft model, 1.6 mg/kg is considered to be 
efficacious for the cancer therapy. 
3.2.2. 
Treatment Schedule 
Based on the result of nonclinical toxicology studies (Section 1.2.2.4), death or moribundity 
were observed in once weekly dosing.  The cause of the death or moribundity appeared to be 
sustained deterioration of the animal physical conditions.  Therefore, Q3W and Q2W dosing 
schedules were selected. 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study: 
4.1.1. 
Common Inclusion Criteria for Dose Escalation and Dose Finding Parts 
1. 
Has a pathologically documented advanced/unresectable or metastatic breast cancer. 
2. 
Has documented HER3-high expressing disease assessed using immunohistochemistry 
(IHC) by the central laboratory. 
3. 
Is refractory to or intolerant to standard treatment, or for whom standard treatment is no 
longer available. 
4. 
Male or female subjects aged 20 years in Japan. 
5. 
Has an ECOG PS 0-1, with no deterioration over the previous 2 weeks. 
6. 
Has LVEF 50% by either ECHO or MUGA within 28 days prior to enrollment. 
7. 
Has adequate bone marrow reserve and organ function within 7 days prior to enrollment, 
defined according to the following: 
Item 
Laboratory value 
Platelet count 
100 000/mm3 
Hemoglobin (Hb) 
≥8.5 g/dL 
Absolute neutrophil count (ANC) 
1500/mm3 
Creatinine 
≤1.5  ULN, or creatinine clearance ≥60 mL/min as 
calculated using the Cockcroft-Gault equation 
AST/ALT 
≤3  ULN (if liver metastases are present, ≤5  ULN) 
Total bilirubin 
≤1.5  ULN 
8. 
Has adequate treatment washout period before enrollment, defined according to the 
following: 
Treatment 
Washout period 
Major surgery 
3 weeks  
Radiation therapy 
≥3 weeks (or 2 weeks for palliative radiation for bone 
metastasis [excluding pelvic radiation] and brain 
metastasis, 1 week for stereotactic radiotherapy) 
Hormonal therapy 
2 weeks 
Chemotherapy (including antibody drug 
therapy) 
3 weeks (2 weeks for 5-fluorouracil-based agents, 
folinate agents, or weekly paclitaxel.  6 weeks for 
nitrosoureas or mitomycin C) 
Immunotherapy 
3 weeks 
CYP3A4 strong inhibitor 
3 elimination half-lives of the inhibitor 
CYP3A4 strong inducer 
2 weeks 
QTc-prolonging medications 
3 elimination half-lives of the medications 
OATP1B inhibitor 
3 elimination half-lives of the inhibitor 


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9. 
Has at least 1 measurable lesion based on RECIST version 1.1 confirmed by the central 
laboratory. 
10. 
Male and female subjects of reproductive/childbearing potential must agree to use a 
highly effective form of contraception or avoid intercourse during the study and for at 
least 7 months after the last dose of study drug.  For the purpose of this protocol, methods 
considered as highly effective methods of contraception include: 
 Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or transdermal delivery). 
 Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, or implantable delivery). 
 Intrauterine device (IUD). 
 Intrauterine hormone-releasing system (IUS). 
 Bilateral tubal occlusion. 
 Vasectomized partner. 
 Complete sexual abstinence. 
Non-childbearing potential is defined as pre-menopausal with documented tubal ligation 
or hysterectomy; OR postmenopausal with documented ≥12 months of spontaneous 
amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating 
hormone [FSH] >40 mIU/mL and estradiol <40 pg/mL [<140 pmol/L] is confirmatory). 
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to discontinue HRT and use 1 of the contraception methods 
outlined above for women of childbearing potential.  Otherwise, they must discontinue 
HRT to allow confirmation of post-menopausal status prior to study enrollment.  For 
most forms of HRT, at least 2 to 4 weeks must elapse between the cessation of therapy 
and the blood draw; this interval depends on the type and dosage of HRT.  Use of HRT is 
not allowed during the study.  Men who are fertile and sexually active should be willing 
to use highly effective methods of contraception if their partners are of reproductive 
potential. 
Male subjects must not freeze or donate sperm starting at Screening and throughout the 
study period, and at least 4 months after the final study drug administration. 
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 ≥7 months after the final 
dose of study drug.  
11. 
Is able to provide written informed consent.   
12. 
Has a life expectancy of ≥3 months. 


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4.1.2. 
Additional Inclusion Criterion for Dose Finding Part 
13. 
Has received ≥2 and ≤6 prior chemotherapeutic regimens for breast cancer, ≥2 of which 
were administered for treatment of advanced/unresectable or metastatic disease.  At least 
1 prior chemotherapeutic regimen must have included a taxane (eg, paclitaxel, docetaxel), 
administered in the neoadjuvant, adjuvant, or advanced setting. 
4.1.3. 
Inclusion Criteria for Dose Expansion Part 
1. 
Has a pathologically documented advanced/unresectable or metastatic breast cancer. 
2. 
Has documented HER3-positive (HER3-high or HER3-low) disease assessed by IHC 
assay by the central laboratory from archival tumor tissue or a screening tumor fresh 
biopsy sample. 
3. 
Is able to submit a fresh tumor biopsy sample prior to starting study treatment.  (If 
subjects have already submitted fresh tumor biopsy sample for HER3 expression, 
resubmission is not necessary.) 
4. 
Has documented HER2-negative expression according to American Society of Clinical 
Oncology – College of American Pathologists (ASCO-CAP) guidelines. 
5. 
Has documented HR (estrogen and/or progesterone receptor) positive disease with 
exception of the TNBC cohort (see inclusion criterion #17 below). 
6. 
Is refractory to or intolerant to standard treatment, or for whom standard treatment is no 
longer available. 
7. 
With the exception of the TNBC cohort (see inclusion criterion #18 below), has received 
≥2 and ≤6 prior chemotherapeutic regimens for breast cancer, ≥2 of which were 
administered for treatment of advanced/unresectable or metastatic disease.  At least 
1 prior chemotherapeutic regimen must have included a taxane (eg, paclitaxel, docetaxel), 
administered in the neoadjuvant, adjuvant, or advanced setting. 
8. 
Male or female subjects aged 20 years in Japan, 18 years in the US. 
9. 
Has an ECOG PS 0-1, with no deterioration over the previous 2 weeks. 
10. 
Has LVEF 50% by either ECHO or MUGA within 28 days prior to enrollment. 
11. 
Has adequate bone marrow reserve and organ function within 7 days prior to enrollment, 
defined according to the following: 


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Item 
Laboratory value 
Platelet count 
100 000/mm3 
Hemoglobin (Hb) 
≥9.0 g/dL 
Prothrombin time (PT) or 
PT- international normalized ratio (INR) 
and partial thromboplastin time (PTT) 
≤1.5 × 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. 
Absolute neutrophil count (ANC) 
1500/mm3 
Creatinine 
≤1.5  ULN, or creatinine clearance ≥50 mL/min as 
calculated using the Cockcroft-Gault equation 
AST/ALT 
≤3  ULN (if liver metastases are present, ≤5  ULN) 
Total bilirubin 
≤1.5  ULN (<3 × ULN in the presence of documented 
Gilbert’s Syndrome [unconjugated hyperbilirubinemia] or 
liver metastases) 
12. 
Has adequate treatment washout period before enrollment, defined according to the 
following: 
Treatment 
Washout period 
Major surgery 
3 weeks  
Radiation therapy 
≥3 weeks (or 2 weeks for palliative radiation for bone 
metastasis [excluding pelvic radiation] and brain 
metastasis, 1 week for stereotactic radiotherapy) 
Hormonal therapy 
2 weeks 
Chemotherapy (including antibody drug 
therapy) 
3 weeks (2 weeks for 5-fluorouracil-based agents, 
folinate agents, or weekly paclitaxel.  6 weeks for 
nitrosoureas or mitomycin C) 
Immunotherapy 
3 weeks 
CYP3A4 strong inhibitor 
3 elimination half-lives of the inhibitor 
QTc-prolonging medications 
3 elimination half-lives of the medications 
OATP1B inhibitor 
3 elimination half-lives of the inhibitor 
13. 
Has at least 1 measurable lesion based on RECIST version 1.1 confirmed by the central 
laboratory. 
14. 
Male and female subjects of reproductive/childbearing potential must agree to use a 
highly effective form of contraception or avoid intercourse during the study and for at 
least 7 months after the last dose of study drug.  For the purpose of this protocol, methods 
considered as highly effective methods of contraception include: 
a. Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or transdermal delivery). 


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b. Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, or implantable delivery). 
c. Intrauterine device (IUD). 
d. Intrauterine hormone-releasing system (IUS). 
e. Bilateral tubal occlusion. 
f. Vasectomized partner. 
g. Complete sexual abstinence. 
Non-childbearing potential is defined as pre-menopausal with documented tubal ligation 
or hysterectomy; OR postmenopausal with documented ≥12 months of spontaneous 
amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating 
hormone [FSH] >40 mIU/mL and estradiol <40 pg/mL [<140 pmol/L] is confirmatory). 
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to discontinue HRT and use 1 of the contraception methods 
outlined above for women of childbearing potential.  Otherwise, they must discontinue 
HRT to allow confirmation of post-menopausal status prior to study enrollment.  For 
most forms of HRT, at least 2 to 4 weeks must elapse between the cessation of therapy 
and the blood draw; this interval depends on the type and dosage of HRT.  Use of HRT is 
not allowed during the study.  Men who are fertile and sexually active should be willing 
to use highly effective methods of contraception if their partners are of reproductive 
potential. 
Male subjects must not freeze or donate sperm starting at Screening and throughout the 
study period, and at least 4 months after the final study drug administration. 
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 ≥7 months after the final 
dose of study drug. 
15. 
Is able to provide written informed consent.   
16. 
Has a life expectancy of ≥3 months. 
4.1.4. 
Additional Inclusion Criteria for the HER3-high, TNBC Cohort 
17. 
Has a pathologically documented advanced/unresectable or metastatic breast cancer with 
HER3-high, HR- (estrogen and progesterone receptor) negative disease and 
HER2-negative expression according to American Society of Clinical Oncology – 
College of American Pathologists (ASCO-CAP) guidelines. 
18. 
Has progressed after receiving 1 to 2 chemotherapy regimens for advanced/unresectable 
or metastatic breast cancer. 
4.2. 
Exclusion Criteria 
4.2.1. 
Exclusion Criteria for Dose Escalation and Dose Finding Parts 
Subjects who meet any of the following criteria will be disqualified from entering the study in 
Dose Escalation and Dose Finding Parts: 


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1. 
Prior treatment with an anti-HER3 antibody. 
2. 
Prior treatment with an ADC which consists of an exatecan derivative that is a 
topoisomerase I inhibitor (eg, DS-8201a). 
3. 
Has a medical history of symptomatic CHF (New York Heart Association (NYHA) 
classes II-IV) or serious cardiac arrhythmia requiring treatment. 
4. 
Has a medical history of myocardial infarction or unstable angina within past 6 months 
prior to enrollment. 
5. 
Has a mean corrected QT by Fridericia’s formula (QTcF) prolongation to 
>450 milliseconds (ms) in males and >470 ms in females in 3 successive screening 
measurements as assessed by central laboratory. 
6. 
Has any history of interstitial lung disease (including pulmonary fibrosis or radiation 
pneumonitis), has current ILD/pneumonitis, or is suspected to have such disease by 
imaging during screening. 
7. 
Has clinically significant corneal disease. 
8. 
Has an uncontrolled infection requiring IV of antibiotics, antivirals, or antifungals. 
9. 
Has a positivity for human immunodeficiency virus (HIV), or active hepatitis B or C 
infection. 
10. 
Is a lactating mother (women who are willing to temporarily interrupt breastfeeding will 
also be excluded), or pregnant as confirmed by pregnancy tests performed within 7 days 
prior to enrollment. 
11. 
Has clinically active spinal cord compression or brain metastases, defined as untreated 
and symptomatic, or requiring therapy with steroids or anticonvulsants to control 
associated symptoms.  Subjects with treated brain metastases that are no longer 
symptomatic for 4 weeks before enrollment and who require no treatment with steroids 
may be included in the study if they have recovered from the acute toxic effect of 
radiotherapy.  A minimum of 2 weeks must have elapsed between the end of whole brain 
radiotherapy and study enrollment (1 week for stereotactic radiotherapy). 
12. 
Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other 
than alopecia) not yet resolved to NCI-CTCAE version 5.0, grade ≤1 or baseline.  
Subjects with chronic grade 2 toxicities may be eligible per the discretion of the 
Investigator. 
13. 
Has a concomitant medical condition that would increase the risk of toxicity, in the 
opinion of the Investigator. 
14. 
Has known hypersensitivity to either the drug substances or inactive ingredients in the 
drug product. 
4.2.2. 
Additional Exclusion Criteria for Dose Finding Part  
15. 
Has multiple primary malignancies within 3 years, except adequately resected 
non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors 
curatively treated. 


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4.2.3. 
Exclusion Criteria for Dose Expansion Part  
Subjects who meet any of the following criteria will be disqualified from entering the study in 
the Dose Expansion Part: 
1. 
Prior treatment with an anti-HER3 antibody. 
2. 
Prior treatment with an antibody-drug conjugate (ADC) which consists of a 
topoisomerase I inhibitor, exatecan derivative (eg, DS-8201a) or govitecan derivative 
(eg, IMMU-132). 
3. 
Has a medical history of symptomatic CHF (New York Heart Association [NYHA] 
classes II-IV) or serious cardiac arrhythmia requiring treatment. 
4. 
Has a medical history of myocardial infarction or unstable angina within past 6 months 
prior to enrollment. 
5. 
Has any clinically important abnormalities in rhythm, conduction or morphology of 
resting ECG, eg, complete left bundle branch block, third-degree heart block, 
second-degree heart block, or PR interval >250 ms. 
6. 
Has a mean QTcF prolongation to >450 ms in males and >470 ms in females in 
3 successive screening measurements as assessed by central laboratory. 
7. 
Has any factors that increase the risk of QTc prolongation or risk of arrhythmic events, 
such as congenital long QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years of age in first-degree relatives. 
8. 
Has any history of interstitial lung disease (including pulmonary fibrosis or radiation 
pneumonitis), has current ILD/pneumonitis, or is suspected to have such disease by 
imaging during screening. 
9. 
Has clinically significant corneal disease. 
10. 
Has any evidence of severe or uncontrolled systemic diseases (including uncontrolled 
hypertension, and active bleeding diatheses or active infection including hepatitis B, 
hepatitis C and HIV infection), psychiatric illness/social situations, substance abuse, or 
other factors which in the Investigator’s opinion makes it undesirable for the subject to 
participate in the study or which would jeopardize compliance with the protocol.  
Screening for chronic conditions is not required. 
11. 
Is a lactating mother (women who are willing to temporarily interrupt breastfeeding will 
also be excluded), or pregnant as confirmed by pregnancy tests performed within 7 days 
prior to enrollment. 
12. 
Has clinically active spinal cord compression or brain metastases, defined as untreated 
and symptomatic, or requiring therapy with steroids or anticonvulsants to control 
associated symptoms.  Subjects with treated brain metastases that are no longer 
symptomatic for 4 weeks before enrollment and who require no treatment with steroids 
may be included in the study if they have recovered from the acute toxic effect of 
radiotherapy.  A minimum of 2 weeks must have elapsed between the end of whole brain 
radiotherapy and study enrollment (1 week for stereotactic radiotherapy). 


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13. 
Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other 
than alopecia) not yet resolved to NCI-CTCAE version 5.0, grade ≤1 or baseline.  
Subjects with chronic grade 2 toxicities may be eligible per the discretion of the 
Investigator. 
14. 
Has a concomitant medical condition that would increase the risk of toxicity, in the 
opinion of the Investigator. 
15. 
Has known hypersensitivity to either the drug substances or inactive ingredients in the 
drug product. 
16. 
Has multiple primary malignancies within 3 years, except adequately resected 
non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors 
curatively treated. 


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5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatment Group(s)/Sequences and Blinding 
5.1.1. 
Treatment Group(s)/Sequences 
See Section 3.1.1.1 to 3.1.1.4. 
5.1.2. 
Method of Treatment Group(s)/Sequences Allocation 
See Section 3.1.1.1 to 3.1.1.4. 
5.1.2.1. 
Enrollment 
Subject enrollment is conducted at central interactive response technology (IRT). Enrollment 
process is described in Figure 5.1. 
Figure 5.1: 
Subject Enrollment Process 
 
HER3 = human epidermal growth factor receptor 3; IRT = interactive response technology; RECIST = Response 
Evaluation Criteria in Solid Tumors 
Investigators will maintain a confidential screening log of all potential study subjects that 
includes limited information of the subjects, date and outcome of screening process. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled and screen 
failed in the study indicating their assigned Subject Number.  The unique Subject Number will 
be assigned by IRT for all subjects who provide written informed consent for tumor screening. 
Each subject will be provided with information about the study, will have all questions answered 
to their satisfaction, and will sign and date an ICF. This must be completed before any 
study-specific procedures are performed.  Separate Informed consent must be obtained for the 
examination of HER3 expression in the tumor tissue.  Additional information about informed 
consent procedures is provided in Section 15.3. 


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After obtaining an informed consent for tumor screening, the Investigator or designee should 
perform a tumor biopsy or should request archive tumor tissue. Tumor tissue (fresh or archived) 
must be sent to a central laboratory selected by the Sponsor to determine HER3 expression. 
Results of HER3 IHC testing will be reported to the Investigator by the central laboratory. 
During the Dose Expansion Part, subjects with HER3 positive expression determined using an 
archived tumor tissue sample will require a fresh tumor biopsy prior to study treatment.  Fresh 
tumor tissue obtained from this biopsy must be sent to the central laboratory selected by the 
Sponsor to determine HER3 expression; these results are not required for study eligibility. The 
Investigator or designee must also send all computed tomography (CT) or magnetic resonance 
imaging (MRI) scans performed within 28 days of enrollment to the central imaging CRO 
selected by the Sponsor for confirmation of measurable disease per RECIST version 1.1. The 
central imaging CRO review results will be reported to the Investigator to confirm eligibility. 
After obtaining written informed consent (Section 15.3), the Investigator or designee must 
determine if all inclusion and exclusion criteria have been satisfied, including obtaining a fresh 
tumor biopsy, if required. A subject is considered enrolled in the study once the Investigator 
enters all required data of eligible subjects into the IRT (IWRS). After the confirmation of the 
eligibility of the subject, the Investigator or designee enters subject data in the IRT. The date of 
enrollment is defined as the date that the subject is confirmed eligible in the IRT. 
When the subject is enrolled, administration dose and dosing schedule will be assigned by the 
IRT. Investigators must confirm the dosing regimen assigned by the IRT before administration of 
U3-1402. 
For screen fail subjects, Investigators must explain the reason of screen failure to the subject and 
then record the date of screen failure and the reason of failure in the IRT. 
Electronic case report form (eCRF) will be created for all subjects who have signed informed 
consent for participation in the study.  An eCRF will not be created for subjects who have signed 
informed consent for examination of the tumor only.  Data for all study visits will be recorded on 
the eCRF for subjects who receive study drug.  Only minimal data will be recorded as screening 
failures on the eCRF for subjects who do not meet eligibility and/or do not receive study drug.  
Further data, such as AEs, will not be collected from subjects once they are considered screen 
failures or have decided to withdraw prior to receiving study drug. 
5.1.3. 
Blinding 
This study is open-label and no blinding will be performed. 
5.1.4. 
Emergency Unblinding Procedure 
Not applicable. 
5.2. 
Study Drug(s) 
5.2.1. 
Description  
The head of the study center in Japan or the Investigator must ensure that the investigational 
product will be used only in accordance with the protocol. 




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A Drug Accountability Record will be provided for the investigational product.  The record must 
be kept current and should contain the dates and quantities of drug received, subject’s 
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 U3-1402 will be returned to a designee as 
instructed by Sponsor or will be destroyed.  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 supervisor of investigational products in Japan and Investigator in the 
US when approved in writing by Sponsor, and after the Sponsor has received copies of the site’s 
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 supervisor of 
investigational products in Japan and Investigator in the US are responsible for the accountability 
of all used and unused study supplies at the site. 
5.2.7. 
Retention Samples 
Not applicable. 
5.3. 
Control Treatment 
Not applicable. 
5.4. 
Dose Interruptions and Reductions 
Specific criteria for dose interruption, re-initiation, reduction and/or discontinuation of U3-1402 
are listed in Table 5.2. Doses may also be interrupted for other AEs per Investigator discretion, 
and supportive therapy may be administered in accordance with local practice guidelines. All 
dose interruptions or dose modifications must be recorded on the AE and drug administration 
eCRF pages. 
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 external experts such as a cardiologist, pulmonologist, etc, should be consulted as 
deemed necessary.   
5.4.1. 
Dose Interruptions 
The dose can be interrupted for up to 4 weeks 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 4 weeks, the subject may be withdrawn from the study following discussion and agreement 
between the Investigator and Sponsor. 




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Table 5.2: 
Dose Delay Criteria and Dose Reduction for U3-1402 
 
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 
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 should be reduced by 50% and subjects should be 
closely monitored. 
If no other reactions appear, the subsequent infusion rate 
could be resumed at the initial planned rate. 
Grade 2 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDs, 
narcotics, IV injection fluids); 
prophylactic medications 
indicated for ≤24 hours 
U3-1402 infusion should be interrupted. 
Symptomatic treatment (eg, antihistamines, NSAIDs, 
narcotics, IV fluids). 
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 should 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). 
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 should be discontinued 
immediately and permanently. 
Urgent intervention indicated.  Antihistamines, 
corticosteroids, epinephrine, bronchodilators, 
vasopressors, IV fluid therapy, oxygen inhalation etc, 
must be administered as clinically indicated. 
Fatigue/ 
Asthenia 
Grade 3  
Delay dose until resolved to ≤Grade 1 or baseline values, 
then: 
If resolved to ≤Grade 1 or baseline values in ≤14 days, 
resume U3-1402. 
If resolved to ≤Grade 1 or baseline values in >14 days, 
U3-1402 may be resumed after discussion and agreement 
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 ≤Grade 2, then resume 
U3-1402. 
Grade 4 
(<500/mm3; <0.5 × 109/L) 
Delay dose until resolved to ≤Grade 2, then reduce U3-
1402 by 1 dose level. 


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Table 5.2: 
Dose Delay Criteria and Dose Reduction for U3-1402 (Continued) 
 
Worst Toxicity NCI-
CTCAE Version 5.0 Grade 
(unless otherwise specified) 
Schedule Modification for U3-1402 
Febrile 
neutropenia (ANC 
<1000/mm3;  
<1 × 109/L, fever 
>38.3°C or a 
sustained 
temperature of 
≥38°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 granulocyte 
colony-stimulating factor as prophylaxis for all 
subsequent cycles and according to local guidelines. 
Grade 4 
Delay dose until resolved, then reduce U3-1402 by 1 dose 
level and resume.   
Administer granulocyte colony-stimulating factor 
as prophylaxis for all subsequent cycles and according to 
local guidelines. 
Anemia 
 
Grade 3  
(Hemoglobin <8.0 g/dL) 
Delay dose until resolved to ≤Grade 2 or baseline; then 
resume U3-1402. 
For recurrent anemia, delay dose until resolved ≤Grade 2 
or baseline, then reduce U3-1402 by 1 dose level and 
resume. 
Consider packed red blood cell transfusion according to 
institutional guidelines. 
Grade 4 (Life-threatening 
consequences; urgent 
intervention indicated) 
Delay dose until resolved to ≤Grade 2 or baseline, then 
reduce U3-1402 by 1 dose level and resume. 
Consider transfusion according to institutional guidelines. 
Platelet count 
decreased 
Grade 3 
(Platelet <50 - 25 × 109/L) 
Delay dose until resolved to ≤Grade 1, then: 
If resolved in ≤14 days, resume U3-1402. 
If resolved in >14 days, U3-1402 may be resumed. 
Consider reducing U3-1402 by 1 dose level. 
Consider platelet transfusion according to institutional 
guidelines. 
Grade 4 
(Platelet <25 × 109/L) 
Delay dose until resolved to ≤Grade 1, then reduce 
U3-1402 by 1 dose level and resume. 
Consider transfusion according to institutional guidelines. 
Lymphocyte 
Count Decreased 
Grade 4 (<0.2 × 109/L) 
Delay dose until resolved to ≤Grade 2, then: 
If resolved in ≤14 days, resume U3-1402. 
If resolved in >14 days, reduce U3-1402 by 1 dose level 
and resume. 
Cardiac disorders 
Heart failure 
Grade ≥2 (Symptoms with 
moderate activity or 
exertion) 
Cardiologist consult as necessary. 
Delay dose until resolved to ≤Grade 1, then reduce U3-
1402 by 1 dose level. 
Ejection fraction 
decreased 
Decrease in LVEF 10% to 
20% (absolute value), but 
LVEF >45% 
Continue treatment with U3-1402. 
LVEF 40% to ≤45% and 
decrease is <10% (absolute 
value) from baseline 
Continue treatment with U3-1402. 
Repeat LVEF assessment within 3 weeks. 


