Conditions: Breast Cancer Urothelial Carcinoma
Keywords: Human epidermal growth factor receptor-2 HER2 Refractory Metastatic Urothelial cancer Breast Cancer
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 86
Healthy volunteers: no

Brief summary:
This is a study of trastuzumab deruxtecan for the treatment of HER2-positive unresectable or metastatic breast cancer following two or more prior anti-HER2 based regimens.

Participants will receive this study drug along with a cancer drug, an immune checkpoint inhibitor, anti-PD1, called nivolumab.

The study will be done in two parts:

* Part 1 is to identify the recommended dose to use for treatment.
* Part 2 is to find out how well the combination works, and how safe and tolerable it is.

Detailed description:
The purpose of this phase 1b (Part 1, Part 2) study is to assess the combination of a test drug (trastuzumab deruxtecan) with nivolumab in participants with HER2-expressing breast and urothelial cancer who had disease progression during or after prior therapies, did not respond to standard therapies, or for whom no standard therapy is available.

The study will be performed in 2 parts.

* Part 1 is to test different doses of trastuzumab deruxtecan when given along with a fixed dose of nivolumab, and establish the maximum tolerated dose/recommended dose for expansion, when used in combination with nivolumab
* Part 2 is to assess the efficacy and safety of this dose combination.

Arms:
arm 1: Participants with HER2-expressing breast cancer who received starting intravenous dose of trastuzumab deruxtecan at 3.2 mg/kg and a fixed intravenous dose of 360mg of nivolumab every 3 weeks (Q3W).

Escalating/de-escalating doses of trastuzumab deruxtecan in combination with a flat dose of nivolumab was administered on Day 1 of each 21-day cycle.

The DLT observation period will be the first 2 cycles. arm 2: Participants with HER2-expressing breast cancer who received starting intravenous dose of trastuzumab deruxtecan at 3.2 mg/kg and a fixed intravenous dose of 360mg of nivolumab every 3 weeks (Q3W).

Escalating/de-escalating doses of trastuzumab deruxtecan in combination with a flat dose of nivolumab was administered on Day 1 of each 21-day cycle.

The DLT observation period will be the first 2 cycles. arm 3: Cohort 1: Participants with pathologically documented advanced/metastatic breast cancer that has centrally-determined positive HER2 expression (IHC 3+ or IHC 2+/ISH+) \[as defined by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines\]. These participants received prior ado-trastuzumab emtansine (T-DM1).

Participants will receive the RDE of trastuzumab deruxtecan and the flat dose of nivolumab. arm 4: Cohort 2: Participants with pathologically documented advanced/metastatic breast cancer that has centrally-determined low HER2 expression (IHC 1+ or IHC 2+/ISH-), who have exhausted treatments that can confer any clinically meaningful benefit (eg, other therapies such as hormonal therapy for patients who are hormone receptor positive).

Participants received the RDE of trastuzumab deruxtecan and the flat dose of nivolumab. arm 5: Cohort 3: Participants with pathologically documented advanced/metastatic urothelial carcinoma that has centrally-determined HER2 expression of IHC 2+ or 3+, who received prior platinum-based therapy with documented progression.

Participants received the RDE of trastuzumab deruxtecan and the flat dose of nivolumab. arm 6: Cohort 4: Participants with pathologically documented advanced/metastatic urothelial carcinoma that has centrally-determined HER2 expression of IHC 1+, who received prior platinum-based therapy with documented progression.

Participants received the RDE of trastuzumab deruxtecan and the flat dose of nivolumab.

Interventions: intervention 1: Trastuzumab deruxtecan intervention 2: Nivolumab
Intervention descriptions: intervention 1: The investigational product is a sterile lyophilized powder, which is made into solution for intravenous administration. intervention 2: Nivolumab is an aqueous solution formulated at 10 mg/mL to be administered at a flat dose of 360 mg IV over 30 minutes. Protocol-defined thyroid testing is required while taking nivolumab.