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Table 5.2: 
Dose Delay Criteria and Dose Reduction for U3-1402 (Continued) 
 
Worst Toxicity NCI-
CTCAE Version 5.0 Grade 
(unless otherwise specified) 
Schedule Modification for U3-1402 
 
LVEF 40% to ≤45% and 
decrease is ≥10% to 20% 
(absolute value) 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. 
LVEF <40% or >20% drop 
from baseline 
Delay U3-1402 dosing. 
Repeat LVEF assessment within 3 weeks; if LVEF <40% 
or >20% (absolute value) drop from baseline is 
confirmed, discontinue U3-1402. 
Cardiologist consult as necessary. 
Cardiac troponin 
increased 
Grade 1 (Levels above the 
upper limit of normal and 
below the level of 
myocardial infarction as 
defined by the manufacturer) 
In subjects without 
symptoms suggestive of 
acute coronary syndrome 
Perform additional troponin I testing by central 
laboratory, at 3 hours (± 1 hour) after initial local troponin 
test. 
Follow institutional guidelines for management of 
detectable troponin testing. 
Otherwise: 
Repeat troponin testing at 3 (± 1 hour) after initial 
troponin test. 
If levels at 3 hours (6 hours post-infusion) rise 
significantly, perform ECG in triplicate and repeat 
troponin testing 6 (± 1 hour) or 24 (± 1 hour) after initial 
troponin test. 
If acute myocardial infarction is ruled out, continue 
U3-1402. 
If acute myocardial infarction is confirmed, discontinue 
subject from U3-1402. 
Grade 3 (Levels consistent 
with myocardial infarction as 
defined by the manufacturer) 
In subjects without 
symptoms suggestive of 
acute coronary syndrome 
Follow institutional guidelines for management of 
detectable troponin testing. 
Perform 12-lead ECG in triplicate. 
Perform additional troponin I testing by central laboratory 
at 6 and 12 hours (± 1 hour) after initial local troponin 
test. 
Cardiologist consult as necessary. 
If acute myocardial infarction is ruled out, resume 
U3-1402. 
If acute myocardial infarction is confirmed, discontinue 
subject from U3-1402. 


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Table 5.2: 
Dose Delay Criteria and Dose Reduction for U3-1402 (Continued) 
 
Worst Toxicity NCI-
CTCAE Version 5.0 Grade 
(unless otherwise specified) 
Schedule Modification for U3-1402 
 
Grade 1 (Levels above the 
upper limit of normal and 
below the level of 
myocardial infarction as 
defined by the manufacturer) 
in subjects with symptoms 
suggestive of acute coronary 
syndrome 
Repeat levels should be obtained every 6 to 8 hours to 
identify a rising and/or falling pattern of values. 
Perform 12-lead ECG in triplicate. 
Perform additional troponin I testing by central laboratory 
at 6 and 12 hours (± 1 hour) after initial local troponin 
test. 
Follow institutional guidelines for management of 
detectable troponin testing. 
Cardiologist consult as necessary. 
If acute myocardial infarction is ruled out, resume 
U3-1402. 
If acute myocardial infarction is confirmed, discontinue 
subject from U3-1402. 
Grade 3 (Levels consistent 
with myocardial infarction as 
defined by the manufacturer) 
in subjects with symptoms 
suggestive of acute coronary 
syndrome 
Discontinue subject from U3-1402. 
Follow institutional guidelines for management of 
detectable troponin testing. 
Repeat levels should be obtained every 6 to 8 hours to 
identify a rising and/or falling pattern of values. 
Perform 12-lead ECG in triplicate. 
Perform additional troponin I testing by central laboratory 
at 6 and 12 hours (± 1 hour) after initial local troponin 
test. 
Cardiologist consult as necessary. 
Electrocardiogram 
QT corrected 
interval prolonged 
Grade 3 (Average 
QTcF ≥501 ms; >60 ms 
change from baseline) 
Delay U3-1402 until resolved to ≤Grade 1 (QTcF 
≤480 ms). 
Determine if another medication the subject was taking 
may be responsible and can be adjusted or if there are any 
changes in serum electrolytes that can be corrected. 
If QTcF prolongation is attributed to U3-1402, then 
reduce U3-1402 by 1 dose level. 
Cardiologist consult as necessary. 
Grade 4 (Torsade de pointes; 
polymorphic ventricular 
tachycardia; signs/symptoms 
of serious arrhythmia) 
Discontinue subject from U3-1402. 
Cardiologist consult as necessary 


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Table 5.2: 
Dose Delay Criteria and Dose Reduction for U3-1402 (Continued) 
 
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 column 
If a subject develops radiographic changes potentially 
consistent with ILD/pneumonitis or develops an acute 
onset of new or worsening pulmonary or other related 
signs/symptoms such as dyspnea, cough or fever, rule out 
ILD/pneumonitis. 
If ILD/pneumonitis is suspected, delay U3-1402 dosing 
pending further evaluation and start corticosteroid 
treatment promptly unless clinically contraindicated.  
Evaluations 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 noninflammatory/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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Table 5.2: 
Dose Delay Criteria and Dose Reduction for U3-1402 (Continued) 
 
Worst Toxicity NCI-
CTCAE Version 5.0 Grade 
(unless otherwise specified) 
Schedule Modification for U3-1402 
Pulmonary toxicity 
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 ≤28 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 to 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 chest CT findings, followed 
by gradual taper over at least 4 weeks. 
 Monitor symptoms closely. 
 Reimage as clinically indicated. 
 If worsening or no improvement in clinical or 
diagnostic observations in 5 days,  
 
Consider increasing dose of steroids (eg, 
2-mg/kg/day prednisone or equivalent) and 
administration may be switched to intravenous 
(eg, methylprednisolone). 
 
Reconsider additional work-up for alternative 
etiologies as described previously. 
Escalate care as clinically indicated. 


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Table 5.2: 
Dose Delay Criteria and Dose Reduction for U3-1402 (Continued) 
 
Worst Toxicity NCI-
CTCAE Version 5.0 Grade 
(unless otherwise specified) 
Schedule Modification for U3-1402 
Pulmonary toxicity 
Grade 3 or 4 
Permanently discontinue subject from study treatment. 
Toxicity Management: 
 Hospitalization is 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. 
 Reimage as clinically indicated. 
 If still no improvement within 3 to 5 days,  
 
Reconsider additional work-up for alternative 
etiologies as described above. 
 
Consider other immuno-suppressants and/or 
treat per local practice. 
Endocrine disorders 
Endocrine 
disorders 
Grade 3 
Delay dose until resolved to ≤Grade 2, then: 
If resolved in ≤14 days, resume U3-1402. 
If resolved in >14 days, U3-1402 may be resumed after 
discussion and agreement between the Investigator and 
Sponsor. 
Grade 4 
Discontinue subject from U3-1402. 
Eye disorders 
Ocular 
Grade 3 
Delay dose until resolved to ≤Grade 2, then: 
If resolved in ≤7 days, resume U3-1402. 
If resolved in >7 days, then reduce U3-1402 by 1 dose 
level. 
Ophthalmologist consultation as clinically indicated. 
Grade 4 
Discontinue subject from U3-1402. 
Ophthalmologist consult as necessary. 
Renal and urinary disorders 
Creatinine 
increased 
Grade 3 (>3.0 × 
baseline; >3.0 - 6.0 × 
ULN) 
Delay dose until resolved to ≤Grade 1 or baseline, then 
reduce U3-1402 by 1 dose level. 
Grade 4 (>6.0 × ULN) 
Discontinue subject from U3-1402. 


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Table 5.2: 
Dose Delay Criteria and Dose Reduction for U3-1402 (Continued) 
 
Worst Toxicity NCI-
CTCAE Version 5.0 Grade 
(unless otherwise specified) 
Schedule Modification for 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. 
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 was ≤ 3 × ULN. 
Delay U3-1402 dose until resolved to ≤Grade 1, then: 
If resolved in ≤7 days, resume U3-1402. 
If resolved in >7 days, then reduce U3-1402 by 1 dose 
level. 
>8.0-20.0 × ULN if baseline 
was normal; >8.0-20.0 × 
baseline level if baseline level 
was abnormal 
In subjects with liver 
metastases, if the baseline 
level was > 3 × ULN. 
Delay U3-1402 dose until resolved to ≤baseline level, 
then: 
If resolved in ≤7 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 consult 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 Gilbert’s syndrome or liver metastases 
at baseline, delay U3-1402 until resolved to ≤Grade 1, 
then: 
If resolved in ≤7 days, resume U3-1402; 
If resolved in >7 days, reduce U3-1402 by 1 dose level. 
If documented Gilbert’s syndrome or liver metastases at 
baseline, continue U3-1402. 


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Table 5.2: 
Dose Delay Criteria and Dose Reduction for U3-1402 (Continued) 
 
Worst Toxicity NCI-
CTCAE Version 5.0 Grade 
(unless otherwise specified) 
Schedule Modification for U3-1402 
TBL increased 
Grade 3 (>3.0-10.0 × ULN if 
baseline level was normal; 
>3.0-10.0 × baseline level if 
baseline level was abnormal) 
If no documented Gilbert’s syndrome or liver metastases 
at baseline, delay U3-1402 dose until resolved to 
≤Grade 1, then: 
 If resolved in ≤7 days, reduce U3-1402 by 1 dose 
level; 
 If resolved in >7 days, discontinue subject from 
U3-1402. 
If documented Gilbert’s syndrome or liver metastases at 
baseline, delay U3-1402 dose until resolved to ≤Grade 2, 
then: 
 If resolved in ≤7 days, reduce U3-1402 by 1 dose 
level; 
 If resolved in >7 days, discontinue subject from 
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 ≥3 × ULN with 
simultaneous TBL 2 × ULN 
Delay U3-1402 until drug-induced liver injury can be 
ruled out.  The Investigator should consult with a 
gastroenterologist or hepatologist as needed, and the 
subject should be treated accordingly. 
Monitor AST/ALT and TBL twice weekly until resolution 
or return to baseline. 
It is strongly recommended to perform a full diagnostic 
workup, to exclude alternative causes such as viral or 
autoimmune hepatitis, alcoholic liver injury, biliary tract 
disorders, or hemodynamic abnormalities.  Results from 
diagnostic workup (including, for example: INR, direct 
bilirubin, serologic tests for hepatitis A, B, and C; alcohol 
use, ultrasound, 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 
should 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. 


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Table 5.2: 
Dose Delay Criteria and Dose Reduction for U3-1402 (Continued) 
 
Worst Toxicity NCI-
CTCAE Version 5.0 Grade 
(unless otherwise specified) 
Schedule Modification for U3-1402 
AST or ALT> 
3.0 × ULN (if liver 
metastases are 
present, 
>5 × ULN) 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 ≤Grade 1, and consider 
treatment with antiemetics and/or corticosteroids as per 
Investigators judgement and local practice/guidelines, 
then: 
If resolved to ≤Grade 1 in ≤14 days, resume U3-1402. 
If does not resolve to ≤Grade 1 in >14 days, reduce U3-
1402 by 1 dose level. 
Vomiting 
Grade 3 (Tube feeding, TPN, 
or hospitalization indicated) 
Delay U3-1402 until resolved ≤Grade 1, and consider 
treatment with antiemetics and/or corticosteroids as per 
Investigators judgement and local practice/guidelines, 
then: 
If resolved to ≤Grade 1 in ≤7 days, resume U3-1402. 
If does not resolve to ≤Grade 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 patients 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 
Investigator’s discretion as per local/institutional guidelines.  Investigators must also consider providing patients 
with an antiemetic regimen for subsequent use as needed. 
 


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Table 5.2: 
Dose Delay Criteria and Dose Reduction for U3-1402 (Continued) 
 
Worst Toxicity NCI-
CTCAE Version 5.0 Grade 
(unless otherwise specified) 
Schedule Modification for U3-1402 
Diarrhea/ 
Colitis 
Grade 3 
Delay U3-1402 until resolved ≤Grade 1, and consider 
treatment per local practice/guidelines, then: 
If resolved to ≤Grade 1 in ≤7 days, resume U3-1402. 
If resolved to ≤Grade 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 ≤Grade 1, and consider 
treatment per local practice/guidelines, then: 
If resolved to ≤Grade 1 in ≤14 days, resume U3-1402; 
If resolved to ≤Grade 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 
(Nonlaboratory or 
Laboratory) 
Grade 3 
Delay U3-1402 until resolved ≤Grade 1 or baseline level, 
then: 
If resolved in ≤7 days, resume U3-1402; 
If resolved >7 days, then reduce U3-1402 by 1 dose level. 
 
Grade 4 
(Life-threatening 
consequences; urgent 
intervention indicated) 
Discontinue subject from U3-1402. 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram, eCRF = electronic case report 
form; g/dL = grams per deciliter; HBV DNA = hepatitis B virus DNA (a measure of the hepatitis B viral load in the 
blood);  HCV DNA = hepatitis C virus DNA (a measure of the hepatitis C viral load in the blood);  ILD = interstitial 
lung  disease, INR = international normalized ratio; IV = intravenous; L = liter; LVEF = left ventricular ejection 
fraction; MRI = magnetic resonance imaging; NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events; NSAIDs  = nonsteroidal anti-inflammatory drugs; QTcF = corrected QT using 
Fridericia’s formula; SpO2 = oxygen saturation of peripheral artery; TBL = total bilirubin; ULN = upper limit of 
normal. 
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.  


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5.6. 
Prior and Concomitant Medications 
5.6.1. 
Prior Medications 
All prior anticancer treatments or procedures for breast cancer (eg, surgery, radiation therapy, 
TKI therapy, chemotherapy, and immune checkpoint inhibitor therapy) will be recorded. 
5.6.2. 
Concomitant Medications 
Medications used from Day 1 of Cycle 1 to the follow-up (F/U) visit or 28 days after the last 
dose of U3-1402 (if the F/U visit is not performed), will be recorded.  If the subject begins 
another anticancer therapy, medications used after these anticancer therapies will not be record.  
All concomitant medications will be recorded on the eCRF. 
Prophylactic treatment for expected toxicities may be administered per Investigator discretion 
and institution guidelines. 
Hematopoietic growth factors may be used per clinical judgment of the Investigator and 
according to prescribing information and institutional guidelines. 
Bisphosphonates (eg, pamidronate or zoledronate) or denosumab for control of bone pain, 
treatment of bony metastases, or treatment of osteoporosis, may be used per clinical judgment of 
the Investigator and according to prescribing information and institutional guidelines. 
Supportive treatment including management of study drug-related adverse events will be per 
Investigator discretion. 
Subjects taking warfarin should be monitored regularly for changes in prothrombin time or INR. 
5.6.3. 
Prohibited Concomitant Medications/Activities 
The following medications and products will be prohibited from Day 1 of Cycle 1 until end of 
treatment (EOT): 
 Other anticancer therapy, including cytotoxic agents, targeted agents, immunotherapy 
or endocrine therapy. 
 Radiotherapy, except for palliative radiation to known metastatic sites (as long as it 
does not affect assessment of tumor response). Whenever possible, subject should 
have a tumor assessment of the lesion(s) prior to receiving radiotherapy in order to 
rule out progression of disease. In case of Progressive Disease (PD), subjects should 
be discontinued from the U3-1402 J101 protocol. 
 Hormonal replacement therapy. 
 Concomitant medications that prolong the QTc interval including but not limited to: 
antipsychotics, tricyclic/tetracyclic antidepressants, selective serotonin and 
norepinephrine reuptake inhibitors (SSNRIs), macrolide antibiotics, fluoroquinolone 
antibacterials, azole antifungals, antimalarials, and antiprotozoals. 
 If the concomitant medication(s) that prolong the QTc interval is unavoidable, 
consider delaying U3-1402 treatment until such drug has cleared from circulation 
(approximately 3 elimination half-lives of the inhibitors) when possible.  If the 


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drug which prolongs the QTc interval is co-administered and U3-1402 treatment 
cannot be delayed, patients should be closely monitored for adverse reactions. 
 Other investigational agents. 
 Chloroquine and hydroxychloroquine 
 CYP3A4 strong inhibitors including but not limited to:  boceprevir, clarithromycin, 
itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, telaprevir, telithromycin, 
voriconazole. 
 If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying 
U3-1402 treatment until the strong CYP3A4 inhibitors have cleared from 
circulation (approximately 3 elimination half-lives of the inhibitors) when 
possible.  If a strong CYP3A4 inhibitor is co-administered and U3-1402 treatment 
cannot be delayed, patients should be closely monitored for adverse reactions. 
 [Dose Escalation and Dose Finding Parts Only] Avoid CYP3A4 strong inducers 
(eg, carbamazepine, phenytoin, and rifampin). 
 Organic anion transporting polypeptide (OATP)1B inhibitors including but not limited 
to:  atazanavir, clarithromycin, cyclosporine, erythromycin, gemfibrozil, lopinavir, 
rifampin, ritonavir, simeprevir. Consult with your local resources as needed to 
evaluate potential OATP1B inhibitors. 
 If concomitant use of OATP1B inhibitors is unavoidable, consider delaying 
U3-1402 treatment until the OATP1B inhibitors have cleared from circulation 
(approximately 3 elimination half-lives of the inhibitors) when possible.  If an 
OATP1B inhibitor is co-administered and U3-1402 treatment cannot be delayed, 
patients should be closely monitored for adverse reactions. 
5.6.4. 
Dietary and Lifestyle Restrictions 
The following foods and products will be prohibited from 14 days before Day 1 of Cycle 1 until 
EOT: 
 Foods containing hypericum perforatum (Saint John's wort) 
The following foods and products will be prohibited from Day 1 of Cycle 1 until EOT: 
 Foods or beverages containing grapefruit 
For Japanese sites, subjects will be hospitalized during Day 1 to Day 21 on Cycle 1 of the Dose 
Escalation Part. 
Female subjects of child bearing potential or those who have been amenorrheic for 12 months or 
longer for medical reasons other than sterilization surgery (eg, effect of medication) will be 
regarded as women of childbearing potential and required along with the partner of subject 
enrolled in study to both use adequate contraceptive methods (eg, concomitant use of a 
spermatocidal agent and barrier contraceptive, intrauterine contraceptive, which are approved or 
certificated in Japan [for Japanese subjects] and US [for US subjects]) during the study and for at 
least 7 months after the last dose of U3-1402. 


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Subjects who wear contact lenses must discontinue wearing their lenses if they have any mild to 
moderate symptoms (CTCAE Grade ≤2) 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 ≥3) 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 by a study doctor, at any time during 
the study and ≥1 week after permanent discontinuation of study treatment. 
Subjects must avoid using tanning lights and booths. When in the sun, subject should cover their 
skin and use sunscreen as possible. 
5.7. 
Subject Withdrawal/Discontinuation 
5.7.1. 
Reasons for Withdrawal 
Any subject who discontinues from the study treatment for any reason will have their study 
treatment discontinuation recorded. 
Subjects may be withdrawn from the study after signing informed consent for the following 
reasons: 
 Progressive disease (PD) per RECIST version 1.1 
 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 version 1.1) 
 AE 
 Death 
 Pregnancy 
 Withdrawal of consent by subject 
 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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5.7.2. 
Withdrawal Procedures 
If a subject is withdrawn from the study, the Investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal, including the date of last 
treatment and the reason for withdrawal. 
If the subject is withdrawn due to an AE, the Investigator will follow the subject until the AE has 
resolved or stabilized as possible. All subjects who are withdrawn from the study and received 
study treatment should complete protocol-specified withdrawal procedures.  Protocol-specified 
withdrawal procedures will involve an EOT visit and a F/U visit 28 days (− 7 days) after the last 
administration of U3-1402. Protocol-specified withdrawal procedures are the same as those to be 
performed at the EOT visit and the F/U visit (Section 6.7 and Section 6.8). 
If the subject is withdrawn due to reasons other than death, withdrawal of consent, loss to 
follow-up, or study closure, and received study treatment, disease progression should be 
followed until PD or starting new anticancer therapy, whichever occurs first regardless of 
Follow-up period (Section 6.4.2). 
If the subject is withdrawn due to reasons other than death, withdrawal of consent, loss to 
follow-up, or study closure, and received study treatment, follow-up for survival and subsequent 
anticancer therapy, if available (Section 6.9). 
5.7.3. 
Subject Replacement 
Subject replacement is not allowed for this study.  
5.7.4. 
Subject Re-screening Procedures 
The study will allow re-screening for any subject who failed to meet eligibility criteria upon 
initial screening. A new Subject Number will be assigned at re-screening. The initial screening 
information and the reason why the subject was ineligible for the initial evaluation will be 
recorded on the Screening Log. 
5.8. 
Criteria for Suspending Study Treatment 
The subject should be discontinued from the study under the following conditions: 
1. If a subject is assessed as requiring a dose delay longer than 4 weeks (See Section 5.4), 
after discussion with the Sponsor. 
2. If a subject is assessed PD (per RECIST version 1.1) or clinical progression by the 
Investigator. 
3. If a subject presents any significant AE, as determined by the Investigator. 
4. If any major protocol violation occurred, at the discretion of Investigator and Sponsor. 
5. If becomes clear that the subject did not meet the inclusion/exclusion criteria, after 
discussion with the Sponsor. 
6. If the subject withdraws consent. 
7. If the study is terminated by the Sponsor. 
8. At the discretion of Investigator, according to the condition of subject. 


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6. 
STUDY PROCEDURES 
Study visit schedules in tabular format are provided in Table 17.7, Table 17.8, Table 17.9, and 
Table 17.10. 
6.1. 
Screening 
Obtain a signed and dated ICF for the study before any study-related procedures or assessments.  
Informed consent for tumor screening should be obtained in a separate ICF. 
In this study, enrollment will be performed as described in Section 5.1.2.1. 
The following activities and/or assessments will be performed during the screening period: 
Tumor Screening 
The following procedures should be conducted: 
Before enrollment 
 Obtain a separate signed and dated ICF for tumor screening before any study-related 
procedures or assessments are performed. 
 Perform a tumor biopsy OR request archive tumor tissue sample. 
 Send tumor tissue to the central laboratory for assay of the HER3 status.  Refer to the 
Laboratory Manual for information regarding archived and/or fresh tumor tissue 
requirements and shipping. 
If HER3 status to determine eligibility was assessed with archived tumor tissue 
sample: 
 A fresh tumor biopsy may be performed for subjects with HER3-negative tissue 
that was assayed using an archived tumor tissue samples.  Tumor tissue obtained 
by this fresh biopsy should be sent to the central laboratory for the re-assay of 
HER3 status.  Tumor samples must be obtained after the date of informed consent 
for tumor screening. 
 In the Dose Finding Part, perform an optional fresh tumor biopsy for subjects 
with HER3-positive tumor tissue that was assayed using an archived tumor tissue 
sample.  Tumor tissue from this fresh biopsy should be sent to the central 
laboratory for analysis of HER3 IHC; these results are not required for study 
entry. 
 In the Dose Expansion Part, perform a fresh tumor biopsy for subjects with 
HER3-positive tumor tissue that was assayed using an archived tumor tissue 
sample.  Tumor tissue from this fresh biopsy should be sent to the central 
laboratory for analysis of HER3 IHC; these results are not required for study 
eligibility. 