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
Page 1 
 
 
CLINICAL STUDY PROTOCOL 
A PHASE 1B, MULTICENTER, TWO-PART, OPEN-LABEL STUDY OF 
TRASTUZUMAB DERUXTECAN, AN ANTI-HUMAN EPIDERMAL 
GROWTH FACTOR RECEPTOR-2 (HER2)-ANTIBODY DRUG 
CONJUGATE (ADC), IN COMBINATION WITH NIVOLUMAB, AN 
ANTI-PD-1 ANTIBODY, FOR SUBJECTS WITH HER2-EXPRESSING 
ADVANCED BREAST AND UROTHELIAL CANCER 
DS8201-A-U105 
 
IND NUMBER 127553/EudraCT 2018-000371-32 
 
VERSION 6.0, 15 JUNE 2020 
 
DAIICHI SANKYO, INC. 
211 MOUNT AIRY ROAD 
BASKING RIDGE, NJ 07920 
 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo Inc.  The information is 
provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement.  Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
Daiichi Sankyo Inc. 




Protocol DS8201-A-U105 
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DOCUMENT HISTORY 
Version Number 
Version Date 
6.0 
15 June 2020 
5.0 
18 Nov 2019 
4.0 
30 April 2019 
3.0 
04 Jan 2019 
2.0 
01 July 2018 
1.0 
09 Feb 2018 
 


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SUMMARY OF CHANGES 
Please refer to the comparison document for protocol Version 6.0 (dated 15 June 2020) vs. 
protocol Version 5.0 (dated 18 Nov 2019) for actual changes in text.  The summary of changes 
below is a top-line summary of main changes in the current DS8201-A-U105 clinical study 
protocol (Version 6.0) by section. 
Amendment Rationale: 
This amendment is primarily driven by the inclusion of an interim analysis for subjects that were 
enrolled in the breast cohorts in Part 1 and Part 2 that achieved at least 12 weeks of follow-up or 
have discontinued study treatment.  The objective of the interim analysis is to obtain preliminary 
efficacy and safety data of the study treatment that could inform further clinical development.  
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it does not significantly impact the safety or physical/mental integrity of subjects 
nor the scientific value of the study. 
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 document. 
Minor edits, such as update to language that does 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 change in case, are 
not noted in the table below. 
Section # and Title 
Description of Change 
Brief Rationale 
Protocol Synopsis 
 
2.3.5 
Pharmacokinetic/Pharmacodynamic 
/Biomarker Endpoint(s) 
The pharmacokinetic (PK) and biomarker 
endpoints were updated 
To provide 
clarification 
Protocol Synopsis 
 
4.1.  
Inclusion Criteria 
Presentation of the Cockcroft-Gault 
equation in criterion #8 was updated. 
 
 Use of 
Chloroquine/Hydroxychloroquine was 
added to criterion #11.   
 
 
To align with the 
latest safety 
information 


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Protocol Synopsis 
 
4.1.  
Inclusion Criteria 
 
9.7. 
Exposure in Utero during Clinical 
Studies 
The contraception periods for males and 
females were updated to 7 months each. 
To align with the 
latest safety 
information 
5.2.4.1.  
Maximum Duration of Treatment 
with Nivolumab 
This section was updated to include the 
maximum number of cycles treatment 
with nivolumab will be administered in 
the absence of disease progression or 
unacceptable toxicity. 
To provide 
clarification 
5.5.1.  
Guidelines for Delay, Reduction 
and/or Discontinuation for 
Trastuzumab Deruxtecan and 
Nivolumab 
The following sentence was added: 
All confirmed or suspected SARS-CoV-2 
infection events must be recorded in the 
eCRF.  Please refer to Appendix 17.8 for 
additional information on dose 
modification. 
To include 
management 
guidelines for 
SARS-CoV-2 
infection (ie, 
COVID-19) 
Table 5.1  
Criteria for Dose Modification for 
Trastuzumab Deruxtecan and 
Nivolumab 
The table was updated   
To align with the 
latest safety 
information 
5.7. 
Prior and Concomitant Medications 
Nivolumab was added to this section 
because Investigators are required to 
record concomitant treatment up to 40 
days (+7 days) after the last dose of 
trastuzumab deruxtecan or nivolumab    
To provide 
clarification 
Table 5.1  
Management Guidelines  
Guidelines for managing cardiac, 
pulmonary and hepatic toxicities were 
updated 
To align with the 
latest safety 
information 
Table 6.1 
End of Combination Treatment 
(EOCT) Assessments 
The table was updated 
To provide 
clarification 
6.1.2 
Screening 
Troponin testing was removed from the 
list of assessments to be performed when 
a subject reports signs or symptoms 
suggesting congestive heart failure, 
myocardial infarction, or other causes of 
myocyte necrosis. 
To align with the 
latest safety 
information 