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Within 28 days prior to enrollment 
 Perform tumor assessment by CT or MRI scans of the brain, chest, abdomen, pelvis, 
and any other sites of disease. A bone scan will be required at screening 
(Section 17.4).  Send all CT or MRI scans to the central imaging CRO selected by the 
Sponsor for confirming the existence of at least 1 measurable lesion per RECIST 
version 1.1.  Confirmation of measurable disease by central imaging review is required 
for subject eligibility. 
Eligibility Screening 
Before enrollment 
 Have the subject sign the ICF before any study-related procedures or assessments are 
performed. 
 Record Subject Number. 
 Record demographics (eg, birth date, sex, race, ethnicity), primary breast cancer 
history (only for Dose Expansion TNBC subjects, include BRCA genomic testing 
results if subject has consented to release this information), significant medical 
history, and history of prior cancer treatment.  
 Confirm eligibility of the subject. 
 Assess for AEs. 
Within 28 days prior to enrollment 
 Ophthalmologic assessments. The assessments will include visual acuity testing, slit 
lamp examination, fundoscopy, and tonometry. 
 Perform either ECHO or MUGA (LVEF).  The same test should be used for the 
subject throughout the study. 
 Perform a complete physical examination and record weight. 
 Perform a 12-lead ECG in triplicate*. 
*: ECGs will be taken in close succession, a few minutes apart, after being in a 
supine/semi-recumbent position for 5 minutes. All ECG data collected will be sent to 
the central laboratory for ECG analysis. 
Within 7 days prior to enrollment 
 Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential.  For postmenopausal subjects (no childbearing potential, as indicated by an 
elapse of at least 12 months after the last menstruation) or female subjects who have 
no possibility of pregnancy due to sterilization surgery, etc., no pregnancy test will be 
required. Female subjects who have been amenorrheic for 12 months or longer for 
medical reasons other than sterilization surgery (eg, effect of medication) will be 
regarded as women of childbearing potential and required to undergo the pregnancy 
test. 
 Assess functional status using the ECOG PS Scale (Section 17.3). 


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 Obtain vital sign measurements (systolic and diastolic blood pressure and pulse rate 
and body temperature). 
 Obtain blood samples for safety laboratories and cardiac troponin T (cTnT) 
(alternatively cTnI) (Section 8.8). 
 Obtain blood sample for cTnI to be sent to central laboratory (Section 6.10.5). 
 [In the Dose Escalation and Dose Finding Parts] Obtain blood samples for human 
epidermal growth factor receptor 3 extracellular domain (HER3ECD) (Section 6.10.5). 
Before the first dose of study drug administration 
 Record height. 
When the subject is confirmed as ineligible during the screening period, Investigators will 
notify the subject and promptly terminate the study-related procedures. The following will be 
recorded in the eCRF; and a F/U visit should not be performed. 
 Informed Consent Date 
 Demographics (eg, birth date, sex, race, ethnicity) 
 Date and reason of screen failure 
6.2. 
Subject Management 
In consideration of subject safety, subjects will be hospitalized from Day 1 to Day 21 on Cycle 1 
of the Dose Escalation Part to allow for careful safety monitoring.  However, a temporary stay 
outside the hospital is permitted at the Investigator’s discretion. The Investigator should examine 
the subject carefully before granting permission and the study site should give subjects 
instructions for emergency contact. Subjects should be instructed to refrain from prolonged 
exposure to ultraviolet rays. Additional safety assessments should be conducted as needed at the 
Investigator’s discretion. 
6.3. 
Randomization 
6.3.1. 
Dose Escalation Part 
Not applicable. 
6.3.2. 
Dose Finding Part 
Eligible subjects will be randomized into open Dose Finding cohorts during the Dose Finding 
Part, if applicable. 
6.3.3. 
Dose Expansion Part 
Approximately 60 eligible subjects with HER3-high metastatic breast cancer will be randomized 
into 1 of 2 cohorts:  4.8 mg/kg and 6.4 mg/kg. 
Eligible subjects with HER3-low metastatic breast cancer will not be randomized. 


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6.4. 
Treatment Period 
6.4.1. 
Administration of U3-1402 
See Sections 3.1.3, 3.1.4, 3.1.5, and 5.2.4. 
6.4.2. 
Tumor Assessment 
Tumor assessments of the chest, abdomen, pelvis, and other areas where scans were performed at 
screening or where new disease is suspected should be performed every 6 weeks (± 7 days) in 
the first 24 weeks after Day 1 of Cycle 1 and every 12 weeks (± 7 days) thereafter. Tumor 
assessments should not be delayed by dose interruptions; they are timed relative to Cycle 1, 
Day 1 and should continue until PD or until a new anticancer therapy is started, whichever 
occurs first. 
CT or MRI scans of the chest, abdomen, and pelvis are mandatory. The same methodology (CT 
or MRI) and scan acquisition techniques (including use or nonuse of IV contrast) that 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 be performed per 
RECIST version 1.1 (Section 17.4). 
A brain scan (CT of the brain with contrast or MRI of the brain pre- and post-gadolinium) should 
be performed at screening.  During the treatment period, CT or MRI of the brain should be 
performed in subjects with baseline brain metastases or where clinically indicated, and within a 
target of 1 week (+ 1 week) after a subject achieves CR. 
A bone scan should be performed at screening.  In subjects whose body CT/MRI scans indicate 
that CR has been achieved, a bone scan (within a target of 1 week [+ 1 week]) will be required at 
confirmation of CR to exclude new bone metastases. 
All images including CT and MRI must be submitted to the central imaging CRO selected by the 
Sponsor for independent tumor assessment. 
6.4.3. 
ECG Measurement 
Triplicate ECGs should be taken in close succession, a few minutes apart, after the subject has 
been in a supine/semi-recumbent position for 5 minutes.  All ECG data that are collected will be 
sent to the central laboratory for ECG analysis. 




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6.4.4. 
Cycle 1, Day 1 (All Parts) 
Pre-infusion 
The following procedures must be completed pre-infusion. If assessments at screening are 
performed within this period, they can be considered to be Day 1 data and there is no need to 
repeat them. 
 Assess for AEs. 
Within 3 days prior to infusion 
 Perform a complete physical examination and record weight. 
 Assess functional status using the ECOG PS Scale (Section 17.3). 
 Obtain vital sign measurements (systolic and diastolic blood pressures, pulse rate, 
body temperature, and oxygen saturation of peripheral artery [SpO2]). 
 Obtain blood samples for safety laboratories (Section 8.8). 
Within 8 hours prior to infusion 
 Perform a 12-lead ECG in triplicate as indicated in Table 6.1. 
 Obtain PK blood sample as indicated (Section 6.10.3). 
 Obtain blood sample for ADA (Section 6.10.6). 
 [Dose Expansion Part Only] Obtain blood samples for HER3ECD, cell-free DNA 
(cfDNA), and cell-free RNA (cfRNA) (Section 6.10.5). 
Administration 
 Administer U3-1402 via IV infusion and record start and stop times. 
 Refer to Pharmacy Instruction for preparation information of U3-1402. 
 Refer to Section 5.2.4 for information regarding administration of U3-1402. 
 Refer to Table 5.2 for information regarding infusion reactions. 
Post-infusion 
The following procedures will be completed post-infusion: 
 Obtain vital sign measurements (systolic and diastolic blood pressures, pulse rate, and 
body temperature). 
 Perform a 12-lead ECG in triplicate, if applicable, as indicated in Table 6.1. 
 Obtain PK blood samples as indicated in Section 6.10.3. 
 Obtain a blood sample for cTnT (alternatively cTnI) 3 hours (± 1 hour) after the end 
of infusion of U3-1402 for on-site safety and repeat as needed (see Table 5.2).  The 
test used to detect troponin should remain the same for the subject throughout the 
study. 


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 Obtain a blood sample 3 hours (± 1 hour) after the end of infusion of U3-1402 for 
cTnI testing by central laboratory. Repeat testing if indicated as described in 
Table 5.2. 
 Record concomitant medications. 
 Assess for AEs. 
6.4.5. 
Cycle 1, Day 2 (Dose Escalation, Dose Finding [Q3W Dosing Cohorts], and Dose 
Expansion Parts) 
The following procedures will be performed on Cycle 1, Day 2 during the Dose Escalation, Dose 
Finding (Q3W Dosing Cohorts), and Dose Expansion Parts: 
 Obtain vital sign measurements (systolic and diastolic blood pressures, pulse rate, and 
body temperature). 
 Perform a 12-lead ECG in triplicate, if applicable, as indicated in Table 6.1. 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 [Dose Escalation Part Only] Obtain blood samples for safety laboratories 
(Section 8.8). 
 Record concomitant medications. 
 Assess for AEs. 
6.4.6. 
Cycle 1, Day 4 (Dose Escalation, Dose Finding [Q3W Dosing Cohorts and Q2W 
Dosing Cohorts], and Dose Expansion Parts) 
The following procedures will be performed on Cycle 1, Day 4 (± 1 day) during the Dose 
Escalation, Dose Finding (Q3W Dosing Cohorts and Q2W Dosing Cohorts), and Dose 
Expansion Parts: 
 Obtain vital sign measurements (systolic and diastolic blood pressures, pulse rate, and 
body temperature). 
 Perform a 12-lead ECG in triplicate, if applicable, as indicated in Table 6.1. 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
  Record concomitant medications. 
 Assess for AEs. 
6.4.7. 
Cycle 1, Day 8 (All Parts) 
The following procedures will be performed on Cycle 1, Day 8: 
 Obtain vital sign measurements (systolic and diastolic blood pressures, pulse rate, and 
body temperature). 
 Perform a 12-lead ECG in triplicate, if applicable, as indicated in Table 6.1. 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 


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 Obtain blood samples for safety laboratories (Section 8.8). 
 Obtain blood sample for ADA (Section 6.10.6). 
 Record concomitant medications. 
 Assess for AEs. 
6.4.8. 
Cycle 1, Day 15 (All Parts) 
The following procedures will be performed on Cycle 1, Day 15: 
Cycle 1, Day 15 (± 1 day) for Dose Escalation, Dose Finding (Q3W Dosing Cohorts and 
Q3W Dosing with Up-titration Cohorts), and Dose Expansion Parts 
 Obtain vital sign measurements (systolic and diastolic blood pressures, pulse rate, and 
body temperature). 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Record concomitant medications. 
 Assess for AEs. 
Cycle 1, Day 15 (+ 2 days; if applicable) for Dose Finding Part (Q2W Dosing Cohorts) 
 If the dose of U3-1402 is delayed for ≥3 days, including if the subject cannot continue 
onto the next cycle, the following procedures should be performed on Day 15 
(+ 2 days): 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Assess for AEs. 
 Record concomitant medications. 
6.4.9. 
Cycle 1, Day 22 (if Applicable; for Dose Escalation, Dose Finding [Q3W Dosing 
Cohorts and Q3W Dosing with Up-titration Cohorts], and Dose Expansion 
Parts) 
 If the dose of U3-1402 is delayed for ≥3 days, including if the subject cannot continue 
onto the next cycle, the following procedures will be performed on Day 22 (+ 2 days). 
 Perform a 12-lead ECG in triplicate, if applicable, as indicated in Table 6.1. 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Record concomitant medications. 
 Assess for AEs. 


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6.4.10. 
Cycle 2, Day 1 (All Parts) 
The following procedures must be completed pre-infusion: 
Pre-infusion 
 Record concomitant medications. 
 Assess for AEs. 
Within 7 days prior to infusion 
 Ophthalmologic assessments. The assessments will include visual acuity testing, slit 
lamp examination, fundoscopy and tonometry.  Investigators must ensure results of 
ophthalmologic assessments are available for review prior to dosing on corresponding 
cycle visits.  Repeat ophthalmologic assessments are not required in the event of dose 
delays that occur after examination if there were no abnormal findings. 
Ophthalmologic assessments may be repeated per Investigator discretion. 
Within 3 days prior to infusion 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and pulse rate, 
body temperature and SpO2). 
 Assess functional status using the ECOG PS Scale (Section 17.3). 
 Perform either ECHO or MUGA (LVEF). Investigators must ensure results of 
ECHO/MUGA are available for review prior to dosing on corresponding cycle visits. 
Repeat ECHO/MUGA assessments are not required in the event of dose delays that 
occur after examination if there are no abnormal findings. ECHO or MUGA may be 
repeated per Investigator discretion. 
 Obtain blood samples for safety laboratories (Section 8.8). 
Within 8 hours prior to infusion 
 Perform a 12-lead ECG in triplicate as indicated in Table 6.1. 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Obtain a blood sample for ADA (Section 6.10.6). 
Administration 
 Administer U3-1402 via IV infusion and record start and stop times. 
 Refer to Pharmacy Instruction for preparation information of U3-1402. 
 Refer to Section 5.2.4 for information regarding administration of U3-1402. 
 Refer to Table 5.2 for information regarding infusion reactions. 


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Post-infusion 
The following procedures will be completed at post-infusion on Cycle 2, Day 1: 
 Obtain vital sign measurements (systolic and diastolic blood pressure and pulse rate 
and body temperature). 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Obtain a blood sample for cTnT (alternatively cTnI) 3 hours (± 1 hour) after the end 
of infusion of U3-1402 for on-site safety and repeated as needed (see Table 5.2). The 
test used to detect troponin should remain the same for the subject throughout the 
study. 
 Obtain a blood sample 3 hours (± 1 hour) after the end of infusion of U3-1402 for 
cTnI testing by central laboratory. Repeat testing if indicated as described in 
Table 5.2. 
 Record concomitant medications. 
 Assess for AEs. 
6.4.11. 
Cycle 2, Day 3 (Dose Expansion Part Only) 
[Optional] An optional on-study tumor biopsy may be performed approximately 48 to 72 hours 
after the end of infusion of U3-1402 on Cycle 2, Day 1 (Section 7.3).  Additionally, a blood 
sample for HER3ECD, cfDNA, cfRNA, and PK should be collected ± 4 hours from the time of 
this optional tumor biopsy, if obtained. Consent for this biopsy should be documented in the 
tissue consent portion of the ICF.  Tumor tissue from this biopsy may be obtained from primary 
tumor or a metastatic site. 
6.4.12. 
Cycle 2, Day 8 (All Parts) 
The following procedures will be performed Cycle 2, Day 8: 
 Obtain vital sign measurements (systolic and diastolic blood pressure and pulse rate 
and body temperature). 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Record concomitant medications. 
 Assess for AEs. 
6.4.13. 
Cycle 2, Day 15 (± 2 days; Dose Escalation, Dose Finding [Q3W Dosing Cohorts, 
Q3W Dosing with Up-Titration Cohorts], and Dose Expansion Parts) 
The following procedures will be performed Cycle 2, Day 15: 
 Obtain vital sign measurements (systolic and diastolic blood pressure and pulse rate 
and body temperature). 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 


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 Obtain blood samples for safety laboratories (Section 8.8). 
 Record concomitant medications. 
 Assess for AEs. 
6.4.14. 
Cycle 2, Day 22 (if Applicable; for Dose Escalation and Dose Finding [Q3W 
Dosing with Up-titration] Parts ) 
If the dose of U3-1402 is delayed for ≥3 days, including if the subject cannot continue onto the 
next cycle, the following procedures will be performed on Cycle 2, Day 22 (± 2 days): 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Record concomitant medications. 
 Assess for AEs. 
6.4.15. 
Cycle 3, Day 1 (All Parts) 
Pre-infusion 
The following procedures must be completed at pre-infusion: 
 Record concomitant medications. 
 Assess for AEs. 
Within 3 days prior to infusion 
 Perform a complete physical examination and record weight. 
 Assess functional status using the ECOG PS Scale (Section 17.3). 
 Obtain vital sign measurements (systolic and diastolic blood pressures, pulse rate, 
body temperature, and SpO2). 
 Perform either ECHO or MUGA (LVEF).  Investigator must ensure results of 
ECHO/MUGA are available for review prior to dosing on corresponding cycle visits.  
If there is a delay after an ECHO/MUGA assessment with no clinically significant 
findings, then repeat assessments are not required but may be repeated per Investigator 
discretion. 
 Obtain blood samples for safety laboratories (Section 8.8). 
Within 8 hours prior to infusion 
 Perform a 12-lead ECG in triplicate as indicated in Table 6.1. 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
Administration 
 Administer U3-1402 via IV infusion and record start and stop times. 
 Refer to Pharmacy Instruction for preparation information of U3-1402. 
 Refer to Section 5.2.4 for information regarding administration of U3-1402. 


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 Refer to Table 5.2 for information regarding infusion reactions. 
Post-infusion 
The following procedures will be completed at post-dose on Cycle 3, Day 1: 
 Obtain vital sign measurements (systolic and diastolic blood pressure and pulse rate 
and body temperature). 
 Perform a 12-lead ECG in triplicate, if applicable, as indicated in Table 6.1. 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Obtain a blood sample for cTnT (alternatively cTnI) 3 hours (± 1 hour) after the end 
of infusion of U3-1402 for on-site safety and repeat as needed (see Table 5.2).  The 
test used to detect troponin should remain the same for the subject throughout the 
study. 
 Obtain a blood sample 3 hours (± 1 hour) after the end of infusion of U3-1402 for 
cTnI testing by central laboratory. Repeat testing if indicated as described in 
Table 5.2. 
 Record concomitant medications. 
 Assess for AEs. 
6.4.16. 
Cycle 3, Day 2 (Dose Escalation Part Only) 
The following procedures will be performed on Cycle 3, Day 2 of the Dose Escalation Part only: 
 Perform a 12-lead ECG in triplicate, if applicable, as indicated in Table 6.1. 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Record concomitant medications. 
 Assess for AEs. 
6.4.17. 
Cycle 3, Day 4 (Dose Escalation and Dose Finding [Q2W Dosing Cohort] Only) 
The following procedures will be performed on Cycle 3, Day 4 (± 1 day) of the Dose Escalation 
and Dose Finding (Q2W Dosing Cohort) Parts: 
 Perform a 12-lead ECG in triplicate, if applicable, as indicated in Table 6.1. 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Record concomitant medications. 
 Assess for AEs. 
6.4.18. 
Cycle 3, Day 8 (All Parts) 
The following procedures will be performed on Cycle 3, Day 8: 
 Obtain vital sign measurements (systolic and diastolic blood pressures, pulse rate, and 
body temperature). 


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 Perform a 12-lead ECG in triplicate, if applicable, as indicated in Table 6.1. 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Record concomitant medications. 
 Assess for AEs. 
6.4.19. 
Cycle 3, Day 15 (All Parts) 
The following procedures will be performed on Cycle 3, Day 15: 
Cycle 3, Day 15 (± 2 days) for Dose Escalation, Dose Finding (Q3W Dosing Cohorts and 
Q3W Dosing with Up-titration Cohorts), and Dose Expansion Parts 
 Obtain vital sign measurements (systolic and diastolic blood pressure and pulse rate 
and body temperature). 
 Perform a 12-lead ECG in triplicate, if applicable, as indicated in Table 6.1. 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Obtain blood samples for safety laboratories, if applicable, as indicated in Section 8.8. 
 Record concomitant medications. 
 Assess for AEs. 
Cycle 3, Day 15 (± 2 days; if Applicable) for Q2W Dosing Schedules 
 If the dose of U3-1402 is delayed for ≥3 days, including if the subject cannot continue 
onto the next cycle, the following procedures should be performed on Cycle 3, 
Day 15 (± 2 days): 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Assess for AEs. 
 Record concomitant medications. 
6.4.20. 
Cycle 3, Day 22 (if Applicable; for Dose Escalation, Dose Finding [Q3W Dosing 
and Q3W Dosing with Up-titration], and Dose Expansion Parts) 
If the dose of U3-1402 is delayed for ≥3 days, including if the subject cannot continue onto the 
next cycle, the following procedures will be performed on Cycle 3, Day 22 (± 2 days): 
 Perform a 12-lead ECG in triplicate, if applicable, as indicated in Table 6.1. 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Record concomitant medications. 
 Assess for AEs. 


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6.4.21. 
Cycle 4 and Subsequent Cycles, Day 1 (All Parts) 
Pre-infusion 
The following procedures must be completed pre-infusion: 
 Record concomitant medications. 
 Assess for AEs. 
 Perform a 12-lead ECG in triplicate as indicated in Table 6.1. 
Within 7 days prior to infusion 
 Day 1 of Cycle 5 and every 4 cycles thereafter to EOT (eg, Day 1 of Cycle 5, 9, 13...) 
 Ophthalmologic assessments.  The assessments will include visual acuity testing, slit 
lamp examination, fundoscopy and tonometry.  Investigators must ensure results of 
ophthalmologic assessments are available for review prior to dosing on corresponding 
cycle visits.  Repeat ophthalmologic assessments are not required in the event of dose 
delays that occur after examination if there were no abnormal findings.  
Ophthalmologic assessments may be repeated per Investigator discretion. 
Within 3 days prior to infusion 
 Perform a complete physical examination and record weight. 
 Assess functional status using the ECOG PS Scale (Section 17.3). 
 Obtain vital sign measurements (systolic and diastolic blood pressures, pulse rate, 
body temperature, and SpO2). 
 Perform either ECHO or MUGA (LVEF). Investigators must ensure results of 
ECHO/MUGA are available for review prior to dosing on corresponding cycle visits. 
Repeat ECHO/MUGA assessments are not required in the event of dose delays that 
occur after examination if there were no abnormal findings.  ECHO or MUGA may be 
repeated per Investigator discretion. 
 Obtain blood samples for safety laboratories (Section 8.8). 
Within 8 hours prior to infusion 
 Cycle 4, Day 1; Cycle 5, Day 1; Cycle 6, Day 1; and Cycle 8, Day 1 only 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Cycle 4, Day 1 and every 2 cycles thereafter to EOT (eg, Day 1 in Cycle 4, 6, 8, 10) 
 Obtain blood sample for ADA (Section 6.10.6). 
COVID-19 Sample 
 Cycle 5, Day 1 and every 4 cycles thereafter, and at EOT (Day 1 in Cycle 5, 9, etc.) 
 Obtain a serum sample for coronavirus disease 2019 (COVID-19) testing from 
each subject who provides consent (Appendix 17.9). 


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Administration 
 Administer U3-1402 via IV infusion and record start and stop times. 
 Refer to Pharmacy Instruction for preparation information of U3-1402. 
 Refer to Section 5.2.4 for information regarding administration of U3-1402. 
 Refer to Table 5.2 for information regarding infusion reactions. 
Post-Infusion 
The following procedures will be completed at post-dose on Day 1: 
 Obtain vital sign measurements (systolic and diastolic blood pressures, pulse rate, and 
body temperature; only in Cycle 4, Day 1 of Q2W Dosing Cohorts). 
 Cycle 4, Day 1; Cycle 5, Day 1; and Cycle 6, Day 1 only 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Obtain a blood sample for cTnT (alternatively cTnI) 3 hours (± 1 hour) after the end 
of infusion of U3-1402 for on-site safety and repeat as needed (see Table 5.2).  The 
test used to detect troponin should remain the same for the subject throughout the 
study. 
 Obtain a blood sample 3 hours (± 1 hour) after the end of infusion of U3-1402 for 
cTnI testing by central laboratory. Repeat testing if indicated as described in 
Table 5.2. 
 Record concomitant medications. 
 Assess for AEs. 
6.4.22. 
Cycle 4, Day 8 (± 2 days) for Dose Finding (Q2W Dosing Cohort) Part 
The following procedures will be performed on Cycle 4, Day 8 (± 2 days): 
 Obtain vital sign measurements (systolic and diastolic blood pressures, pulse rate, and 
body temperature). 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Record concomitant medications. 
 Assess for AEs. 
6.4.23. 
Cycle 4, Day 15 (± 2 days) for Dose Finding (Q2W Dosing Cohort) Part 
The following procedures will be performed on Cycle 4, Day 15 (± 2 days): 
 Obtain vital sign measurements (systolic and diastolic blood pressure and pulse rate 
and body temperature). 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 


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 Obtain blood samples for safety laboratories, if applicable, as indicated in Section 8.8. 
 Record concomitant medications. 
 Assess for AEs. 
6.4.24. 
Cycle 4, Day 22 (± 2 days) for Dose Finding (Q2W Dosing Cohort) Part 
If the dose of U3-1402 is delayed for ≥3 days, including if the subject cannot continue onto the 
next cycle, the following procedures will be performed on Cycle 4, Day 22 (± 2 days): 
 Obtain PK blood samples, if applicable, as indicated in Section 6.10.3. 
 Record concomitant medications. 
 Assess for AEs. 
6.5. 
Washout 
Not applicable. 
6.6. 
Check-out or Early Termination 
See Section 5.7. 
6.7. 
End of Treatment 
The date of discontinuation of treatment is defined as the date of decision by Investigator.  The 
following assessments will be performed at the EOT Visit (within 7 days after the date of 
discontinuation).  If the EOT assessment is performed in the treatment period, then it may be 
considered as EOT data and need not be repeated. 
 Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential.  For postmenopausal subjects (no childbearing potential, as indicated by an 
elapse of at least 12 months after the last menstruation) or female subjects who have 
no possibility of pregnancy due to sterilization surgery, etc., no pregnancy test will be 
required.  Female subjects who have been amenorrheic for 12 months or longer for 
medical reasons other than sterilization surgery (eg, effect of medication) will be 
regarded as women of childbearing potential and required to undergo the pregnancy 
test. 
 Perform a complete physical examination and record weight. 
 Assess functional status using the ECOG PS Scale (Section 17.3). 
 Obtain vital sign measurements (systolic and diastolic blood pressures, pulse rate, 
body temperature, and SpO2). 
 Perform a 12-lead ECG in triplicate. 
 Ophthalmologic assessments. The assessments will include visual acuity testing, slit 
lamp examination fundoscopy and tonometry. 
 Perform either ECHO or MUGA (LVEF). 


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 Obtain blood samples for ADA (Section 6.10.6). 
 Obtain blood samples for safety laboratories and cTnT (alternatively cTnI) 
(Section 8.8). 
 Obtain blood sample for cTnI to be sent to central laboratory (Section 6.10.5). 
 Obtain a serum sample for COVID 19 testing from each subject who provides consent 
(Appendix 17.9). 
 [Dose Expansion Part Only] Obtain blood samples for HER3ECD, cfDNA, and 
cfRNA (Section 6.10.5). 
 [Dose Expansion Part Only] Optional tumor biopsy should be obtained from primary 
tumor or a metastatic site, preferably from a site of recent radiographic progression, 
within 30 days of the date of discontinuation and prior to starting any new anticancer 
treatment. 
 Perform same imaging tumor assessment as at the time of screening by CT or MRI 
scans. If the previous tumor assessment was performed within the last 21 days, this 
assessment does not need to be performed. CT or MRI scans of the chest, abdomen 
and pelvis are mandatory.  CT or MRI of the brain should be performed in subjects 
with baseline brain metastases or if clinically indicated. 
 Record concomitant medications. 
 Assess for AEs. 
 Record reason for treatment discontinuation. 
6.8. 
Follow-up 
The F/U visit should occur 28 days (– 7 days) after the last administration of U3-1402.  If the 
subject begins another anticancer therapy before the end of the 28 days (– 7 days), every effort 
will be made to complete all the F/U assessments prior to commencing the new therapy.  In case 
of unresolved AEs, the Investigator will follow the AEs until the event has resolved or the 
condition has stabilized as possible. If assessments at EOT or in the treatment period are 
performed within this period, they can be considered as the F/U data and there is no need to 
repeat them. If discontinuation of treatment is decided later than 28 days after the last 
administration of U3-1402, there is no need to perform the F/U visit. 
The following information will be collected at this F/U visit: 
 Perform a complete physical examination and record weight. 
 Assess functional status using the ECOG PS Scale (Section 17.3). 
 Obtain vital sign measurements (systolic and diastolic blood pressure and pulse rate 
and body temperature). 
 Obtain blood samples for safety laboratories (Section 8.8) and ADA* (Section 6.10.6). 
*For subjects with positive ADA at F/U visit (or EOT visit if F/U visit was not 
performed), additional serum ADA samples may be collected every 3 months 
(± 1 month) up to 1 year from the last dose of study drug, or if the ADA becomes 
negative, or if ADA titer becomes less than baseline (applicable when pre-existing 


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ADA is observed), or if the subject starts another therapy for cancer, or withdraws 
consent from the study, whichever occurs first. 
 Record concomitant medications. 
 Assess for AEs. 
6.9. 
New Cancer Treatment and Survival Follow-up 
After discontinuation from all study treatment, follow-up information for survival and 
subsequent anticancer therapy, if available, will be obtained approximately every 3 months from 
the date of F/U visit or Safety Follow-up, whichever is later, until death, withdrawal of consent, 
loss to follow-up, or study closure, whichever occurs first.  If direct contacts are not possible due 
to withdrawal of consent or loss to follow-up, the site must make every effort to collect survival 
status from public records (eg, death certificates) in accordance with local laws.  
Subsequent anticancer treatment and survival follow-up information will not be collected after 
the implementation of protocol Version 8.0, which occurs upon the IRB approval of protocol 
Version 8.0 at study sites. 
6.10. 
Pharmacokinetics, Pharmacodynamics, Exploratory Biomarkers, 
and Anti-drug Antibodies 
6.10.1. 
Blood Sampling 
Blood samples for PK, exploratory biomarkers (eg, HER3ECD, cfDNA, cfRNA and cTnI), and 
ADA will be collected into blood sampling tubes supplied by the Sponsor.  The collected blood 
will be centrifuged to separate the serum/plasma.  The serum samples will be shipped to a central 
laboratory. 
Refer to the Laboratory Manual for information regarding the handling of blood samples and 
shipping of serum samples. 
6.10.2. 
Tumor Sampling 
In the Dose Expansion part, for those subjects with HER3-positive tissue assayed using an 
archived tumor tissue sample, a fresh tumor biopsy should be collected before the first dose of 
U3-1402.  This fresh tumor biopsy is optional for the Dose Finding Part. 
It is recommended (although optional) to perform a tumor biopsy approximately 48 to 72 hours 
after the end of infusion of U3-1402 on Cycle 2, Day 1 in the Dose Expansion Part.  
Additionally, blood samples for HER3ECD, cfDNA, cfRNA, and PK assessments should be 
collected ± 4 hours from the time of this optional biopsy, if obtained.  A minimum of 20 subjects 
in the HER3-high, HR-positive cohorts, a minimum of 6 subjects in the HER3-low, HR-positive 
cohort and a minimum of 9 subjects in the HER3-high, TNBC cohort will be required to submit 
on-treatment biopsies during the Dose Expansion Part. 
An optional tumor biopsy may be performed at EOT in the Dose Expansion Part. 
Tissue from these biopsies will be examined for biomarkers, mutational status (DNA/RNA), and 
gene expression analysis (RNA) to elucidate mechanism of action and resistance to study drug. 


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Refer to the Laboratory Manual for information regarding archived and/or fresh tumor tissue 
requirements. 
Any SAEs directly related to a tumor biopsy procedure performed after signing the appropriate 
ICF should be reported according to Section 8.5. 
6.10.3. 
Pharmacokinetic 
Blood samples of approximately 5 mL for PK analyses will be collected at the time points as 
specified in Table 6.2, Table 6.3, Table 6.4, Table 6.5, and Table 6.6. 
The actual time of study drug administration and the exact time of blood sampling must be 
recorded in source document and the eCRF. 


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6.10.3.1. Dose Escalation Part Pharmacokinetic Sampling Time Points 
Table 6.2: 
Pharmacokinetic Sampling Time Points (Dose Escalation Part) 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
 
BI (– 8 hours)a 
 
EOI (within 30 minutes after EOI)a 
 
2 hours after the start of infusion (± 15 minutes)a 
 
4 hours after the start of infusion (± 15 minutes)a 
 
7 hours after the start of infusion (± 15 minutes)a 
Day 2 
 24 hours after the start of infusion (± 2 hours)a 
Day 4 
3 days after the start of infusion (± 1 day)a 
Day 8 
7 days after the start of infusion (± 1 day) 
Day 15 
14 days after the start of infusion (± 1 day) 
Day 22b 
21 days after the start of infusion (+ 2 days)a 
Cycle 2 
Day 1 
 
BI (– 8 hours)a,c 
 
EOI (within 30 minutes after EOI) 
Day 8 
7 days after the start of infusion (± 2 days) 
Day 15 
14 days after the start of infusion (± 2 days) 
Day 22b 
21 days after the start of infusion (± 2 days) 
Cycle 3 
Day 1 
 
BI (– 8 hours)a 
 
EOI (within 30 minutes after EOI)a 
 
2 hours after the start of infusion (± 15 minutes)a 
 
4 hours after the start of infusion (± 15 minutes)a 
 
7 hours after the start of infusion (± 15 minutes)a 
Day 2 
24 hours after the start of infusion (- 2 to + 4 hours, within 
15 minutes after the end of ECG measurement)a 
Day 4 
3 days after the start of infusion (± 1 day)a 
Day 8 
7 days after the start of infusion (± 2 days) 
Day 15 
14 days after the start of infusion (± 2 days) 
Day 22b 
21 days after the start of infusion (± 2 days)a 
Cycle 4 
Day 1 
BI (– 8 hours)a,c 
Cycle 6 and 
Cycle 8 
Day 1 
BI (– 8 hours) 
BI = before infusion; ECG = electrocardiogram; EOI = end of infusion; PK = pharmacokinetic. 
a Blood for PK should be collected within 15 minutes of the end of ECG measurement. 
b If dosing for the next cycle is delayed for ≥3 days, including if the subject cannot continue onto the next cycle. 
c If blood for PK was collected on Day 22 of the previous cycle, a PK blood sample should be collected BI 
(−8 hours), if possible. 


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6.10.3.2. Dose Finding Part Pharmacokinetic Sampling Time Points 
Table 6.3: 
Q3W Dosing Cohorts 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
 
BI (– 8 hours)a 
 
EOI (within 30 minutes after EOI)a 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes)a 
 
7 hours after the start of infusion (± 15 minutes) 
Day 2 
24 hours after the start of infusion (± 2 hours) 
Day 4 
3 days after the start of infusion (± 1 day) 
Day 8 
7 days after the start of infusion (± 1 day)a 
Day 15 
14 days after the start of infusion (± 1 day) 
Day 22b 
21 days after the start of infusion (+ 2 days) 
Cycle 2 
Day 1 
 
BI (– 8 hours)c 
 
EOI (within 30 minutes after EOI) 
Cycle 3 
Day 1 
 
BI (– 8 hours)a 
 
EOI (within 30 minutes after EOI)a 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes)a 
 
7 hours after the start of infusion (± 15 minutes) 
Day 8 
7 days after the start of infusion (± 2 days)a 
Day 15 
14 days after the start of infusion (± 2 days) 
Day 22b 
21 days after the start of infusion (± 2 days) 
Cycle 4 
Day 1 
BI (– 8 hours)c 
Cycle 5 
Day 1 
 
BI (– 8 hours) 
 
EOI (within 30 minutes of the EOI) 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes) 
 
7 hours after the start of infusion (± 15 minutes) 
Cycle 6 and 
Cycle 8 
Day 1 
BI (– 8 hours) 
BI = before infusion; ECG = electrocardiogram; EOI = end of infusion; PK = pharmacokinetic. 
a Blood for PK should be collected within 15 minutes of the end of ECG measurement. 
b If dosing for the next cycle is delayed for ≥3 days, including if the subject cannot continue onto the next cycle. 
c If blood for PK was collected on Day 22 of the previous cycle, a PK blood sample should be collected BI 
(−8 hours), if possible. 


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Table 6.4: 
Q3W Dosing with Up-titration Cohorts 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
 
BI (– 8 hours) 
 
EOI (within 30 minutes after EOI) 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes) 
 
7 hours after the start of infusion (± 15 minutes) 
Day 8 
7 days after the start of infusion (± 1 day) 
Day 15 
14 days after the start of infusion (± 1 day) 
Day 22a 
21 days after the start of infusion (+ 2 days) 
Cycle 2 
Day 1 
 
BI (– 8 hours)b 
 
EOI (within 30 minutes after EOI) 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes) 
 
7 hours after the start of infusion (± 15 minutes) 
Day 8 
7 days after the start of infusion (± 2 days) 
Day 15 
14 days after the start of infusion (± 2 days) 
Day 22a 
21 days after the start of infusion (± 2 days) 
Cycle 3 
Day 1 
 
BI (– 8 hours)b 
 
EOI (within 30 minutes after EOI) 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes) 
 
7 hours after the start of infusion (± 15 minutes) 
Day 8 
7 days after the start of infusion (± 2 days) 
Day 15 
14 days after the start of infusion (± 2 days) 
Day 22a 
21 days after the start of infusion (± 2 days) 
Cycle 4 
Day 1 
BI (– 8 hours)b 
Cycle 5 
Day 1 
 
BI (– 8 hours) 
 
EOI (within 30 minutes after EOI) 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes) 
 
7 hours after the start of infusion (± 15 minutes) 
Cycle 6 and 
Cycle 8 
Day 1 
BI (– 8 hours) 
BI = before infusion; EOI = end of infusion; PK = pharmacokinetic. 
a If dosing for the next cycle is delayed for ≥3 days, including if the subject cannot continue onto the next cycle. 
b If blood for PK was collected on Day 22 of the previous cycle, a PK blood sample should be collected BI 
(−8 hours), if possible. 


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Table 6.5: 
Q2W Dosing Cohorts 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
 
BI (– 8 hours) 
 
EOI (within 30 minutes after EOI) 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes) 
 
7 hours after the start of infusion (± 15 minutes) 
Day 4 
3 days after the start of infusion (± 1 day) 
Day 8 
7 days after the start of infusion (± 1 day) 
Day 15a 
14 days after the start of infusion (+ 2 day) 
Cycle 2 
Day 1 
 
BI (– 8 hours)b 
 
EOI (within 30 minutes after EOI) 
Cycle 3 
Day 1 
 
BI (– 8 hours) 
 
EOI (within 30 minutes after EOI) 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes) 
 
7 hours after the start of infusion (± 15 minutes) 
Day 4 
3 days after the start of infusion (± 1 day) 
Day 8 
7 days after the start of infusion (± 2 days) 
Day 15a 
14 days after the start of infusion (± 2 days) 
Cycle 4 
Day 1 
 
BI (– 8 hours)b 
 
EOI (within 30 minutes after EOI) 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes) 
 
7 hours after the start of infusion (± 15 minutes) 
Day 8 
7 days after the start of infusion (± 2 day) 
Day 15 
14 days after the start of infusion (± 2 days) 
Day 22a 
21 days after the start of infusion (± 2 days) 
Cycle 5 
Day 1 
BI (– 8 hours)c 
Cycle 6 
Day 1 
 
BI (– 8 hours) 
 
EOI (within 30 minutes after EOI) 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes) 
 
7 hours after the start of infusion (± 15 minutes) 
Cycle 8 
Day 1 
BI (– 8 hours) 
BI = before infusion; EOI = end of infusion; PK = pharmacokinetic. 
a If dosing for the next cycle is delayed for ≥3 days, including if the subject cannot continue onto the next cycle. 
b If blood for PK was collected on Day 15 of the previous cycle, a PK blood sample should be collected BI 
(−8 hours), if possible. 
c If blood for PK was collected on Day 22 of the previous cycle, a PK blood sample should be collected BI 
(−8 hours), if possible. 


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6.10.3.3. Dose Expansion Part Pharmacokinetic Sampling Time Points 
Table 6.6: 
Pharmacokinetic Sampling Time Points (Dose Expansion Part) 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
 
BI (– 8 hours)a 
 
EOI (within 30 minutes after EOI)a 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes)a 
 
7 hours after the start of infusion (± 15 minutes) 
Day 2 
24 hours after the start of infusion (± 2 hours) 
Day 4 
3 days after the start of infusion (± 1 day) 
Day 8 
7 days after the start of infusion (± 1 day)a 
Day 15 
14 days after the start of infusion (± 1 day) 
Day 22b 
21 days after the start of infusion (+ 2 days) 
Cycle 2 
Day 1 
 
BI (– 8 hours)c 
 
EOI (within 30 minutes after EOI) 
Day 3 
± 4 hours from the time of optional biopsy, if obtained 
Cycle 3 
Day 1 
 
BI (– 8 hours)a 
 
EOI (within 30 minutes after EOI)a 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes)a 
 
7 hours after the start of infusion (± 15 minutes) 
Day 8 
7 days after the start of infusion (± 2 days)a 
Day 15 
14 days after the start of infusion (± 2 days) 
Day 22b 
21 days after the start of infusion (± 2 days) 
Cycle 4 
Day 1 
BI (– 8 hours)c 
Cycle 5 
Day 1 
 
BI (– 8 hours) 
 
EOI (within 30 minutes after EOI) 
 
2 hours after the start of infusion (± 15 minutes) 
 
4 hours after the start of infusion (± 15 minutes) 
 
7 hours after the start of infusion (± 15 minutes) 
Cycle 6 and 
Cycle 8 
Day 1 
BI (– 8 hours) 
BI = before infusion; ECG = electrocardiogram; EOI = end of infusion; PK = pharmacokinetic. 
a Blood for PK should be collected within 15 minutes of the end of ECG measurement. 
b If dosing for the next cycle is delayed for ≥3 days, including if the subject cannot continue onto the next cycle. 
c If blood for PK was collected on Day 22 of the previous cycle, a PK blood sample should be collected BI 
(−8 hours), if possible. 
6.10.4. 
Pharmacodynamics 
Not applicable. 


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6.10.5. 
Exploratory Biomarkers 
Based on the evaluation of pre-treatment tumor sample, the levels of HER3 in fresh biopsies will 
be assessed by IHC.  The exploratory biomarkers (eg, HER3ECD, mRNA, cfDNA, cTnI, and 
PD-L1) will be assessed accordingly, at pre-treatment, on-treatment, and post-treatment time 
points.  Tissue biopsy samples will be used for analyses of IHC, and mRNA; and liquid biopsy 
will be used for analyses of proteins, mRNA, cfRNA, and cfDNA. 
The purpose of the HER3ECD assay is to determine its potential to be a predictive marker of 
drug efficacy or a surrogate for IHC. 
A variety of assays may be used to help us to understand U3-1402 mechanism of action 
(ie, tumor cell apoptosis, immune profiling), mechanism of resistance (ie, downregulation / 
mutation of HER3, loss of ADC internalization, attenuation of cathepsin levels/activity, 
upregulation of drug export, etc.) and correlation of biomarkers with clinical activity 
(ie, HER3ECD, mutational profiling of cfDNA, cfRNA, and mRNA). 
cTnI will be assessed as an exploratory biomarker for drug safety. 
Blood samples of approximately 4 mL for HER3ECD analyses will be collected at the time 
points specified in Table 6.7. 
Table 6.7: 
HER3ECD Sampling Time Points 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Screening (Dose Escalation and Dose 
Finding Parts Only) 
- 
Latest data within 7 days prior to enrollment 
Cycle 1 (Dose Expansion Part Only) 
Day 1  
BI (– 8 hours)  
Cycle 2 (Dose Expansion Part Only, if 
optional tumor biopsy is obtained) 
Day 3 
±4 hours from time of biopsy, if obtained 
EOT (Dose Expansion Part Only) 
- 
The date Investigator decides the discontinuation 
of the study treatment (+ 7 days) 
EOT = end of treatment; BI = before infusion. 
Refer to the Laboratory Manual for information regarding the handling and shipping of blood 
samples. 
Blood samples of approximately 10 mL for cfDNA analyses and 10 mL for cfRNA analyses will 
be collected at the time points specified in Table 6.8.  


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Table 6.8: 
cfDNA and cfRNA Sampling Time Points 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 (Dose Expansion Part Only) 
Day 1 
BI (– 8 hours) 
Cycle 2 (Dose Expansion Part Only, if 
optional tumor biopsy is obtained) 
Day 3 
± 4 hours from time of optional biopsy, if obtained 
EOT (Dose Expansion Part Only) 
- 
The date Investigator decides the discontinuation 
of the study treatment (+ 7 days) 
EOT = end of treatment; BI = before infusion. 
Refer to the Laboratory Manual for information regarding the handling and shipping of whole 
blood samples. 
Blood samples of approximately 4 mL for cTnI analyses will be collected at the time points 
specified in Table 6.9. 
Table 6.9: 
cTnI Sampling Time Points 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Screening 
- 
Latest data within 7 days prior to enrollment 
At every cycle 
Day 1 
3 hours after EOI (± 1 hour) 
EOT 
- 
The date Investigator decides the discontinuation 
of the study treatment (+ 7 days) 
EOI = end of infusion; EOT = end of treatment. 
Refer to the Laboratory Manual for information regarding handling and shipping of serum 
samples. 
Exploratory biomarker (HER3ECD, cfDNA, cfRNA) samples will not be collected after the 
implementation of protocol Version 8.0, which occurs upon the IRB approval of protocol 
Version 8.0 at study sites. 
6.10.6. 
Anti-Drug Antibodies 
Blood samples for ADA of approximately 4 mL analyses will be collected at the time points 
specified in Table 6.10.  Serum concentrations of U3-1402 and/or total anti-HER3 antibody may 
be measured using the same ADA samples for purpose of anti-drug antibody assessment. 
Refer to the Laboratory Manual for information regarding the handling and shipping of serum 
samples. 


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Table 6.10: 
ADA Sampling Time Points 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
Day 8 
BI (– 8 hours) 
7 days after infusion (± 1 day) 
Cycle 2 
Day 1 
BI (– 8 hours) 
After Cycle 4 at every 2 cycles 
(eg, Cycle 4, 6, 8, 10, 12...) 
Day 1 
BI (– 8 hours) 
EOT 
- 
The date Investigator decides the discontinuation 
of the study treatment (+ 7 days) 
F/U visita 
- 
28 days (− 7 days) after the last study drug 
administration or until starting new anticancer 
treatment, whichever comes first 
BI = before infusion; EOT = end of treatment; F/U = follow up. 
a For subjects with positive ADA at F/U visit, additional serum ADA samples may be collected every 3 months 
(± 1 month) up to 1 year from the last dose of study drug, or if the ADA becomes negative, or if ADA titer 
becomes less than baseline (applicable when pre-existing ADA is observed), or if the subject starts another therapy 
for cancer, or withdraws consent from the study, whichever occurs first. 


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7. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
7.1. 
Pharmacokinetic Assessment(s) 
The serum PK parameters listed in Table 7.1 of U3-1402, total anti-HER3 antibody and 
MAAA-1181a for each subject will be estimated using standard noncompartmental methods.  
The other PK parameters (elimination rate constant associated with the terminal phase [Kel], 
T1/2, CL, volume of distribution based on the terminal phase [Vz], and Vss) will be calculated if 
data permits.  Population PK and exposure-response analyses for U3-1402, total anti-HER3 
antibody and MAAA-1181a will be performed to characterize the relationships between dose and 
exposure and between exposure and efficacy and/or safety endpoints.  If performed, results of 
population PK or exposure-response analyses will be reported separately (ie, not in the Clinical 
Study Report). 
Table 7.1: 
Pharmacokinetic Parameters 
Analyte 
PK parameters 
U3-1402, total anti-HER3 
antibody and MAAA-1181a 
AUClast, AUCtau, Cmax, Tmax, Ctrough 
7.2. 
Pharmacodynamic Assessment(s) 
Not applicable. 
7.3. 
Biomarker and Exploratory Assessment(s) 
Subjects will be requested to provide a tumor sample for assessing HER3 expression at study 
entry and optionally at some additional time points during the course of clinical study.  
Clinical samples, including tumor tissue and blood, will be retained until the end of the defined 
storage period and may be analyzed for exploratory research purposes. The sample collection 
information should be recorded in the eCRF.  
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 supply tumor tissue (archival tissue or 
fresh tumor biopsy) and blood samples for research purposes prior to study entry. 
7.3.1. 
HER3 expression 
The level of HER3 expression will be assessed by IHC using archival or fresh biopsy provided 
by the patient. In the Dose Expansion Part, the level of HER3 expression in pre-study treatment, 
on-study treatment and post-study treatment will be assessed with the biopsy sample.  
7.3.1.1. 
Tumor Sample Collection 
Refer to the Laboratory Manual for instructions regarding archived and fresh tumor tissue 
handling and shipping. 