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6.6 
Additional PK assessments due to 
SARS-CoV-2 infection 
 
Table 8.2  
Schedule of PK Sample Collections 
in case of Chloroquine and 
Hydroxychloroquine Treatment 
The section and table were added.  
To monitor potential 
drug-drug 
interactions between 
investigational/study 
drug treatment and 
SARS-CoV-2 
infection (ie, 
COVID-19) specific 
treatment 
8.3.  
Immunogenicity 
This section was updated. 
 
To align with the 
latest changes to 
anti-drug antibody 
analyses  
9.2.  
Adverse Event Collection and 
Reporting 
This section was updated 
To provide 
clarification and 
to align with the 
latest safety 
information 
9.3.1.3.  
Interstitial Lung Disease 
Adjudication Committee 
This section was updated 
To align with the 
latest safety 
information 
9.4.  
Adverse Events 
This section was updated 
To provide 
clarification 
9.5. 
Serious Adverse Events and 
Adverse Event of Special Interest 
Reporting–Procedure For 
Investigators 
This section was updated 
To align with the 
latest safety 
information 
9.8. Clinical Laboratory 
Evaluations 
The description of Troponin testing was 
updated and testing by local laboratory 
deleted 
To align with the 
latest safety 
information 
11.1. 
 
General Statistical Considerations 
This section was updated 
To introduce an 
interim analysis 
11.2  
Analysis Sets 
The definition of Full Analysis Set (FAS) 
was updated 
 
Safety Analysis Set (SAF) was added 
To introduce an 
interim analysis 
11.4  
Efficacy Analyses 
This section and its subsections were 
updated  
To introduce an 
interim analysis 
11.6  
Interim Analysis 
This section was added 
To introduce an 
interim analysis 


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Table 17.1  
Schedule of Events 
The table was updated 
To provide 
clarification 
To align with the 
latest safety 
information 
17.8 
Instructions related to 
SARS-CoV-2 infection 
This section was added. 
To provide 
management 
guidelines for 
SARS-CoV-2 
infection (ie, 
COVID-19) 
Throughout the protocol 
The phrase, “interstitial lung disease 
(ILD)” was replaced by “interstitial lung 
disease (ILD)/pneumonitis” 
To align with the 
latest safety 
information 
 


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PROTOCOL SYNOPSIS 
EudraCT: 
2018-000371-32 
IND Number: 
127553 
Protocol Number: 
DS8201-A-U105 
Investigational Product: 
Trastuzumab deruxtecan and nivolumab 
Active 
Ingredient(s)/International 
Non-proprietary Name: 
Trastuzumab deruxtecan consists of an antibody component, 
MAAL-9001, covalently conjugated via a maleimide 
tetrapeptide linker, to a drug component MAAA-1181a. 
Nivolumab is a human monoclonal antibody directed against 
the programmed death 1 (PD-1) receptor.  
Study Title: 
A Phase 1b, Multicenter, Two-Part, Open-Label Study of 
trastuzumab deruxtecan, an Anti-Human Epidermal Growth 
Factor Receptor-2 (HER2)-Antibody Drug Conjugate (ADC), 
in Combination with Nivolumab, an Anti-PD-1 Antibody, for 
Subjects with HER2-Expressing Advanced Breast and 
Urothelial Cancer  
Study Phase: 
Phase 1b 
Indication Under 
Investigation: 
Combination therapy with trastuzumab deruxtecan and 
nivolumab will be evaluated in subjects with HER2-
expressing advanced/metastatic solid tumors.  This study will 
enroll HER2-expressing breast or urothelial cancer subjects 
that are refractory to standard therapies or for which no 
standard therapy is available.  Part 1 enrollment will start 
first.  Part 2 will start enrolling after completion of Part 1 and 
determination of recommended expansion dose 
(RDE)/maximum tolerated dose (MTD). 
Study Objectives: 
Primary Objectives: 
 To determine the MTD or the RDE of trastuzumab 
deruxtecan when used in combination with 
nivolumab (Part 1). 
 To evaluate the efficacy of combination treatment 
with trastuzumab deruxtecan and nivolumab in 
HER2-expressing advanced breast cancer as well 
as HER2-expressing advanced urothelial cancer 
(Part 2). 


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Secondary Objectives: 
 To assess the safety and tolerability of the 
combination of trastuzumab deruxtecan and 
nivolumab.  
 To determine the pharmacokinetics (PK) of 
trastuzumab deruxtecan when dosed 
concomitantly with nivolumab.  
 To further evaluate the efficacy of the 
combination of trastuzumab deruxtecan and 
nivolumab. 
Exploratory Objectives: 
 To evaluate the efficacy of the combination of 
trastuzumab deruxtecan and nivolumab by using 
the immune Response Evaluation Criteria in Solid 
Tumors (iRECIST) guidelines as assessed by the 
study investigator (Part 2) 
 To further evaluate the efficacy of the 
combination of trastuzumab deruxtecan and 
nivolumab in terms of clinical benefit rate (CBR) 
in breast cancer cohorts.  
 To perform biomarker analyses related to the 
combination to understand the mechanism of 
action and resistance based on pretreatment, 
post-treatment, and on-treatment biopsies. 
 To evaluate the immunogenicity of trastuzumab 
deruxtecan and nivolumab (if analyzed) 
Study Design: 
This is a Phase 1b, open-label, 2-part, multicenter, non-
randomized, multiple-dose study of trastuzumab deruxtecan 
in combination with nivolumab.  The study will include both 
a dose escalation part, to identify the RDE/MTD of 
trastuzumab deruxtecan in combination with nivolumab and a 
dose expansion part, to evaluate efficacy, safety, and 
tolerability. 
Part 1 (Dose Escalation) 
Part 1 will enroll subjects meeting the eligibility criteria set 
up for any of the 4 cohorts of Part 2 specified below using a 3 
+ 3 + 3 design.  As noted in the table below, escalating doses 
of trastuzumab deruxtecan in combination with nivolumab 


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will be assessed.  Trastuzumab deruxtecan and nivolumab 
will be administered on Day 1 of each 21-day cycle. 
Dose Escalation of Trastuzumab deruxtecan 
Dose Level Trastuzumab deruxtecan Nivolumab 
1  
3.2 mg/kg  Q3W 
360 mg 
2  
5.4 mg/kg  Q3W  
360 mg 
Enrollment starts at 3.2 mg/kg trastuzumab deruxtecan and 
360 mg nivolumab combination.  Escalation/de-escalation to 
the next dose will be based on an acceptable safety signal 
from the earlier dose cohort.  Escalations from the start dose 
of either trastuzumab deruxtecan or nivolumab for individual 
subjects are not allowed.  Additionally, dose reduction for 
nivolumab is not permitted.  
The dose-limiting toxicity (DLT) observation period will be 
2 cycles (6 weeks).  Upon completion of the DLT 
observation period, subjects may continue to receive study 
treatments in subsequent cycles as previously described, until 
unacceptable toxicity, progressive disease (PD), or 
withdrawal of consent.  Subjects may continue to receive 
nivolumab beyond disease progression if the investigator 
believes this will provide clinical benefit to the subject. 
Nivolumab treatment can continue for a maximum of 24 
months (approximately 35 cycles).   
Part 2 (Dose Expansion) 
Upon completion of dose escalation (Part 1) with 
determination of RDE, the dose expansion part will begin.   
Part 2 will consist of 4 cohorts as follows: 
Cohort 1 (n=30): Pathologically documented 
advanced/metastatic breast cancer that has centrally-
determined HER2-positive expression (IHC 1+ or IHC 
2+/ISH-) as per ASCO-CAP guidelines. Subjects who have 
received prior trastuzumab emtansine (T-DM1) with 
documented progression.  
Cohort 2 (n=15): Pathologically documented 
advanced/metastatic breast cancer that has centrally-
determined low HER2 expression (IHC 1+ or IHC 2+/ISH-). 
Subjects who have exhausted treatments that can confer any 
clinically meaningful benefit (e.g., other therapies such as 
hormonal therapy for subjects who are hormone receptor 
positive). 