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Study Entry 
Tissue to analyze for HER3 expression for study eligibility may be obtained from fresh tumor 
biopsy or from archived tumor samples.  
 A fresh tumor biopsy may be requested from subjects with a HER3-negative tissue 
result that was assayed using an archived tumor tissue sample. Tumor tissue obtained 
from this fresh biopsy should be sent to the central laboratory for the re-assay of the 
HER3 status. Tumor samples must be obtained after the date of informed consent for 
tumor screening. 
Pre-treatment Biopsy 
 For the Dose Finding Part, perform an optional tumor biopsy for subjects with 
HER3-positive tissue that was assayed using an archived tumor tissue sample.  Tumor 
tissue from the fresh biopsy should be sent to the central laboratory for analysis of 
HER3 IHC; these results are not required for study entry. 
 For the Dose Expansion Part, perform a tumor biopsy for subjects with 
HER3-positive tumor tissue that was assayed using an archived tumor tissue sample.  
Tumor tissue from this fresh biopsy should be sent to the central laboratory for 
analysis of HER3 IHC; these results are not required for study entry. 
On-study Biopsy (Dose Expansion Part Only) 
An optional on-study tumor biopsy may be performed approximately 48 to 72 hours after the 
end of the U3-1402 infusion on Cycle 2, Day 1. Additionally, blood for HER3ECD, cfDNA, 
cfRNA, and PK should be collected ± 4 hours from the time of this optional biopsy, if obtained.  
A minimum of 20 subjects in the HER3-high, HR-positive cohorts, a minimum of 6 subjects in 
the HER3-low, HR-positive cohort, and a minimum of 9 subjects in the HER3-high, TNBC 
cohort will be required to submit on-treatment biopsies during the Dose Expansion Part. Consent 
for this biopsy should be documented in the tissue consent portion of the ICF. Tumor tissue from 
this biopsy should be obtained from the primary tumor or metastatic site. 
End-of-treatment Biopsy (Dose Expansion Part Only) 
An optional end-of-treatment tumor biopsy may be performed at the time of progression or 
discontinuation from study treatment.  Consent for this biopsy should be documented in the 
tissue consent portion of the appropriate ICF.  Tumor biopsy should be obtained from the 
primary tumor or a metastatic site, preferably from a site of recent radiographic progression, 
within 30 days of the date of discontinuation, and prior to starting any new anticancer treatment. 
Any SAEs directly related to a tumor biopsy procedure and performed after signing the 
appropriate ICF should be reported according to Section 8.5. 
7.3.2. 
Biomarker Assessments in Tumor Tissue and Blood Samples  
The biomarkers will be analyzed with the intent of identifying those subjects who will most 
likely derive clinical benefit from treatment with U3-1402.  Further exploratory tissue or 
blood-based biomarkers may be analyzed based on emerging scientific knowledge to better 
understand the target disease and also possibly the effects of study treatment. 


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Exploratory analysis will be done to assess the status of some biomarkers (eg, HER3ECD, 
mRNA, cfDNA, cfRNA, PD-L1 and cTnI). 
During the study, in addition to the biomarkers specified above, other exploratory biomarker 
research may be conducted on tissue and/or blood samples. These studies would extend the 
search for other potential biomarkers relevant to the effects of U3-1402, cancer, and/or resistance 
to the treatment. This may include the development of ways to detect, monitor or treat cancer. 
These additional investigations would be dependent upon clinical outcome, reagent and sample 
availability. 
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. 
7.4. 
Immunogenicity 
Blood samples will be obtained at the time points specified in Section 17.1.  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 anti-drug antibodies 
(ADA) assay which is comprised of tiered steps including screening, confirmatory as well as titer 
determination.  ADA samples confirmed positive will be banked until availability of a 
neutralizing anti-drug antibody assay. 
Immunogenicity will be assessed through characterization of incidence and titer of ADA.  The 
number and percentage of subjects will be calculated for the presence or absence of development 
of ADA after the start of administration, defining subjects who are negative for ADA at all time 
points as negative and subjects who are positive for ADA at least 1 time point as positive.  The 
raw values and change from baseline for ADA titers will be summarized by time point and 
treatment group using descriptive statistics. 
7.5. 
Pharmacogenomic Analysis 
7.5.1. 
Genomic or Genetic Banking and Analysis 
7.5.1.1. 
Genomic or Genetic Banking and Analysis 
In the Dose Expansion Part, a single blood sample (20 mL) for cfDNA (10 mL) and 
cfRNA (10 mL) analysis will be collected pretreatment on Cycle 1, Day 1; on treatment Cycle 2, 
Day 3; and at EOT 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. 


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7.5.1.2. 
Collection of Specimens for Genomic or Genetic Banking and Analysis 
Instructions for collection of specimens for genomic or genetic banking and analysis are included 
in the Laboratory Manual. 
7.5.1.3. 
Disclosure of the Results of Genomic or Genetic Analysis 
Because the nature and value of future pharmacogenomic research cannot be known at this time, 
any results obtained from research involving pharmacogenomic samples will not be disclosed to 
the subject or Investigators now or in the future. 
7.5.1.4. 
Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis 
Samples will be retained until exhausted, or 15 years if required by local regulations, or until the 
Sponsor requests disposition.  
If the subject withdraws consent, the banked tumor and blood samples will be promptly managed 
regarding proper disposition.  However, the data will not be discarded if genetic analysis has 
been completed before the subject withdraws consent. 


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8. 
SAFETY EVALUATION AND REPORTING 
8.1. 
Assessment of Safety Endpoint Event(s) 
Safety endpoints will include DLTs, SAEs, TEAEs, AESIs, physical examination findings 
(including ECOG PS), vital sign measurements, standard clinical laboratory parameters, ECG 
parameters, ECHO/MUGA findings, and ophthalmologic assessments. Dose escalation will be 
determined by the incidence of DLTs. 
8.2. 
Adverse Event Collection and Reporting 
All clinical AEs occurring after the subject signs the ICF and up to F/U visit 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 Adverse Event Case Report Form (CRF) page.  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 8.5. 
All clinical laboratory results, vital signs, and ECG results or findings should be appraised 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 Investigator’s 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 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 8.4.  The Investigator’s assessment must be clearly documented in the study site’s source 
documentation with the Investigator’s signature. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization).  A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to signing the ICF) 
procedures or treatments requiring hospitalization for pre-existing conditions that do not worsen 
in severity should not be reported as SAEs (see Section 8.4.2 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 


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subsequent to the reporting period that the Investigator assesses as related to study drug should 
also be reported and managed as an SAE. The Investigator should follow subjects with AEs until 
the event has resolved or the condition has stabilized.  In case of unresolved AEs, including 
significant abnormal clinical laboratory values at the end of study assessment, these events will 
be followed until resolution or until they become clinically not relevant. 
8.3. 
Adverse Events of Special Interest 
Based on the available preclinical data, review of the cumulative literature, and reported AEs for 
agents of the same class of ADC components of monoclonal antibody or payload of U3-1402; 
the events described below are considered to be AESIs.  AESIs will be collected through targeted 
questionnaires within the eCRF or via paper form (in the event an eCRF is unavailable).  Please 
refer to the IB for additional information. 
8.3.1. 
Cardiotoxicity (Cardiac-related Events Including QT Prolongation and LVEF 
Decreased) 
LVEF will be measured by either ECHO or MUGA scan.  All ECHOs/MUGAs must be 
evaluated by the Investigator or a delegated physician for monitoring cardiac function.  The same 
modality (ECHO or MUGA) should be used for the subject throughout the study.  In addition, 
standard ECG parameters will be measured, including RR, PR, and QT intervals, and QRS 
duration.  All ECGs must be evaluated by Investigator or a delegated physician for the presence 
of abnormalities.  In this study, cTnI testing will be used as an exploratory biomarker in parallel 
with standard clinical assessments of cardiac function (eg, ECHO/MUGA and ECG). 
8.3.2. 
Pulmonary Toxicity (Interstitial Lung Disease/Pneumonitis) 
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/pneumonitis.  If ILD/pneumonitis 
is suspected, delay U3-1402 dosing pending further evaluation.  Refer to Table 5.2 for guidance 
on further evaluation and management of ILD/pneumonitis.  
8.3.2.1. 
Interstitial Lung Disease Adjudication Committee 
An independent ILD Adjudication Committee for U3-1402 is responsible for reviewing all cases 
of potential ILD/pneumonitis. 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 triggered for adverse events reported using MedDRA 
preferred terms (PT) from the current ILD Standard MedDRA Query (SMQ) and the PTs of 
acute respiratory failure and respiratory failure. 
8.3.3. 
Hepatotoxicity (Potential Hy’s Law) 
All hepatic events (both serious and non-serious, and clinical laboratory results) which meet the 
potential Hy’s Law criteria defined as an elevated (ALT or AST) ≥3 × ULN and an elevated total 
bilirubin >2 × ULN that may occur simultaneously or at different time points during the study, 
regardless of whether these hepatic events are symptomatic, lead to study drug discontinuation, 
dose reduction or dose interruption, require corrective treatment, constitute an AE in the 
Investigator’s clinical judgment and/or are related to disease progression. 


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8.4. 
Adverse Event 
8.4.1. 
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 clinical 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 
Harmonization (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 clinical laboratory findings which should be considered AEs. 
8.4.2. 
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. 
Note:  The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe (ICH E2A Guideline.  Clinical 
Safety Data Management:  Definitions and Standards for Expedited Reporting, Oct 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above.  Examples 
include allergic bronchospasm, convulsions, and blood dyscrasias or development of drug 
dependency or drug abuse. 
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. 
8.4.3. 
Severity Assessment 
All AEs will be graded (1 to 5; see below) according to the NCI-CTCAE version 5.0: 


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 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 patient/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. 
8.4.4. 
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 
available. 
 Related: 
 The AE follows a reasonable temporal sequence from study drug administration 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
or 
 The AE follows a reasonable temporal sequence from study drug administration 
and is a known reaction to the drug under study or its chemical group or is 
predicted by known pharmacology. 
 Unrelated: 
 The AE does not follow a reasonable sequence from study drug administration or 
can be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
8.4.5. 
Action Taken Regarding Study Drug(s) 
 Dose Not Changed:  No change in study drug dosage was made. 
 Drug Withdrawn:  The study product was permanently stopped. 
 Dose Reduced:  The dosage of study product was reduced. 
 Drug Interrupted:  The study product was temporarily stopped. 
 Not Applicable 


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8.4.6. 
Other Action Taken for Event 
 None. 
 No treatment was required. 
 Medication required. 
 Prescription and/or OTC medication was required to treat the AE. 
 Hospitalization or prolongation of hospitalization required. 
 Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
 Other. 
8.4.7. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the AE with no residual effect observed. 
 Recovering/Resolving 
 The AE improved but has not fully resolved. 
 Recovered/Resolved with Sequelae 
 The residual effects of the AE are still present and observable. 
 Include sequelae/residual effects. 
 Not Recovered/Not Resolved 
 The AE itself is still present and observable. 
 Fatal 
 Fatal should be used when death is a direct outcome of the adverse event. 
 Unknown 
8.5. 
Serious Adverse Events Reporting – Procedure for Investigators 
All AEs, AESIs, events of overdose, and SAEs will be reported in the CRF. 
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 designated 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 8.4.2 for definition) 


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 All potential ILD/pneumonitis cases should be reported within 24 hours; including 
both serious and non-serious potential ILD/pneumonitis cases (potential 
ILD/pneumonitis is defined by the Event Adjudication Site Manual List of Preferred 
Terms [PTs]). 
 All hepatic events (both serious and non-serious, and clinical laboratory results) which 
meet the potential Hy’s Law criteria defined as an elevated ALT or AST ≥3 × ULN 
and an elevated total bilirubin 2 × ULN that may occur simultaneously or at different 
time points during the study, regardless of whether these hepatic events are 
symptomatic, lead to study drug discontinuation, dose reduction or dose interruption, 
require corrective treatment, constitute an AE in the Investigator’s clinical judgment 
and/or are related to disease progression (see Section 8.3 for details). 
 Overdose, defined as the accidental or intentional administration of any dose of study 
drug that is considered both excessive and medically important. An “excessive and 
medically important” overdose includes any overdose in which either an SAE, a 
non-serious AE, or no AE occurs, and is considered by the Investigator as clinically 
relevant, ie, poses an actual or potential risk to the subject. 
All events (serious and non-serious) must be reported with Investigator’s assessment of the 
event’s seriousness, severity, and causality to the study drug. A detailed narrative summarizing 
the course of the event, including its evaluation, treatment, and outcome should be provided. 
Specific or estimated dates of event onset, treatment, and resolution should be included when 
available. Medical history, concomitant medications, and laboratory data that are relevant to the 
event should also be summarized in the narrative. For fatal events, the narrative should state 
whether an autopsy was or will be performed and include the results if available.  Source 
documents (including medical reports) will be retained at the study center and should not be 
submitted to the Sponsor for SAE reporting purposes. 
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 CRO/sponsor 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 eCRF is 
unavailable, report SAEs 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. 
Please call the local SAE Hotline (see Study Manual) or your study monitor for any questions on 
SAE reporting. 
8.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee 
Daiichi Sankyo and/or CRO will inform Investigators, IRBs/Ethics Committees (ECs), and 
regulatory authorities of any Suspected Unexpected Serious Adverse Reactions (SUSARs) 


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occurring in other sites as appropriate per local reporting requirements.  Daiichi Sankyo and/or 
CRO will comply with any additional local safety reporting requirements. 
In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the 
investigational product, unless delegated to the Sponsor, it is the Investigator’s responsibility to 
inform the IRB per Sponsor’s instruction. 
In Japan, it is the Sponsor’s responsibility to report all the fatal/life-threatening adverse reactions 
to the regulatory authorities regardless of expectedness, and SUSARs to the regulatory 
authorities and IRB/ECs. 
8.7. 
Exposure in Utero During Clinical Studies 
Daiichi Sankyo must be notified of any subject or partner of a male subject who becomes 
pregnant while receiving or within 7 months of discontinuing the study drug. 
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome.  This information is important for both drug safety and public health 
concerns.  It is the responsibility of the Investigator, or designee, to report any pregnancy in a 
female subject or a 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 subject or partner until 
completion of the pregnancy and complete the EIU Reporting form with complete pregnancy 
outcome information, including normal delivery and induced abortion.  The adverse pregnancy 
outcome, either serious or non-serious, should be reported in accordance with study procedures.  
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE 
(ie, post-partum complications, spontaneous or induced abortion, stillbirth, neonatal death, or 
congenital anomaly, including that in an aborted fetus), the Investigator should follow the 
procedures for reporting SAEs outlined in Section 8.5. 
8.8. 
Clinical Laboratory Evaluations 
The following clinical laboratory tests will be performed: 
Laboratory tests 
Parameters 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, white blood 
cell count, differential white blood cell count (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils), mean platelet volume, reticulated 
platelet fractiona 
Chemistry 
Total protein, albumin, ALP, ALT, AST, total bilirubin, BUN, Ca, Cl, 
serum creatinine, lactate dehydrogenase (LDH), K, Na, Mg 
Coagulation (only at 
Screening in Dose 
Expansion Part) 
Prothrombin time, PT international normalized ratio (INR), partial 
thromboplastin time 
a if available 
In addition, the following laboratory tests will be performed at the visits indicated in 
Appendix 17.8. 
 Cardiac troponin T (alternatively cardiac troponin I) 


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 Pregnancy test (serum or urine) for all female subjects of childbearing potential must 
be performed during the Screening Period.  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 page of the eCRF.  If the 
abnormal laboratory value constitutes an SAE, it should be reported by the Investigator with a 
targeted questionnaire is in-built as an eCRF or a SAVER form within 24 hours of awareness and 
other relevant procedures must be followed (see Section 8.5).  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. 
8.9. 
Vital Signs 
Vital sign measurements will include systolic and diastolic blood pressure and pulse rate and 
body temperature.  Additionally, SpO2 will be measured before administration on Day 1 of each 
cycle and EOT. 
8.10. 
Electrocardiograms 
Standard 12-lead ECGs in triplicate will be performed as described in the Schedule of Events 
(Table 17.7, Table 17.8, Table 17.9, and Table 17.10). Triplicate ECGs should be taken in close 
succession, a few minutes apart, after being in a supine/semi-recumbent position for 5 minutes.  
Standard ECG parameters will be measured, including RR, PR, QT intervals, and QRS duration.  
All ECGs must be evaluated by Investigator or delegated physician for the presence of 
abnormalities. All ECG data collected will be sent to the central laboratory for ECG analysis. 
8.11. 
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. 
8.12. 
Other Examinations 
Ophthalmologic assessments will include visual acuity testing, slit lamp examination, 
fundoscopy and tonometry.  Ophthalmologic assessments must be evaluated by the Investigator 
or delegated physician. 
LVEF will be measured by either ECHO or MUGA, as described in the Schedule of Events.  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. 
Additional safety assessments should be conducted as needed, per Investigator’s discretion. 


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9. 
EFFICACY ASSESSMENTS 
Efficacy endpoints will include ORR (the sum of CR rate and PR rate), DCR (the sum of CR 
rate, PR rate, and SD rate), DOR, CBR, TTR, PFS, OS, and percentage change in target 
lesion(s). 
Tumor response will be evaluated using RECIST version 1.1 (Section 17.4) by the Investigator 
and the independent central imaging CRO selected by the Sponsor. Tumor assessments will be 
performed at screening and every 6 weeks in the first 24 weeks after Day 1 of Cycle 1 and every 
12 weeks thereafter, independent of dosing schedule.  Tumor assessments should not be delayed 
by dose interruptions; they are timed relative to Cycle 1, Day 1 and should continue until 
progressive disease or until a new anticancer therapy is started, whichever occurs first. 


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10. 
OTHER ASSESSMENTS 
Not applicable. 


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11. 
STATISTICAL METHODS 
11.1. 
General Statistical Considerations 
The primary analysis is to assess the efficacy, safety, and tolerability of U3-1402 in subjects with 
HER3-positive metastatic breast cancer and to determine the MTD/RDE or establish the safety 
and tolerability of the maximum administered dose of U3-1402. 
The data cutoff for the primary analysis will occur after all subjects have either discontinued the 
study or have been followed for at least 9 months following the first dose of study treatment, 
whichever is earlier. The primary analysis data cutoff may be extended if emerging data show 
responses are occurring later. The final analysis of the study will occur after all subjects have 
discontinued from the study. Data collected beyond the primary analysis cut-off time point will 
be presented as appropriate in a Clinical Study Report (CSR) addendum. 
The data analyses will also be conducted during  the Dose Escalation and Dose Finding Parts. 
Descriptive statistics will be provided for selected demographic, safety, and PK data by cohort 
and time as appropriate.  Descriptive statistics on continuous data will include means, medians, 
standard deviations, and ranges (as well as geometric means and geometric coefficient of 
variation for Cmax and AUC 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 
nonmissing value of a variable taken before the first dose of study drug 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. 
Safety analyses will be performed based on the safety analysis set.  Analysis of PK parameters 
will be based on the PK analysis set and biomarker analyses will be based on the Full Analysis 
Set (FAS).  Efficacy endpoints will be analyzed based on the FAS.  Data will be summarized by 
cohort, RDE cohort(s) (Dose Escalation and Dose Finding Parts), and overall. 
A detailed Statistical Analysis Plan (SAP) describing the methodology to be used in the final 
analysis will be prepared and finalized before database lock.  Statistical methods described 
within this document may be changed based on advances in research. 
11.2. 
Analysis Sets 
11.2.1. 
Full Analysis Set 
The FAS will include all subjects enrolled in the study who received at least 1 dose of U3-1402. 
11.2.1.1. Dose-Limiting Toxicity Evaluable Set  
The DLT-evaluable set will include all subjects enrolled in the study who received at least 1 dose 
of U3-1402, with the exception of those subjects for whom DLT evaluation could not be 
adequately conducted. 


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11.2.1.2. Safety Analysis Set 
The safety analysis set will include all subjects enrolled in the study who received at least 1 dose 
of U3-1402. 
11.2.1.3. Pharmacokinetic Analysis Set 
The PK analysis set will include all subjects enrolled in the study who received at least 1 dose of 
U3-1402 and had measurable serum concentrations of U3-1402, total anti-HER3 antibody or 
MAAA-1181a. 
11.3. 
Study Population Data 
Disposition and reasons for ending the treatment and discontinuing from the study will be 
summarized and listed for subjects in the enrolled analysis set. 
Demographic and baseline characteristics such as age, sex, race, ethnicity, baseline ECOG PS, 
histology, cancer stage, best response to prior chemotherapy, lines of prior regimens, and prior 
treatment type will be summarized for the FAS, and safety analysis set.  If 2 analysis sets within 
a part of the study are identical to each other, the table will be presented only once. 
11.4. 
Statistical Analysis 
11.4.1. 
Efficacy Analyses 
Efficacy endpoints will include ORR (the sum of CR and PR rates); DCR (the sum of CR rate, 
PR rate, and SD rate), DOR, CBR, TTR, PFS, OS, and percent change in target lesion(s).  Tumor 
responses will be assessed by an Investigator and an independent central imaging CRO 
according to RECIST 1.1. 
The efficacy endpoints will be listed and summarized.  For ORR and DCR and CBR, point 
estimates 2-sided 95% exact binomial confidence intervals will be provided.  Time to event 
variables including PFS, OS, TTR, and DOR will be summarized descriptively using the 
Kaplan-Meier method.  PFS is defined as the time from the date of the first dose to the earlier of 
the dates of the first objective documentation of radiographic PD or death due to any cause.  
Censoring rules for the PFS analysis will be specified in the SAP.   
Descriptive statistics for the best percent change from baseline in the sum of diameters of 
measurable tumors will be provided.  A waterfall plot of the best percent change in the sum of 
diameters for each subject will be presented. 
11.4.2. 
Pharmacokinetic Analyses 
PK analyses will be performed on the PK analysis set.  Serum concentration-time data for 
U3-1402, total anti-HER3 antibody and MAAA-1181a will be listed, plotted, and summarized 
using descriptive statistics by cohort at each point and in study period. 
PK parameters of U3-1402, total anti-HER3 antibody and MAAA-1181a will be listed and 
summarized using descriptive statistics. 
The comparison of the PK profile between each region (Japan and the US) will also be assessed. 


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Serum concentration data will be used to perform a population PK modeling.  The influences of 
intrinsic or extrinsic factor will be assessed in the population PK analysis.  If performed, results 
of population PK analyses will be reported separately (ie, not in the Clinical Study Report). 
11.4.3. 
Pharmacodynamic Analyses 
Not applicable. 
11.4.4. 
Biomarker and Exploratory Analyses 
Explorative analyses for biomarkers will be listed and summarized using descriptive statistics. 
11.4.5. 
Safety Analyses 
Safety endpoints will include TEAEs, SAEs, AESIs, clinical laboratory measurements, vital sign 
measurements, ECG recordings, physical examination findings, ECHO/MUGA findings, and 
ophthalmologic findings.  In the Dose Escalation Part, the incidence of DLTs will also be 
evaluated. 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics. In the Dose Escalation Part, the number of DLTs identified 
among the DLT-evaluable subjects in the DLT-evaluable set will be listed and summarized by 
cohort. Additional details regarding safety analyses will be described in the SAP. 
11.4.5.1. Adverse Event Analyses 
A TEAE is defined as an AE that emerges or worsens during the on-treatment period. The 
on-treatment period is defined as from the start date of study treatment (inclusive) to 47 days 
after the end date of study treatment (inclusive). SAEs starting or worsening after the 
on-treatment period, if reported as related to the study treatment, are also considered TEAEs. 
The AE summary will only include TEAEs. 
The number and percentage of subjects reporting TEAEs will be tabulated by the worst 
NCI-CTCAE grade, System Organ Class (SOC), and preferred term. 
Similarly, the number and percentage of subjects reporting treatment-emergent SAEs will be 
tabulated, as well as TEAEs/SAEs considered related to U3-1402. 
A by-subject AE (including TEAE) data listing will be provided including, but not limited to, 
verbatim term, preferred term, SOC, NCI-CTCAE grade, and relationship to study drug. 
Deaths, other SAEs, and other significant AEs, including those leading to permanent 
discontinuation from U3-1402, will be listed. 
11.4.5.2. Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for selected clinical laboratory test results (hematology 
and chemistry) and changes from baseline by scheduled time of evaluation, including the EOT 
visit, maximum post-treatment value, and minimum post-treatment value. 
Abnormal laboratory results will be graded according to NCI-CTCAE version 5.0, if applicable.  
A shift table, presenting the 2-way frequency tabulation for baseline and the worst post-treatment 


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value according to the NCI-CTCAE grade, will be provided for selected clinical laboratory tests.  
Abnormal clinical laboratory test results that are deemed of clinical significance or of Grade 3 or 
4 will be listed. 
11.4.5.3. Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements and changes from 
baseline by scheduled time of evaluation, including the EOT visit and the maximum and 
minimum post-treatment values. 
11.4.5.4. Electrocardiogram Analyses 
Descriptive statistics will be provided for ECG parameters and changes from baseline by 
scheduled time of evaluation, including the EOT visit and the maximum post-treatment value.  In 
addition, the number and percentage of subjects with ECG interval values meeting the criteria 
will be tabulated (eg, QTc ≤450 ms, >450 to ≤480 ms, >480 ms to ≤500 ms, and >500 ms). 
The QT intervals will be corrected for heart rate by Fridericia’s formula (QTcF = QT/[RR]1/3). 
Relationship between drug concentrations and QTcF may be analyzed.  This analysis will be 
performed for subjects across all dose levels. 
11.4.5.5. Exploratory Safety Analyses 
Not Applicable. 
11.4.5.6. Other Safety Analyses 
All other safety variables (physical examination findings including ECOG PS, ECHO/MUGA 
findings, and ophthalmologic findings) will be listed. 
11.5. 
Sample Size Determination 
The Dose Escalation Part of this study consists of mCRM with EWOC design with at least 
3 DLT-evaluable subjects per dose level.  Sample size has been determined by practical 
considerations and no formal statistical assessment has been performed for the Dose Escalation 
Part. 
A total of approximately 12 subjects will be enrolled between Dose Escalation and Dose Finding 
for each of the Q3W Dosing Cohorts evaluated in Dose Finding. For the alternative dosing 
cohorts evaluated in Dose Finding, a total of approximately 12 subjects will be enrolled into each 
cohort.  RDE(s) will be determined based on the risk and benefit assessment. 
For the Dose Expansion Part, there are 4 planned expansion cohorts (HER3-high, HR-positive 
[6.4 mg/kg], HER3-high, HR-positive [4.8 mg/kg], HER3-low, HR-positive [6.4 mg/kg] and 
HER3-high, TNBC [6.4 mg/kg]): 
 Approximately 60 eligible subjects with HER3-high, HER2-negative, HR-positive 
disease will be randomized into 1 of 2 cohorts: 4.8 mg/kg or 6.4 mg/kg. 


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 Subjects with HER3-low, HER2-negative, HR-positive breast cancer will not be 
randomized. Approximately 20 eligible subjects in this setting will be enrolled into a 
HER3-low, HR-positive (6.4 mg/kg) cohort. 
 Subjects with HER3-high, TNBC will not be randomized. Approximately 30 eligible 
subjects in this setting will be enrolled into an HER3-high, TNBC (6.4 mg/kg) cohort.  
A total of approximately 110 subjects will be enrolled into the Dose Expansion Part. 
In HER3-high, HR-positive cohorts of the Dose Expansion Part, if target ORR is more than 10% 
(null hypothesis: ORR 0.10, alternative hypothesis: ORR >0.10), then the probability of no 
response out of 30 subjects will be less than 5%.  The probability that more than 6 responders out 
of 30 subjects (ORR >20%) are observed will be less than 5% under the null hypothesis with 
ORR 0.10 but more than 80% under alternative hypothesis with ORR = 0.30. 
In the HER3-low, HR-positive cohort of the Dose Expansion Part, if target ORR is more than 
10% (null hypothesis: ORR 0.10, alternative hypothesis: ORR >0.10), then the probability of 
no response out of 20 subjects will be less than 15%. The probability that more than 3 responders 
out of 20 subjects (ORR >15.0%) are observed will be less than 15% under the null hypothesis 
with ORR 0.10 but more than 75% under alternative hypothesis with ORR = 0.25. 
In the HER3-high, TNBC cohort of the Dose Expansion Part, if target ORR is more than 20% 
(null hypothesis: ORR 0.20, alternative hypothesis: ORR >0.20), then the probability of no 
response out of 30 subjects will be less than 5%. The probability that more than 9 responders out 
of 30 subjects (ORR >30.0%) are observed will be less than 10% under the null hypothesis with 
ORR 0.20 but more than 80% under alternative hypothesis with ORR = 0.40. 
The probability values for the sample size are derived based on binomial distribution using SAS® 
version 9.4. 
11.6. 
Statistical Analysis Process 
The clinical study will be analyzed by DS or its agent/CRO followed by this protocol, and SAP 
which will demonstrate all methodologies and displays/shells for statistical analyses. 
The SAP will provide the statistical methods and definitions for the analysis of the efficacy and 
safety data, as well as describe the approaches to be taken for summarizing other clinical study 
information such as subject disposition, demographic and baseline characteristics, study drug 
exposure, and prior and concomitant medications.  The SAP will also include a description of 
how missing, unused, and spurious data will be addressed. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP will be 
finalized prior to database lock. 
All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, Cary, 
NC 27513). 


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11.7. 
Specification of Modified Continuous Reassessment Method with 
Escalation with Overdose Control  
11.7.1. 
Bayesian Logistic Regression Model for Modified Continuous Reassessment 
Method 
The dose-toxicity relationship for mCRM with EWOC principle will be described by following 
2-parameter BLRM: 
logit(π(d)) = log(α) + β log(d/d*), α>0, β>0 
where logit(π(d)) = ln (π(d)/(1-π(d))), π(d) is the probability of a DLT or the DLT rate at dose d.  
Doses are rescaled as d/d* with the reference dose d* = 9.7 mg/kg.  As a consequence, log(α) is 
equal to logit(π(d*)) at dose d*.  Note that for a dose equal to zero, the probability of toxicity is 
zero. 
11.7.2. 
Prior Specification for Bayesian Logistic Regression Model Parameters 
The Bayesian approach requires the specification of a prior distribution for the BLRM 
parameters.  A minimally-informative bivariate normal prior for the model parameters 
(log(α),log(β)) is obtained as follows21: 
 Based on extrapolation of nonclinical toxicology studies in monkeys, the MTD is 
projected to be greater than 9.7 mg/kg in humans (the HNSTD of monkeys is 
30 mg/kg and assuming humans and monkeys are equally sensitive, the MTD is 
projected to be greater than 9.7 mg/kg in humans). The median prior probabilities of 
DLT are set to be approximately 8.0% and 24.5% at 1.6 mg/kg (projected starting dose 
for dose escalation using mCRM) and at 9.7 mg/kg, respectively. 
 For the remaining doses, the medians of probability of DLT are assumed linear in log-
dose on the logit-scale. 
 Based on the above medians for the probability of DLT at each dose and wide prior 
credible intervals (obtained from minimally informative Beta distributions), the 
optimal parameters of the bivariate normal distribution can be obtained as follows: 
Parameters 
Means 
Standard deviations 
Correlation 
log(α), log(β) 
(-1.0981, -0.4913) 
(2.0445, 0.8677) 
-0.3317 
11.7.3. 
Escalation with Overdose Control Principle 
Dose recommendation for the next cohort will be based on summaries of the posterior 
probability of the DLT rate for provisional doses: 1.6, 3.2, 4.8, 6.4, and 8.0 mg/kg.  After 
subjects of each cohort complete DLT evaluation during Cycle 1, the posterior distributions of 
the DLT rate are derived for all provisional dose levels based on the BLRM using the DLT 
outcome data from all assessed doses and a pre-specified prior distribution for the model 
parameters.  The posterior probability of the DLT rate in the following 4 intervals at each dose 
level will then be calculated: 0% ≤DLT rate ≤16% as the DLT rate interval for under-dosing, 
16% <DLT rate ≤33% as the target DLT rate interval, 33% <DLT rate ≤60% as the DLT rate 
interval for excessive toxicity, and 60% <DLT rate ≤100% as the DLT rate interval for 


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unacceptable toxicity, and used for dose recommendation for the next cohort according to the 
EWOC principle.  The above provisional doses are based on an initial estimate of the human 
MTD of 9.7 mg/kg using the HNSTD of monkeys in nonclinical toxicology studies (30 mg/kg).  
It is therefore conceivable that the posterior probability of DLT rate for dose recommendation 
may be generated using alternative provisional doses as long as the predicted exposure 
increments are no more than 100% (Section 3.1.3). 
The EWOC principle requires that the mCRM recommended dose for the next cohort of subjects 
is the one with the highest posterior probability of the DLT rate in the target DLT rate interval of 
16% <DLT rate ≤33% among all doses fulfilling the overdose control constraint: there is less 
than 25% of probability for the DLT rate >33% (probability for excessive or unacceptable 
toxicity). 


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/investigational site will permit study-related monitoring, audits, IRB/IEC 
review and regulatory inspections by providing direct access to source data/documents.  Direct 
access includes permission to examine, analyze, verify, and reproduce any records and reports 
that are important to the evaluation of a clinical study. 
12.1. 
Monitoring and Inspections 
The CRO monitor and regulatory authority inspectors are responsible for contacting and visiting 
the Investigator for the purpose of inspecting the facilities and, upon request, inspecting the 
various records of the study (eg, CRFs, source data, and other pertinent documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to ICH Good Clinical Practice (GCP) and local regulations on the conduct of 
clinical research will be accomplished through a combination of onsite visits by the monitor and 
review of study data remotely.  The frequency of the monitoring visit will vary based on the 
activity at each site.  The monitor is responsible for inspecting the CRFs 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 CRFs.  
Detailed information is provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, SOPs, GCP, and applicable 
regulations to the Investigator and will ensure that appropriate action (s) designed to prevent 
recurrence of the detected deviations is taken and documented. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are addressed to the satisfaction of the Sponsor and 
documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study site may be selected for 
audit by representatives from the Sponsor.  Audit of site facilities (eg, pharmacy, drug storage 
areas, laboratories) and review of study related records will occur in order to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory requirements.  
The Investigator should respond to audit findings.  In the event that a regulatory authority 
informs the Investigator that it intends to conduct an inspection, the Sponsor shall be notified 
immediately. 
12.2. 
Data Collection 
The Investigator or study staff will enter the data in the eCRF (see Section 17.6) in accordance 
with the CRF Completion Guidelines that are provided by the Sponsor. 
eCRF completion should be kept current to enable the monitor to review the subject’s status 
throughout the course of the study.  The eCRF will be completed, reviewed and signed off or 
e-signed by the Investigator after all queries have been satisfactorily resolved. 
The Investigator e-signs according to the study data flow. 


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Any data recorded on the study CRF will be collected and included in the database according to 
Clinical Data Interchange Standards Consortium (CDISC) standards and subjected to the same 
procedures as other data. 
12.3. 
Data Management 
Each subject will be identified in the database by a unique Subject Number as defined by the 
Sponsor. 
To ensure the quality of clinical data across all subjects and study sites, a Clinical Data 
Management review will be performed on subject data according to specifications given to 
Sponsor or CRO.  Data will be vetted both electronically and manually for CRFs and the data 
will be electronically vetted by programmed data rules within the application.  Queries generated 
by rules and raised by reviewers will be generated within the Electronic Data Capture (EDC) 
application.  During this review, subject data will be checked for consistency, completeness, and 
any apparent discrepancies.  To resolve any questions arising from the Clinical Data 
Management review process for eCRFs queries will be raised and resolved within the EDC 
application. 
Data received from external sources such as central laboratories will be reconciled to the clinical 
database. 
SAEs in the clinical database will be reconciled with the safety database. 
All medical and surgical history and Adverse Events will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA). All prior cancer therapy and prior/concomitant medications 
entered into the database will be coded by using the latest version of World Health Organization 
Drug Dictionary. 
12.4. 
Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties.  All persons authorized to make entries and/or corrections on 
CRFs will be included on the Signature List. 
Investigators will maintain a confidential screening log of all potential study candidates that 
includes limited information of the subjects, date and outcome of screening process. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study number. 
Investigators will maintain a confidential 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 subject’s CRF 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, CRFs, 
inventory of study drug, regulatory documents (eg, protocol and amendments, IRB/EC 
correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, clinical 


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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 (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 the institution or study site 
policy.  Prior to transfer or destruction of these records, the Sponsor must be notified in writing 
and be given the opportunity to further store such records. 
12.5. 
Record Keeping 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related documentation, suitable for inspection at any 
time by representatives from the Sponsor and/or applicable regulatory authorities.  Trial Master 
File includes: 
 Subject files containing completed CRFs, ICFs, and supporting copies of source 
documentation (if kept). 
 Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of relevant essential documents required prior to commencing a clinical study, 
and all correspondence to and from the IRB/EC and the Sponsor. 
 Records related to the study drug(s) including acknowledgment of receipt at site, 
accountability records, final reconciliation, and applicable correspondence. 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
Trial Master File will be retained by the Investigator until at least 3 years after the last approval 
of a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have lapsed since the formal 
discontinuation of clinical development of the investigational drug.  These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements or by 
an agreement with the Sponsor.  It is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained. 
Subject’s medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice. 
No study document should be destroyed without prior written agreement between Sponsor and 
the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify Sponsor in writing of the new responsible 
person and/or the new location. 


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


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


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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
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 ICH consolidated Guideline E6 for Good Clinical 
Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory requirement(s) including the 
following: 
 US Food and Drug Administration (FDA) GCP Regulations:  Code of Federal 
Regulations (CFR) Title 21, parts 11, 50, 54, 56 and 312, as appropriate. 
 Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 of 27 Mar 1997. 
 The Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical 
Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and 
Cosmetics No. 1 of 25 Nov 2014. 
 Other applicable local regulations. 
15.2. 
Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in accordance with GCP and local regulations. 
The Investigator must ensure that the subject’s anonymity is maintained.  On the CRFs or other 
documents submitted to the Sponsor or the CRO, subjects should be identified by a unique 
Subject Number as designated by the Sponsor.  Documents that are not for submission to the 
Sponsor or the CRO (eg, signed ICF) should be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the IRB/EC 
direct access to review the subject’s original medical records for verification of study-related 
procedures and data.  The Investigator is obligated to inform the subject that his/her study-related 
records will be reviewed by the above-named representatives without violating the 
confidentiality of the subject. 
15.3. 
Informed Consent 
Before a subject’s participation in the study, it is the Investigator’s responsibility to obtain freely 
given consent, in writing, from the subject after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
screening procedures or any study drugs are administered.  ICF for examination of tumor tissue 
will be prepared in a separate ICF.  Subjects should be given the opportunity to ask questions and 
receive satisfactory answers to their inquiries and should have adequate time to decide whether 
or not to participate in the study.  The written ICF should be prepared in the local language(s) of 
the potential subject population. 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 


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have their origin in the Declaration of Helsinki. The consent form and any revision(s) should be 
approved by the IRB prior to being provided to potential subjects. 
The subject’s written informed consent should be documented in the subject’s medical records.  
The ICF should be signed and personally dated by the subject, and by the person who conducted 
the informed consent discussion (not necessarily the Investigator).  The original signed ICF 
should be retained in accordance with institutional policy, and a copy of the signed consent form 
should be provided to the subject.  The date and time (if applicable) that informed consent was 
given should be recorded on the eCRF. 
If the subject cannot read, then according to ICH GCP Guideline, Section 4.8.9, an impartial 
witness should be present during the entire informed consent discussion.  This witness should 
sign the ICF after the subject has consented to the subject’s participation and, if possible, signed 
the ICF.  By signing the ICF, the witness attests that the information in the ICF and any other 
written information was adequately explained to and apparently understood by the subject and 
that informed consent was freely given by the subject. 
Suggested model text for the ICF for the study and any applicable subparts (genomic, PK, etc.) is 
provided in the Sponsor ICF template for the Investigator to prepare the documents to be used at 
his or her site. 
For study site in the US, an additional consent is required for the HIPAA. 
15.4. 
Regulatory Compliance 
The study protocol, subject information and consent form, the Investigator’s Brochure, any 
subject written instructions to be given to the subject, available safety information, subject 
recruitment procedures (eg, advertisements), information about payments and compensation 
available to the subjects and documentation evidencing the Investigator’s qualifications should 
be submitted to the IRB for ethical review and approval according to local regulations, prior to 
the study initiation.  The written approval should identify all documents reviewed by name and 
version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The Investigator must submit and, where necessary, obtain approval from the IRB and/ or 
Sponsor for all subsequent protocol amendments and changes to the informed consent document 
or changes of the investigational site, facilities or personnel.  The Investigator should notify the 
IRB of deviations from the protocol or SAEs occurring at the site and other AE reports received 
from Sponsor/CRO, in accordance with local procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group or representative 
to whom this responsibility has been delegated will insure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to study initiation. If changes to the 
initial protocol and other relevant study documents are made, this representative will also ensure 
that any revised documents required for submission are submitted to regulatory authorities and 
implementation of these changes happen only after approval by the relevant regulatory bodies, as 
required. 


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


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15.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses will 
be communicated to the Investigator by Daiichi Sankyo or the CRO.  Also, the Sponsor will 
ensure the timely submission of amendments to regulatory authorities. 
Changes made by protocol amendments will be documented in a Summary of Changes 
document.  These protocol amendments will undergo the same review and approval process as 
the original protocol. 
A protocol amendment may be implemented after it has been approved by the IRB/EC and by 
regulatory authorities where appropriate, unless immediate implementation of the change is 
necessary for subject safety. 
15.8. 
Study Termination 
Refer to Section 3.1.6. 
15.9. 
Data and Safety Monitoring Board 
Not applicable. 
15.10. 
Address List 
Address list will be addressed in Supplement 3. 


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16. 
REFERENCES 
1. World Health Organization (WHO). Breast cancer: prevention and control. Breast cancer 
burden [Internet]. [cited 2017 Dec]. Available from: 
http://www.who.int/cancer/detection/breastcancer/en/index1.html 
2. American Cancer Society: Cancer Facts and Figures 2016. Atlanta, Ga: American Cancer 
Society, 2016. 
3. Sauvaget C, Nishino Y, Konno R, et al. Challenges in breast and cervical cancer control 
in Japan. Lancet Oncol. 2016;17:e305-12. 
4. Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of breast cancer based 
on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160-7. 
5. Dawood S, Broglio K, Gonzalez-Angulo AM, et al. Trends in Survival Over the Past 
Two Decades Among White and Black Patients With Newly Diagnosed Stage IV Breast 
Cancer. J Clin Oncol. 2008;26:4891-98. 
6. Giordano SH, Buzdar AU, Smith TL, et al. Is Breast Cancer Survival Improving? Trends 
in Survival for Patients with Recurrent Breast Cancer Diagnosed from 1974 through 
2000. Cancer. 2004;100:44-52. 
7. Gennari A, Conte P, Rosso R, et al. Survival of Metastatic Breast Carcinoma Patients 
over a 20-Year Period. A Retrospective Analysis Based on Individual Patient Data from 
Six Consecutive Studies. Cancer. 2005;104:1742-50. 
8. Gonzalez-Angulo, AM, Morales-Vasquez, F, and Hortobagyi, GN. Overview of 
resistance to systemic therapy in patients with breast cancer. Adv Exp Med Biol. 2007; 
608: 1–22. 
9. Colozza, M, de Azambuja, E, Personeni, N, et al. Achievements in systemic therapies in 
the pregenomic era in metastatic breast cancer. Oncologist. 2007; 12: 253–270. 
10. Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of 
physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 
open-label randomised study. Lancet. 2011;377(9769):914-23. 
11. Lebert JM, Lester R, Powell E, et al. Advances in the systemic treatment of 
triple-negative breast cancer. Curr Oncol. 2018;25(Suppl 1):S142-50. 
12.  Park JH, Ahn JH, Kim SB. How shall we treat early triple-negative breast cancer 
(TNBC): from the current standard to upcoming immuno-molecular strategies. ESMO 
Open. 2018;3(Suppl 1):e000357. 
13. Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of 
physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 
open-label randomised study. Lancet. 2011;377(9769):914-23. 
14. Kaufman PA, Awada A, Twelves C, et al. Phase III open-label randomized study of 
eribulin mesylate versus capecitabine in patients with locally advanced or metastatic 
breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 
2015;33(6):594-601. 


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15. Abou-Alfa GK, Letourneau R, Harker G, et al. Randomized phase III study of exatecan 
and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic 
cancer. J Clin Oncol. 2006;24(27):4441-7. 
16. Cheverton P, Friess H, Andras C, et al. Phase III results of exatecan (DX-8951f) versus 
gemcitabine (Gem) in chemotherapy-naïve patients with advanced pancreatic cancer 
(APC). J Clin Oncol. 22:14s, 2004 (abstr 4005). 
17. De Jager R, Cheverton P, Tamanoi K, et al. DX-8951f: summary of phase I clinical trials. 
Ann N Y Acad Sci. 2000;922:260-73. 
18. Koutras A, Kalogeras KT, Wirtz RM, et al. Evaluation of the prognostic significance of 
HER family mRNA expression in high-risk early breast cancer: a Hellenic Cooperative 
Oncology Group (HeCOG) validation study. J Transl Med. 2015;13:171. 
19. Ocana A1, Vera-Badillo F, Seruga B, et al. HER3 overexpression and survival in solid 
tumors: a meta-analysis. J Natl Cancer Inst. 2013;105(4):266-73. 
20. Bae SY, La Choi Y, Kim S, et al. HER3 status by immunohistochemistry is correlated 
with poor prognosis in hormone receptor-negative breast cancer patients. Breast Cancer 
Res Treat. 2013;139(3):741-50. 
21. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Stat Med. 2008;27(13):2420-39. 


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17. 
APPENDICES 
17.1. 
Blood Collection Volume by Category and Total 
Table 17.1: 
Blood Collection in Dose Escalation Part 
Time Point 
Test Item 
Frequencya 
Collection Volume 
Screening examination 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
- 
- 
Biomarker (HER3ECD, cTnI) 
1 
8 mL 
ADA 
- 
- 
Cycle 1 
Laboratory test 
4 
(Collected in each site) 
Pharmacokinetics 
9 
(10b) 
45 mL 
(50 mLb) 
Biomarker (HER3ECD, cTnI) 
1 
4 mL 
ADA 
2 
8 mL 
Cycle 2 
Laboratory test 
3 
(Collected in each site) 
Pharmacokinetics 
4 
(5b) 
20 mL 
(25 mLb) 
Biomarker (HER3ECD, cTnI) 
1 
4 mL 
ADA 
1 
4 mL 
Cycle 3 
Laboratory test 
3 
(Collected in each site) 
Pharmacokinetics 
9 
(10b) 
45 mL 
(50 mLb) 
Biomarker (HER3ECD, cTnI) 
1 
4 mL 
ADA 
- 
- 
Cycle 4 
and subsequent cycles 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
(Only Cycle 4, 6, and 8) 
1 
5 mL 
Biomarker (HER3ECD, cTnI) 
1 
4 mL 
ADA 
(Every 2 cycles from Cycle 4 to EOT) 
1 
4 mL 
End of Treatment 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
- 
- 
Biomarker (HER3ECD, cTnI) 
1 
4 mL 
ADA 
1 
4 mL 
Follow-up examination 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
- 
- 
Biomarker (HER3ECD, cTnI) 
- 
- 
 
ADAc 
1 
4 mL 
 
 
 
 
ADA = anti-drug antibody; cTnI = cardiac troponin I; F/U = follow-up; HER3ECD = human epidermal growth 
factor receptor 3 extracellular domain. 
a Blood collection in subjects with adverse events should be continued until resolution of the events (even after the 
scheduled observation period). 
b If the schedule on Day 1 of the next cycle is delayed for 3 days or more, including if the subject cannot continue 
onto the next cycle. 
c For subjects with positive ADA at F/U visit, additional serum ADA samples (4 mL) may be collected every 3 
months (± 1 month) up to 1 year from the last dose of study drug, or if the ADA becomes negative, or if ADA titer 
becomes less than baseline (applicable when pre-existing ADA is observed), or if the subject starts another therapy 
for cancer, or withdraws consent from the study, whichever occurs first. 


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Table 17.2: 
Blood Collection in Dose Finding (Q3W Dosing Schedule) and Dose 
Expansion Parts 
Time Point 
Test Item 
Frequencya 
Collection Volume 
Screening 
examination 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
- 
- 
Biomarker (cTnI) 
1 
4 mL 
Biomarker (HER3ECD) 
1d 
4 mLd 
ADA 
- 
- 
Cycle 1 
Laboratory test 
3 
(Collected in each site) 
Pharmacokinetics 
9 (10b) 
45 mL (50 mLb) 
Biomarker (cTnI) 
1 
4 mL 
Biomarker (HER3ECD, cfDNA, 
cfRNA)e 
1e 
24 mLe 
ADA 
2 
8 mL 
Cycle 2 
Laboratory test 
3 
(Collected in each site) 
Pharmacokinetics 
2 (3e,f) 
10 mL (15 mLe,f) 
Biomarker (cTnI) 
1 
4 mL 
ADA 
1 
4 mL 
Biomarker (HER3ECD, cfDNA, 
cfRNA)e,f 
1e,f 
24 mLe,f 
Cycle 3 
Laboratory test 
3 
(Collected in each site) 
Pharmacokinetics 
7 (8b) 
35 mL (40 mLb) 
Biomarker (cTnI) 
1 
4 mL 
ADA 
- 
- 
Cycle 4 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
1 
5 mL 
Biomarker (cTnI) 
1 
4 mL 
ADA 
1 
4 mL 
Cycle 5 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
5 
25 mL 
Biomarker (cTnI) 
1 
4 mL 
Cycle 6 and 
subsequent cycles 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
(Only Cycles 6 and 8) 
1 
5 mL 
Biomarker (cTnI) 
1 
4 mL 
ADA 
(Every 2 cycles from Cycle 6 to 
EOT) 
1 
4 mL 
End of Treatment 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
- 
- 
Biomarker (cTnI) 
1 
4 mL 
Biomarker (HER3ECD, cfDNA, 
cfRNA)e 
1e 
24 mLe 
ADA 
1 
4 mL 
Follow-up 
examination 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
- 
- 
Biomarker (cTnI) 
- 
-  
ADAc 
1 
4 mL 
ADA = anti-drug antibody; cTnI = cardiac troponin I; F/U = follow-up; HER3ECD = human epidermal growth 
factor receptor 3 extracellular domain. 


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a Blood collection in subjects with adverse events should be continued until resolution of the events (even after the 
scheduled observation period). 
b If the schedule on Day 1 of the next cycle is delayed for 3 days or more, including if the subject cannot continue 
onto the next cycle. 
c For subjects with positive ADA at F/U visit, additional serum ADA samples (4 mL) may be collected every 
3 months (± 1 month) up to 1 year from the last dose of study drug, or if the ADA becomes negative, or if ADA 
titer becomes less than baseline (applicable when pre-existing ADA is observed), or if the subject starts another 
therapy for cancer, or withdraws consent from the study, whichever occurs first. 
d Dose Finding Part only. 
e Dose Expansion Part only. 
f ± 4 hours from time of optional biopsy, if obtained. 


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Table 17.3: 
Blood Collection in Dose Finding Part (Q2W Dosing Schedule) 
Time Point 
Test Item 
Frequencya 
Collection Volume 
Screening 
examination 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
- 
- 
Biomarker (cTnI) 
1 
4 mL 
Biomarker (HER3ECD) 
1 
4 mL 
ADA 
- 
- 
Cycle 1 
Laboratory test 
2 
(Collected in each site) 
Pharmacokinetics 
7 (8b) 
35 mL (40 mLb) 
Biomarker (cTnI) 
1 
4 mL 
ADA 
2 
8 mL 
Cycle 2 
Laboratory test 
2 
(Collected in each site) 
Pharmacokinetics 
2 
10 mL 
Biomarker (cTnI) 
1 
4 mL 
ADA 
1 
4 mL 
Cycle 3 
Laboratory test 
2 
(Collected in each site) 
Pharmacokinetics 
7 (8b) 
35 mL (40 mLb) 
Biomarker (cTnI) 
1 
4 mL 
ADA 
- 
- 
Cycle 4 
and subsequent 
cycles 
Laboratory test 
3d 
1e 
(Collected in each site) 
Pharmacokinetics 
7 (8b)d 
1g 
5f 
35 mL (40 mLb)d 
5 mLg 
25 mLf 
Biomarker (cTnI) 
1 
4 mL 
ADA 
(Every 2 cycles from Cycle 4 to 
EOT) 
1 
4 mL 
End of Treatment 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
- 
- 
Biomarker (cTnI) 
1 
4 mL 
ADA 
1 
4 mL 
Follow-up 
examination 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
- 
- 
Biomarker (cTnI) 
- 
-  
ADAc 
1 
4 mL 
ADA = anti-drug antibody; cTnI = cardiac troponin I; F/U = follow-up; HER3ECD = human epidermal growth 
factor receptor 3 extracellular domain 
a Blood collection in subjects with adverse events should be continued until resolution of the events (even after the 
scheduled observation period). 
b If the schedule on Day 1 of the next cycle is delayed for 3 days or more, including if the subject cannot continue 
onto the next cycle. 
c For subjects with positive ADA at F/U visit, additional serum ADA samples (4 mL) may be collected every 
3 months (± 1 month) up to 1 year from the last dose of study drug, or if the ADA becomes negative, or if ADA 
titer becomes less than baseline (applicable when pre-existing ADA is observed), or if the subject starts another 
therapy for cancer, or withdraws consent from the study, whichever occurs first. 
d In Cycle 4. 
e In Cycle 5 and subsequent cycles. 
f In Cycle 6. 
g In Cycles 5 and 8. 


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Table 17.4: 
Blood Collection in Dose Finding Part (Q3W Dosing Schedule with 
Up-titration) 
Time Point 
Test Item 
Frequencya 
Collection Volume 
Screening 
examination 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
- 
- 
Biomarker (cTnI) 
1 
4 mL 
Biomarker (HER3ECD) 
1 
4 mL 
ADA 
- 
- 
Cycle 1 
Laboratory test 
3 
(Collected in each site) 
Pharmacokinetics 
7 (8b) 
35 mL (40 mLb) 
Biomarker (cTnI) 
1 
4 mL 
ADA 
2 
8 mL 
Cycle 2 
Laboratory test 
3 
(Collected in each site) 
Pharmacokinetics 
7 (8b) 
35 mL (40 mLb) 
Biomarker (cTnI) 
1 
4 mL 
ADA 
1 
4 mL 
Cycle 3 
Laboratory test 
3 
(Collected in each site) 
Pharmacokinetics 
7 (8b) 
35 mL (40 mLb) 
Biomarker (cTnI) 
1 
4 mL 
ADA 
- 
- 
Cycle 4 
and subsequent cycles 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
1e 
5d 
5 mLe 
25 mLd 
Biomarker (cTnI) 
1 
4 mL 
ADA 
(Every 2 cycles from Cycle 4 to EOT) 
1 
4 mL 
End of Treatment 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
- 
- 
Biomarker (cTnI) 
1 
4 mL 
ADA 
1 
4 mL 
Follow-up 
examination 
Laboratory test 
1 
(Collected in each site) 
Pharmacokinetics 
- 
- 
Biomarker (cTnI) 
- 
-  
ADAc 
1 
4 mL 
ADA = anti-drug antibody; cTnI = cardiac troponin I; F/U = follow-up; HER3ECD = human epidermal growth 
factor receptor 3 extracellular domain.  
a Blood collection in subjects with adverse events should be continued until resolution of the events (even after the 
scheduled observation period). 
b If the schedule on Day 1 of the next cycle is delayed for 3 days or more, including if the subject cannot continue 
onto the next cycle. 
c For subjects with positive ADA at F/U visit, additional serum ADA samples (4 mL) may be collected every 
3 months (± 1 month) up to 1 year from the last dose of study drug, or if the ADA becomes negative, or if ADA 
titer becomes less than baseline (applicable when pre-existing ADA is observed), or if the subject starts another 
therapy for cancer, or withdraws consent from the study, whichever occurs first. 
d Only in Cycle 5. 
e In Cycle 4, 6, and 8. 


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17.2. 
Additional Information (for Japanese Study Sites Only) 
17.2.1. 
GCP compliance 
With regard to related regulations in Section 15.1 (for Japanese study sites only):  This study will 
be conducted in compliance with the standards stipulated in Article 14-3 and Article 80-2 of the 
Pharmaceutical Affairs Law and by the “Ordinance Regarding Good Clinical Practice” (MHLW 
Ordinance No. 28, dated 27 Mar 1997) (referred to below as the “GCP Ordinance”).  In 
compliance with the ethical principles of the Declaration of Helsinki, the human rights, welfare, 
and safety of the subjects will be the first considerations in the conducting of this study. 
17.2.2. 
Study Period 
During 01 Nov 2016 to 31 Dec 2023. 
17.2.3. 
Payment for Participation, Compensation for Study-Related Injuries, and 
Insurance 
17.2.3.1. Payment for Participation 
If the subjects receive payment, the money will be paid to the subjects by the study site(s).  That 
money will be taken from the fees paid by the Sponsor to each study site and will be paid in 
accordance with each study site’s regulations. 
17.2.3.2. Compensation 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 
Supplement 5. 


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17.3. 
Eastern Cooperative Oncology Group Performance Status Scale 
GRADE DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
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 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
5 
Dead 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
17.4. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
Tumor response will be assessed in accordance with the RECIST v1.1, described below.  The 
details will be described in the Independent Review Charter developed by the imaging CRO 
selected by the Sponsor. 
17.4.1. 
Measurability of Tumor at Baseline 
17.4.1.1. Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
17.4.1.1.1. 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: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
 Measurable malignant lymph nodes:  To be considered pathologically enlarged and 
measurable, a lymph node must be 15 mm in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm).  At baseline and 
in 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. 


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17.4.1.1.2. Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis), as well as truly non-measurable lesions.  Lesions considered 
truly non-measurable include:  leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
17.4.1.1.3. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment. 
17.4.1.1.3.1. Bone Lesions 
 Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
17.4.1.1.3.2. 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. 
17.4.1.1.3.3. 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. 
17.4.1.2. Specifications by Methods of Measurements 
17.4.1.2.1. 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 28 days of the first dose of study drug administration. 


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17.4.1.2.2. 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 F/U.  Imaging based evaluation should 
always be performed rather than clinical examination unless the lesion(s) being followed cannot 
be imaged but are assessable by clinical exam. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (eg, for body scans). 
17.4.2. 
Tumor Response Evaluation 
17.4.2.1. 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. 
17.4.2.2. 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 15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor.  Nodal size is normally reported as 2 dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but <15 mm) should be considered non-target lesions.  Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. 


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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression.”  In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg, “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”). 
17.4.2.3. Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
17.4.2.3.1. 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 <10 mm. 
PR:  At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
PD:  At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm.   
SD:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
17.4.2.3.2. 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 zero even if CR criteria are 
met, since a normal lymph node is defined as having a short axis of <10 mm.  For PR, SD, and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become “too small to measure”:  While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes lesions or lymph 
nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
“too small to measure.”  When this occurs, it is important that a value be recorded on the eCRF.  
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 


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should be recorded as 0 mm.  If the lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned (note:  it is less likely that this rule 
will be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well).  This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness).  The 
measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error.  To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if 
it is below 5 mm. 
Lesions that split or coalesce on treatment:  When non-nodal lesions “fragment,” the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum.  
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the “coalesced lesion.” 
17.4.2.3.3. 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.  All lymph nodes must be non-pathological in size 
(<10 mm short axis). 
Non-CR/Non-PD:  Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
PD:  Unequivocal progression (see comments below) of existing non-target lesions. 
17.4.2.3.4. 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 
“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 


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non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable) a useful test that can be applied when assessing subjects for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease (ie, an increase in tumor burden representing an additional 
73% increase in ‘volume’ [which is equivalent to a 20% increase diameter in a measurable 
lesion]).  If ‘unequivocal progression’ is seen, the subject should be considered to have had 
overall PD at that point.  While it would be ideal to have objective criteria to apply to 
non-measurable disease, the very nature of that disease makes it impossible to do so, therefore 
the increase must be substantial. 
17.4.2.3.5. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of preexisting lesions).  This is particularly 
important when the subject’s baseline lesions show PR or CR.  For example, necrosis of a liver 
lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a F/U study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression.  An example of this is the subject 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases.  The subject’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and F/U 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
17.4.2.4. Evaluation of Best Overall Response 
 Best response in this study is defined as the best response across all time points (eg, a subject 
who has SD at first assessment, PR at second assessment, and PD on last assessment has a best 
overall response of SD).  When SD is believed to be best response, it must also meet the protocol 
specified minimum time from baseline, 6 weeks (± 7 days).  If the minimum time is not met 
when SD is otherwise the best time point response, the subject’s best response depends on the 
subsequent assessments.  For example, a subject who has SD at first assessment, PD at second 
and does not meet minimum duration for SD, will have a best response of PD.  The same subject 
lost to follow-up after the first SD assessment would be considered inevaluable. 
The subject’s best overall response assignment will depend on the findings of both target and 
non-target disease and will also take into consideration the appearance of new lesions. 


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17.4.2.4.1. Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 17.5 provides a summary of the overall response status calculation at each time point for 
subjects who have measurable disease at baseline. 
When subjects have non-measurable (therefore non-target) disease only, Table 17.6 is to be used. 
Table 17.5: 
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. 
Table 17.6: 
Overall Response: Subjects with Non-target Disease Only 
Time Point Response: Subjects with Non-target Disease Only 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; NE = inevaluable; PD = progressive disease. 
17.4.2.4.2. 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 are 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 PD.  For 
example, if a subject had a baseline sum of 50 mm with 3 measured lesions and at F/U only 


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2 lesions were assessed, but those gave a sum of 80 mm, the subject will have achieved PD 
status, regardless of the contribution of the missing lesion. 
17.4.2.4.3. Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject is known. 
Best response determination in this study where confirmation of CR or PR IS NOT required: 
Best response in this study is defined as the best response across all time points (eg, a subject 
who has SD at first assessment, PR at second assessment, and PD on last assessment has a best 
overall response of PR).  When SD is believed to be best response, it must also meet the protocol 
specified minimum time from baseline, 6 weeks (± 1 week).  If the minimum time is not met 
when SD is otherwise the best time point response, the subject’s best response depends on the 
subsequent assessments. 
17.4.2.4.4. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (<10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that subjects with CR may 
not have a total sum of “zero” on the eCRF. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such subjects is to be determined by evaluation of target and non-target disease. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
17.4.2.5. Frequency of Tumor Re-evaluation 
In this study, tumor measurement will be conducted every 6 weeks in the first 24 weeks after 
Day 1 of Cycle 1 and thereafter every 12 weeks while the subject remains on study until 
progression of disease, withdrawal of consent, death, or loss to F/U.  Scan dates should not be 
adjusted or rescheduled due to dose delay of any type. 
Baseline tumor assessments must be performed within 28 days of the first dose of study drug 
administration. 
All efforts should be made to ensure consistency between the baseline measurements and all 
subsequent measurements in reference to utilization of scanning method, equipment, technique 
(including slice thickness and field of view), and radiographic interpreter. 
The radiographic evaluation must include CT or MRI scanning of the brain, chest, abdomen, and 
pelvis at screening period.  Any additional suspected sites of disease should also be imaged.  


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Every effort should be made to use the same assessment modality for all assessments for each 
subject.  However, if there is no brain metastasis at the time of screening, CT or MRI should 
only be done when symptoms associated with brain metastasis occur during study period.  If no 
clinical symptoms are observed, brain CT or MRI is not mandatory during study period.  All 
evaluations should meet the standard of care for imaging of lesions in the respective organ(s) and 
should conform to the image acquisition guidelines according to institutional standards. 
All target and non-target sites are evaluated at each time point of tumor assessment. 
17.5. 
New York Heart Association Functional Classification 
Class 
Functional Capacity 
I 
No limitation of physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity.  Comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort.  Symptoms of heart 
failure at rest.  If any physical activity is undertaken, discomfort increases. 
Source: https://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-
Failure_UCM_306328_Article.jsp (Updated: Apr 23, 2014)  
17.6. 
Electronic Data Capture System 
The EDC system used for completing eCRF in this study is shown below. 
Name of EDC system 
Medidata Rave® 
EDC system developer 
Medidata Solutions Inc. 
Entry method 
Web-based data entry 
Input terminal 
Desktop/laptop computer at the study site 
Incompatible operating 
systems 
None 
Recommended browsers 
The Medidata Rave® supports any browser which is HTML 5 and CSS2 
compliant. Browsers must have JavaScript enabled. 
Screen Resolution 
The minimum screen resolution required to properly display Medidata 
Rave applications is 1024 × 764. 
Connection Speed 
128kbps is the minimum connection speed recommended for using 
Medidata Rave. 
Other 
Adobe Flash Player:  ver. 10 or above is required. 


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17.7. 
Supplement List 
Supplements are printed separately from protocol, and their versions are independent from study 
protocol.  Some supplement will be applied to specific study sites or specific country.  
Supplement 3, 4 and 5 is only submitted for Japanese site’s IRB. 
Supplements are listed as follow:  
 Supplement 1:  Serious Adverse Event Report (SAVER) form 
 Supplement 2:  EIU Reporting Form 
 Supplement 3:  Address list 
 Supplement 4:  The list of Study Centers and Investigators (for Japanese Study Center 
Only) 
 Supplement 5:  Compensation and Insurance (for Japanese Study Center Only) 
 Supplement 6:  Targeted Questionnaire 


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17.8. 
Schedule of Events 
Table 17.7: 
Schedule of Events (Dose Escalation Part) 
 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
subsequent 
cycles 
EOTa 
F/Ub 
Day 1 
Day 2 Day 4 Day 8 Day 
15 
(Day 
22)c 
Day 1 
Day 8 Day 
15 
(Day 
22)c 
Day 1 
Day 2 Day 4 Day 8 Day 
15 
(Day 
22)c 
Day 1 
 
 
BI 
EOI 
 
 
 
 
 
BI 
EOI 
 
 
 
BI 
EOI 
 
 
 
 
 
BI 
EOI 
 
 
± 1d 
± 1d 
± 1d 
(+ 2d) 
 
 
± 2d 
± 2d 
(± 2d) 
 
 
± 1d 
± 2d 
± 2d 
(± 2d) 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
the HER3 
statusd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration 
of U3-1402 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical 
examination, 
weight 
Xg 
Xf 
 
 
 
 
 
 
Xf 
 
 
 
 
Xf 
 
 
 
 
 
 
Xf 
 
X 
X 
ECOG PS 
Xe 
Xf 
 
 
 
 
 
 
Xf 
 
 
 
 
Xf 
 
 
 
 
 
 
Xf 
 
X 
X 
Vital sign 
Xe 
Xf 
X 
X 
X 
X 
X 
 
Xf 
X 
X 
X 
 
Xf 
X 
 
 
X 
X 
 
Xf 
 
X 
X 
SpO2 
Xf 
 
 
 
 
 
 
Xf 
 
 
 
 
Xf 
 
 
 
 
 
 
Xf 
 
X 
 


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Table 17.7: 
Schedule of Events (Dose Escalation Part) (Continued) 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
subsequent cycles 
EOTa F/Ub 
 
 
Day 1 
Day 
2 
Day 
4 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
Day 
2 
Day 
4 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
 
 
 
 
BI 
EOI 
 
 
 
 
 
BI 
EOI 
 
 
 
BI 
EOI 
 
 
 
 
 
BI 
EOI 
 
 
± 1d ± 1d ± 1d (+ 2d) 
 
 
± 2d ± 2d (± 2d) 
 
 
± 1d ± 2d ± 2d 
(± 2d) 
Ophthalmo-logic 
assessments 
Xg 
 
 
 
 
 
 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
Xh,i 
 
X 
 
ECHO or MUGA 
(LVEF) 
Xg 
 
 
 
 
 
 
 
Xf 
 
 
 
 
Xf 
 
 
 
 
 
 
Xf 
 
X 
 
12-lead ECG in 
triplicatej 
Xg 
Xk 
Xl,m 
Xn 
X 
 
 
X 
Xk 
 
 
 
 
Xk 
Xl,m 
Xp 
X 
 
 
X 
Xu 
 
X 
 
Laboratory tests 
Xe 
Xf 
X 
X 
X 
 
Xf 
X 
X 
 
Xf 
X 
X 
 
Xf 
 
X 
X 
PKx 
Xk,o Xl,m,o Xn,o 
Xo 
X 
X 
Xo 
Xk,o 
Xl 
X 
X 
X 
Xk,o Xl,m,o Xo,p 
Xo 
X 
X 
Xo 
Xk,o,q 
PK Sampling for 
CQ/HCQ 
Administration 
 
If CQ or HCQ is administered for COVID-19, and if subject provides consent, additional PK blood samples should be collected at the following visits: 
 Prior to the first CQ or HCQ dose (Day 1) 
 Day 3 or Day 4 of CQ or HCQ treatment, prior to CQ or HCQ dose (within 4h) 
 Last day of the CQ/HCQ treatment, prior to CQ/HCQ dose (within 4h) 
 The day of U3-1402 resumption, after the CQ/HCQ washout period*, (within 8h BI of U3-1402). 
* A washout period of more than 14 days is required before restarting U3-1402. 
 
 
ADA 
Xk 
 
 
 
X 
 
 
Xk 
 
 
 
 
 
 
 
 
Xk,r 
X 
Xs 
HER3ECD (blood) 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cTnI (blood) 
Xe,w 
Xv 
 
 
 
 
 
Xv 
 
 
 
Xv 
 
 
 
 
 
Xv 
Xw 
COVID-19Samplex 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xx 
 
Xx 
 
Tumor assessment 
Xd,g 
Xt 
Every 6 weeks ( ± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and thereafter every 12 weeks ( ± 7 days) 
X 
Concomitant 
medications 
 
X 
AEs 
X 
F/U = follow-up, BI = before infusion, EOI = end of infusion, EOT = end of treatment; .ADA = anti-drug antibody; AEs = adverse events; COVID-19 = coronavirus disease 2019; 
CQ/HCQ = chloroquine/hydroxychloroquine; cTnI = cardiac troponin I; cTnT = cardiac troponin T; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; h = hour; HER3 = human 
epidermal growth factor receptor 3; HER3ECD = human epidermal growth factor receptor 3 extracellular domain; ICF = informed consent form; MUGA = multiple gated acquisition scan; PK = 
pharmacokinetic; PS = performance status; LVEF = left ventricular ejection fraction; SCR = screening; SpO2 = oxygen saturation of peripheral artery.  


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a The date Investigator decides the discontinuation of the study treatment (+ 7 days). 
b 28 days (− 7 days) after the last study drug administration or before starting new anticancer treatment, whichever comes first. 
c If the schedule on Day 1 of the next cycle is delayed for 3 days or more, including if the subject cannot continue onto the next cycle. 
d Obtain a separate signed and dated ICF for examination of the tumor (confirmation of HER3 status and existence of a measurable lesion by RECIST version1.1). 
e Latest data within 7 days prior to enrollment. 
f Latest data within 3 days prior to infusion. 
g Latest data within 28 days prior to enrollment. 
h Latest data within 7 days prior to infusion. 
i Every 4 cycles from Cycle 5 to EOT (eg, Cycle 5, 9, 13...). 
j ECGs will be taken in close succession, a few minutes apart, after being in a supine/semi-recumbent position for 5 minutes. 
k Within 8 hours BI. 
l Within 30 minutes after EOI 
m 2, 4, 7 hours (± 15 minutes) after start of infusion. 
n 24 hours (± 2 hours) after the start of Day 1 infusion. 
o  Blood collection will be performed within 15 minutes after the end of ECG measurement. 
p 24 hours (- 2 to + 4 hours) after the start of Day 1 infusion. 
q Every 2 cycles from Cycle 4 to 8 (ie, Cycle 4, 6, 8). 
r Every 2 cycles from Cycle 4 to EOT (eg, Cycle 4, 6, 8, 10...). 
s For subjects with positive ADA at F/U visit, additional serum ADA samples may be collected every 3 months (± 1 month) up to 1 year from the last dose of study drug, or if the ADA becomes 
negative, or if ADA titer becomes less than baseline (applicable when pre-existing ADA is observed), or if the subject starts another therapy for cancer, or withdraws consent from the study, 
whichever occurs first. 
t Tumor assessments should not be delayed by dose interruptions; they are timed relative to Cycle 1, Day 1 and should continue until progressive disease or until a new anticancer therapy is started, 
whichever occurs first. 
u Within 8 hours BI for Cycle 4 only; then within 3 days prior to infusion for Cycle 5 and subsequent cycles. 
v Obtain a blood sample for cTnT (alternatively cTnI) 3 hours (± 1 hour) after the end of infusion of U3-1402 for on-site safety.  In addition, obtain a blood sample 3 hours (± 1 hour) after the end of 
infusion of U3-1402 for cTnI testing by central laboratory. 
w Obtain a blood sample for cTnT (alternatively cTnI) for on-site safety.  In addition, obtain a blood sample for cTnI testing by central laboratory. 
x If subject provides consent, obtain a serum sample prior to study drug infusion on Cycle 5, Day 1 and every 4 cycles thereafter, and at EOT. For subjects with suspected or confirmed COVID-19 
infections, follow the dose modifications in Appendix 17.9. 


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Table 17.8: 
Schedule of Events (Dose Finding [Q3W Dosing Cohorts] and Dose Expansion Parts) 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
subsequent 
cycles 
EOTa 
F/Ub 
Day 1 
Day 
2 
Day 
4 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
Day 
3 
Day 
8 
Day 
15 
Day 1 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
 
 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
 
 
 
± 1d 
± 1d 
± 1d 
(+ 2d) 
 
 
+ 
1d 
± 2d 
± 2d 
 
 
± 2d 
± 2d 
(± 2d) 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation 
of the HER3 
statusd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy 
Xe,r 
 
 
 
 
 
 
 
 
Xs,t 
 
 
 
 
 
 
 
 
 
Xx 
 
I/E Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration 
of U3-1402 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical 
examination, 
weight 
Xh 
Xg 
 
 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
X 
ECOG PS 
Xf 
Xg 
 
 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
X 
Vital sign 
Xf 
Xg 
X 
X 
X 
X 
X 
 
Xg 
X 
 
X 
X 
Xg 
X 
X 
X 
 
Xg 
 
X 
X 
SpO2 
Xg 
 
 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
 


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Table 17.8: 
Schedule of Events (Dose Finding [Q3W Dosing Cohorts] and Dose Expansion Parts) (Continued) 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
subsequent 
cycles 
EOTa 
F/Ub 
Day 1 
Day 
2 
Day 
4 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
Day 
3 
Day 
8 
Day 
15 
Day 1 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
 
 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
 
 
 
± 1d 
± 1d 
± 1d 
(+ 2d) 
 
 
+ 
1d 
± 2d 
± 2d 
 
 
± 2d 
± 2d 
(± 2d) 
 
 
 
 
Ophthalm-
ologic 
assessments 
Xh 
 
 
 
 
 
 
 
Xi 
 
 
 
 
 
 
 
 
Xi,j 
 
X 
 
ECHO or 
MUGA 
(LVEF) 
Xh 
 
 
 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
 
12-lead ECG 
in triplicatek 
Xh 
Xl 
Xm,v 
 
 
X 
 
Xl 
 
 
 
Xl 
Xm,v 
X 
 
 
Xg 
 
X 
 
Laboratory 
tests 
Xf 
Xg 
 
 
X 
X 
 
Xg 
 
X 
X 
Xg 
X 
X 
 
Xg 
 
X 
X 
PK 
Xl,y 
Xm,n,y 
X 
X 
Xy 
X 
X 
Xl 
Xm 
Xt,z 
 
 
Xl,y 
Xm,n,y 
Xy 
X 
X 
Xl,o 
Xbb 
PK Sampling 
for CQ/HCQ 
Administration 
 
If CQ or HCQ is administered for COVID-19, and if subject provides consent, additional PK blood samples should be collected at the following visits: 
 Prior to the first CQ or HCQ dose (Day 1) 
 Day 3 or Day 4 of CQ or HCQ treatment, prior to CQ or HCQ dose (within 4h) 
 Last day of the CQ/HCQ treatment, prior to CQ/HCQ dose (within 4h) 
 The day of U3-1402 resumption, after the CQ/HCQ washout period*, (within 8h BI of U3-1402). 
* A washout period of more than 14 days is required before restarting U3-1402. 
 
 
ADA 
Xl 
 
 
X 
Xl 
 
Xl,p 
X 
Xq 
cfDNA, 
cfRNA 
 
Xl,t 
 
 
 
 
 
 
 
 
Xt,z 
 
 
 
 
 
 
 
 
 
Xt 
 
HER3ECD 
(blood) 
Xf,w 
Xl,t 
 
 
 
Xt,z 
 
  
 
 
Xt 
 
cTnI (blood) 
Xf,cc 
Xaa 
 
 
Xaa 
 
Xaa 
Xaa 
Xcc 
COVID-19 
Sample dd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xdd 
 
Xdd 
 
Tumor 
assessment 
Xd,h 
Xu 
Every 6 weeks ( ± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and thereafter every 12 weeks ( ± 7 days) 
X 
Concomitant 
medications 
X 
AEs 
X 
COVID-19 = coronavirus disease 2019; CQ/HCQ = chloroquine/hydroxychloroquine; SCR =screening; F/U = follow-up; BI = before infusion; EOI = end of infusion; EOT = end of treatment; ADA = 
anti-drug antibody; AEs = adverse events; cfDNA = cell-free DNA; cdRNA = cell-free RNA; cTnI = cardiac troponin I; cTnT = cardiac troponin T; ECG = electrocardiogram; ECOG = Eastern 


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Cooperative Oncology Group; HER3 = human epidermal growth factor receptor 3; h = hour; HER3ECD = human epidermal growth factor receptor 3 extracellular domain; ICF = informed consent form; 
LVEF = left ventricular ejection fraction; MUGA = multiple gated acquisition scan;  PK = pharmacokinetic; PS = performance status. 
a The date Investigator decides to discontinue study drug (+ 7 days). 
b 28 days (− 7 days) after the last dose of study drug or before starting new anticancer treatment, whichever comes first. 
c If the schedule on Day 1 of the next cycle is delayed for 3 days or more, including if the subject cannot continue onto the next cycle. 
d Obtain a separate signed and dated ICF for examination of the tumor. 
e Perform a fresh tumor biopsy for subjects with HER3-positive tumor tissue that was assayed using an archived tumor tissue sample.  This is mandatory in Dose Expansion Part and optional in Dose 
Finding Part. 
f Latest data within 7 days prior to enrollment. 
g Latest data within 3 days of infusion. 
h Latest data within 28 days prior to enrollment. 
i Latest data within 7 days of infusion. 
j Every 4 cycles from Cycle 5 to EOT (eg, Cycle 5, 9, 13...). 
k ECGs will be taken in close succession, a few minutes apart, after being in a supine/semi-recumbent position for 5 minutes. 
l Within 8 hours BI. 
m Within 30 minutes after EOI. 
n 2, 4, 7 hours (± 15 minutes) after the start of infusion.  
o Only in Cycle 4, Day 1; Cycle 5, Day1; Cycle 6, Day 1; and Cycle 8, Day 1. 
p Every 2 cycles from Cycle 4 to EOT (eg, Cycle 4, 6, 8, 10...). 
q For subjects with positive ADA at F/U visit, additional serum ADA samples may be collected every 3 months (± 1 month) up to 1 year from the last dose of study drug, or if the ADA becomes 
negative, or if ADA titer becomes less than baseline (applicable when pre-existing ADA is observed), or if the subject starts another therapy for cancer, or withdraws consent from the study, 
whichever occurs first. 
r Mandatory in Dose Expansion Part. 
s [Optional] In Dose Expansion Part only, approximately 48 to 72 hours after EOI on Cycle 2, Day 1.  Additionally, blood samples for HER3ECD, cfDNA, cfRNA and PK should be collected ±4 hours 
from the time of this optional biopsy, if obtained. Consent for this biopsy should be documented in the tissue consent portion of the ICF. Tumor tissue from this biopsy may be obtained from primary 
tumor or metastatic site. 
t In Dose Expansion Part only. 
u Tumor assessments should not be delayed by dose interruptions; they are timed relative to Cycle 1, Day 1 and should continue until progressive disease or until a new anticancer therapy is started, 
whichever occurs first. 
v 4 hours (± 15 minutes) after start of infusion.  
w Dose Finding Part only 
x [Optional] In Dose Expansion Part only. 
y Blood collection will be performed within 15 minutes after the end of ECG measurement. 
z ± 4 hours from the time of the optional on-study tumor biopsy, if obtained. 
aa Obtain a blood sample for cTnT (alternatively cTnI) 3 hours (± 1 hour) after the end of infusion of U3-1402 for on-site safety.  Obtain a blood sample 3 hours (± 1 hour) after the end of infusion of 
U3-1402 for cTnI testing by central laboratory. 
bb [Cycle 5, Day 1 only] Blood for PK should be collected within 30 minutes after EOI and 2, 4, and 7 hours (± 15 minutes) after the start of infusion. 
cc Obtain a blood sample for cTnT (alternatively cTnI) for on-site safety.  In addition, obtain a blood sample for cTnI testing by central laboratory. 
dd If subject provides consent, obtain a serum sample prior to study drug infusion on Cycle 5, Day 1 and every 4 cycles thereafter, and at EOT. For subjects with suspected or confirmed COVID-19 
infections, follow the dose modifications in Appendix 17.9. 
 


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Page 164 
Table 17.9: 
Schedule of Events (Dose Finding Part [Q2W Dosing Cohorts]) 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
and 
subsequent 
cycles 
EOTa 
F/Ub 
Day 1 
Day 
4 
Day 
8 
(Day 
15)c 
Day 1 
Day 
8 
Day 1 
Day 
4 
Day 
8 
(Day 
15)c 
Day 1 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
 
 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
 
 
± 1d 
± 1d 
(+ 2d) 
 
 
± 2d 
 
 
± 1d 
± 2d 
(± 2d) 
 
 
± 2d 
± 2d 
(± 2d) 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation 
of the HER3 
statusd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration 
of U3-1402 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical 
examination, 
weight 
Xh 
Xg 
 
 
 
 
Xg 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
X 
ECOG PS 
Xf 
Xg 
 
 
 
 
Xg 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
X 
Vital sign 
Xf 
Xg 
X 
X 
X 
 
Xg 
X 
X 
Xg 
X 
 
X 
 
Xg 
X 
X 
X 
 
Xg 
 
X 
X 
SpO2 
Xg 
 
 
 
 
Xg 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
 
Ophthalm-
ologic 
assessments 
Xh 
 
 
 
 
 
Xi 
 
 
 
 
 
 
 
 
 
 
 
Xi,j 
 
X 
 


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Table 17.9: 
Schedule of Events (Dose Finding Part [Q2W Dosing Cohorts]) (Continued) 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
and 
subsequent 
cycles 
EOTa 
F/Ub 
Day 1 
Day 
4 
Day 
8 
(Day 
15)c 
Day 1 
Day 
8 
Day 1 
Day 
4 
Day 
8 
(Day 
15)c 
Day 1 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
 
 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
 
 
± 1d 
± 1d 
(+ 2d) 
 
 
± 2d 
 
 
± 1d 
± 2d 
(± 2d) 
 
 
± 2d 
± 2d 
(± 2d) 
 
 
 
 
ECHO or 
MUGA 
(LVEF) 
Xh 
 
 
 
 
 
Xg 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
 
12-lead ECG 
in triplicatek 
Xh 
Xl 
 
 
 
 
Xl 
 
 
Xl 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
 
Laboratory 
tests 
Xf 
Xg 
 
X 
 
Xg 
X 
Xg 
 
X 
 
Xg 
 
X 
X 
 
Xg 
 
X 
X 
PKv 
Xl 
Xm,n 
X 
X 
X 
Xl 
Xm 
 
Xl 
Xm,n 
X 
X 
X 
Xl 
Xm,n 
X 
X 
X 
Xl,o 
Xm,u 
PK Sampling 
for CQ/HCQ 
Administration 
 
If CQ or HCQ is administered for COVID-19, and if subject provides consent, additional PK blood samples should be collected at the following visits: 
 Prior to the first CQ or HCQ dose (Day 1) 
 Day 3 or Day 4 of CQ or HCQ treatment, prior to CQ or HCQ dose (within 4h) 
 Last day of the CQ/HCQ treatment, prior to CQ/HCQ dose (within 4h) 
 The day of U3-1402 resumption, after the CQ/HCQ washout period*, (within 8h BI of U3-1402). 
* A washout period of more than 14 days is required before restarting U3-1402. 
 
 
ADA 
Xl 
 
X 
 
Xl 
 
Xl 
 
 
 
 
Xl,p) 
X 
Xq 
HER3ECD 
(blood) 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cTnI (blood) 
Xf,s 
Xt 
 
 
Xt 
Xt 
 
 
Xt 
 
 
 
Xt 
Xs 
COVID-19 
Samplev 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xv 
 
Xv 
 
Tumor 
assessment 
Xd,h 
Xr 
Every 6 weeks ( ± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and thereafter every 12 weeks ( ± 7 days) 
X 
Concomitant 
medications 
X 
AEs 
X 


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Page 166 
CQ/HCQ = chloroquine/hydroxychloroquine; SCR = screening; F/U = follow-up; BI = before infusion; EOI = end of infusion; EOT = end of treatment; ADA = anti-drug antibody; AEs = adverse 
events; cTnI = cardiac troponin I; cTnT = cardiac troponin T; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HER3 = human epidermal growth factor receptor 3; HER3ECD 
= human epidermal growth factor receptor 3 extracellular domain; ICF = informed consent form; LVEF = left ventricular ejection fraction; MUGA = multiple gated acquisition scan;  PK = 
pharmacokinetic; PS = performance status; RECIST = Response Evaluation Criteria in Solid Tumors; SpO2 = oxygen saturation of peripheral artery. 
a The date Investigator decides to discontinue study drug (+ 7 days). 
b 28 days (− 7 days) after the last dose of study drug or before starting new anticancer treatment, whichever comes first. 
c If the schedule on Day 1 of the next cycle is delayed for 3 days or more, including if the subject cannot continue onto the next cycle. 
d Obtain a separate signed and dated ICF for examination of the tumor (confirmation of HER3 status and existence of a measurable lesion by RECIST version 1.1). 
e  [Optional] Perform a tumor biopsy for subjects with an archived sample for confirmation of the HER3 status in a fresh tumor tissue. 
f Latest data within 7 days prior to enrollment. 
g Latest data within 3 days prior to infusion. 
h Latest data within 28 days prior to enrollment. 
i Latest data within 7 days prior to infusion. 
j Every 4 cycles from Cycle 5 to EOT (eg, Cycle 5, 9, 13...). 
k ECGs will be taken in close succession, a few minutes apart, after being in a supine/semi-recumbent position for 5 minutes. 
l Within 8 hours BI. 
m Within 30 minutes after EOI. 
n 2, 4, 7 hours (± 15 minutes) after the start of administration. 
o Only in Cycle 5, Day1; Cycle 6, Day 1; and Cycle 8, Day 1. 
p Every 2 cycles from Cycle 6 to EOT (eg, Cycle 6, 8, 10...). 
q For subjects with positive ADA at F/U visit, additional serum ADA samples may be collected every 3 months (± 1 month) up to 1 year from the last dose of study drug, or if the ADA becomes 
negative, or if ADA titer becomes less than baseline (applicable when pre-existing ADA is observed), or if the subject starts another therapy for cancer, or withdraws consent from the study, 
whichever occurs first. 
r Tumor assessments should not be delayed by dose interruptions; they are timed relative to Cycle 1, Day 1 and should continue until progressive disease or until a new anticancer therapy is started, 
whichever occurs first. 
s Obtain a blood sample for cTnT (alternatively cTnI) for on-site safety.  In addition, obtain a blood sample for cTnI testing by central laboratory. 
t Obtain a blood sample for cTnT (alternatively cTnI) 3 hours (± 1 hour) after the end of infusion of U3-1402 for on-site safety.  Obtain a blood sample 3 hours (± 1 hour) after the end of infusion of 
U3-1402 for cTnI testing by central laboratory. 
u [Cycle 6, Day 1 only] Blood for PK should be collected 2, 4, 7 hours (± 15 minutes) after the start of infusion. 
v If subject provides consent, obtain a serum sample prior to study drug infusion on Cycle 5, Day 1 and every 4 cycles thereafter, and at EOT. For subjects with suspected or confirmed COVID-19 
infections, follow the dose modifications in Appendix 17.9. 
 


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Page 167 
Table 17.10: Schedule of Events (Dose Finding Part [Q3W with Up-titration Cohorts]) 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
subsequent 
cycles 
EOTa 
F/Ub 
Day 1 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
Day 8 
Day 
15 
(Day 
22)c 
Day 1 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
 
 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
 
 
± 1d 
± 1d 
(+ 2d) 
 
 
± 2d 
± 2d 
(± 2d) 
 
 
± 2d 
± 2d 
(± 2d) 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation 
of the HER3 
statusd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration 
of U3-1402 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Physical 
examination, 
weight 
Xh 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
X 
ECOG PS 
Xf 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
X 
Vital sign 
Xf 
Xg 
X 
X 
X 
 
Xg 
X 
X 
X 
 
Xg 
X 
X 
X 
 
Xg 
 
X 
X 
SpO2 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
 
Ophthalm-
ologic 
assessments 
Xh 
 
 
 
 
 
Xi 
 
 
 
 
 
 
 
 
Xi,j 
 
X 
 


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Page 168 
Table 17.10: Schedule of Events (Dose Finding Part [Q3W with Up-titration Cohorts]) (Continued) 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
subsequent 
cycles 
EOTa 
F/Ub 
Day 1 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
Day 8 
Day 
15 
(Day 
22)c 
Day 1 
Day 
8 
Day 
15 
(Day 
22)c 
Day 1 
 
 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
 
 
± 1d 
± 1d 
(+ 2d) 
 
 
± 2d 
± 2d 
(± 2d) 
 
 
± 2d 
± 2d 
(± 2d) 
 
 
 
 
ECHO or 
MUGA 
(LVEF) 
Xh 
 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
 
 
 
Xg 
 
X 
 
12-lead ECG 
in triplicatek 
Xh 
Xl 
 
 
 
 
Xl 
 
 
 
 
Xl 
 
 
 
 
Xg 
 
X 
 
Laboratory 
tests 
Xf 
Xg 
X 
X 
 
Xg 
X 
X 
Xg 
X 
X 
 
Xg 
 
X 
X 
PK 
Xl 
Xm,n 
X 
X 
X 
Xl 
Xm,n 
X 
X 
X 
Xl 
Xm,n 
X 
X 
X 
Xl,o 
Xs,u 
PK Sampling 
for CQ/HCQ 
Administration 
 
If CQ or HCQ is administered for COVID-19, and if subject provides consent, additional PK blood samples should be collected at the following visits: 
 Prior to the first CQ or HCQ dose (Day 1) 
 Day 3 or Day 4 of CQ or HCQ treatment, prior to CQ or HCQ dose (within 4h) 
 Last day of the CQ/HCQ treatment, prior to CQ/HCQ dose (within 4h) 
 The day of U3-1402 resumption, after the CQ/HCQ washout period*, (within 8h BI of U3-1402). 
* A washout period of more than 14 days is required before restarting U3-1402. 
 
 
ADA 
Xl 
X 
Xl 
Xl,p 
X 
Xq 
HER3ECD 
(blood) 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cTnI (blood) 
Xf,v 
Xt 
 
Xt 
Xt 
Xt 
Xv 
COVID-19 
Samplew 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xw 
 
Xw 
 
Tumor 
assessment 
Xd,h 
Xr 
Every 6 weeks ( ± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and thereafter every 12 weeks ( ± 7 days) 
X 
Concomitant 
medications 
X 
AEs 
 
X 
COVID-19 = coronavirus disease 2019; CQ/HCQ = chloroquine/hydroxychloroquine; SCR =  screening; F/U = follow-up; BI = before infusion; EOI = end of infusion; EOT = end of treatment; ADA = 
anti-drug antibody; AEs = adverse events; cTnI = cardiac troponin I; cTnT = cardiac troponin T; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HER3 = human epidermal 


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Proprietary and Confidential 
Page 169 
growth factor receptor 3; HER3ECD = human epidermal growth factor receptor 3 extracellular domain; LVEF = left ventricular ejection fraction; MUGA = multiple gated acquisition scan;  PK = 
pharmacokinetic; PS = performance status. 
a The date Investigator decides to discontinue study drug (+ 7 days). 
b 28 days (− 7 days) after the last dose of study drug or before starting new anticancer treatment, whichever comes first. 
c If the schedule on Day 1 of the next cycle is delayed for 3 days or more, including if the subject cannot continue onto the next cycle. 
d Obtain a separate signed and dated ICF for examination of the tumor (Confirmation of HER3 status and existence of a measurable lesion by RECIST version 1.1). 
e [Optional] Perform a tumor biopsy for subjects with an archived sample for confirmation of the HER3 status in a fresh tumor tissue. 
f Latest data within 7 days prior to enrollment. 
g Latest data within 3 days of infusion. 
h Latest data within 28 days prior to start of enrollment. 
i Latest data within 7 days of infusion. 
j Every 4 cycles from Cycle 5 to EOT (eg, Cycle 5, 9, 13...). 
k ECGs will be taken in close succession, a few minutes apart, after being in a supine/semi-recumbent position for 5 minutes. 
l Within 8 hours BI. 
m Within 30 minutes after EOI. 
n 2, 4, 7 hours (± 15 minutes) after the start of infusion. 
o On Cycle 4, 5, 6, and 8. 
p Every 2 cycles from Cycle 4 to EOT (eg, Cycle 4, 6, 8, 10...). 
q For subjects with positive ADA at F/U visit, additional serum ADA samples may be collected every 3 months (± 1 month) up to 1 year from the last dose of study drug, or if the ADA becomes 
negative, or if ADA titer becomes less than baseline (applicable when pre-existing ADA is observed), or if the subject starts another therapy for cancer, or withdraws consent from the study, 
whichever occurs first. 
r Tumor assessments should not be delayed by dose interruptions; they are timed relative to Cycle 1, Day 1 and should continue until progressive disease or until a new anticancer therapy is started, 
whichever occurs first. 
s [Cycle 5, Day 1 only] Blood for PK should be collected 2, 4, and 7 hours (± 15 minutes) after the start of infusion. 
t Obtain a blood sample for cTnT (alternatively cTnI) 3 hours (± 1 hour) after the end of infusion of U3-1402 for on-site safety.  Obtain a blood sample 3 hours (± 1 hour) after the end of infusion of 
U3-1402 for cTnI testing by central laboratory. 
u [Cycle 5, Day 1 only] Within 30 minutes after EOI. 
v Obtain a blood sample for cTnT (alternatively cTnI) for on-site safety.  In addition, obtain a blood sample for cTnI testing by central laboratory. 
w If subject provides consent, obtain a serum sample prior to study drug infusion on Cycle 5, Day 1 and every 4 cycles thereafter, and at EOT. For subjects with suspected or confirmed COVID-19 
infections, follow the dose modifications in Appendix 17.9. 
 


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17.9. 
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 COVID-19 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 17.11 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 17.11: 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 resolved 
Grade 3 
Reduce by 1 dose level if chest CT findings are 
completely resolved 
Discontinue study drug if chest CT findings are 
not completely resolved 
Grade 4 
Discontinue study drug 
COVID-19 = coronavirus 2019; CT = computed tomography 
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 17.11, Investigators may consider dose 
modifications of the study drug according to the subject’s 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; 
 Concomitant treatment is not allowed during the study treatment. 
 If treatment is absolutely required for COVID-19, U3-1402 must be interrupted. 
 If administered, then a washout period of more 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 (Appendix 17.8 ). 
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.   
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 (Section 17.8), shipped to a central laboratory, and stored there until 
the tests become available. 
If subjects consent, 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. 


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