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Cohort 3 (n=30): Pathologically documented 
advanced/metastatic urothelial carcinoma that has 
centrally-determined HER2 expression of IHC 2+ or 3+. 
Subjects who received prior platinum-based therapy with 
documented progression. 
Cohort 4 (n=15): Pathologically documented 
advanced/metastatic urothelial carcinoma that has 
centrally-determined HER2 expression of IHC 1+. Subjects 
who have received prior platinum-based therapy with 
documented progression. 
Study Duration: 
The screening period is up to 28 days. Upon commencing study 
drug, subjects may continue receiving study drug until the 
occurrence of unacceptable toxicity, PD, or withdrawal of 
consent. 
Enrollment for both Part 1 and Part 2 combined is planned to 
occur over approximately 18 months.  Anticipated total duration 
of the study is approximately 24 months. 
The primary database lock will occur 6 months from the last 
subject enrolled in the study or when 80% of the subjects have 
experienced disease progression or discontinued study treatment, 
whichever occurs first.  The end of study is defined as the date of 
completion of the last visit or procedure shown in the Schedule of 
Events in the trial globally.  
There will be a 40-Day Follow-up Visit (+7 days) and a 100-Day 
Safety Follow-up, followed by Long Term Follow-up Visits.  
Subjects who discontinue study treatment for any reason other 
than disease progression will be followed every 6 weeks (± 7 
days) for tumor assessment during the first year and every 12 
weeks (± 14 days) thereafter until disease progression or start of 
new anticancer therapy.  Subjects who discontinue study 
treatment due to disease progression will be followed every 3 
months (± 14 days) from the date of the 40-Day Follow-up Visit 
until death, withdrawal of consent, loss to follow-up, or study 
closure, whichever occurs first.  When the subject discontinues 1 
study drug due to any reason(s), they may continue on the other 
study drug at investigator discretion until they meet a 
discontinuation criterion applicable to the remaining study drug.   
Study Sites and Location: 
Approximately 5 sites for Part 1 and 25 sites for Part 2 in the 
United States and Europe  


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Subject Eligibility Criteria: 
Key Inclusion Criteria: 
1. Adults ≥18 years old. (Please follow local regulatory 
requirements if the legal age of consent for study 
participation is >18 years old.) 
2. Eastern Cooperative Oncology Group (ECOG) 
performance status 0-1. 
3. Pathologically documented HER2-expressing locally 
advanced/metastatic breast cancer or urothelial cancer 
that is unresectable, and refractory to or intolerant of 
existing therapy(ies) known to provide clinical benefit 
and as specified in each study cohort. 
Note: Subjects with urothelial cancer eligible to receive 
anti PD-1/PD-L1 treatment as per the approved local 
label may be considered eligible for the study. 
4. Subjects must have an adequate archival tumor sample 
available for determination of HER2 status by the central 
laboratory (most recent tumor tissue preferred).  Subjects 
are eligible to participate if they meet HER2 status 
criteria based on results from the central laboratory.  
5. Presence of at least 1 measurable lesion per Response 
Evaluation Criteria in Solid Tumors (RECIST) Version 
1.1. 
6. Has adequate cardiac function, as defined by LVEF 
≥50% within 28 days before enrollment.  
7. Adequate bone marrow function, defined as: 
 Absolute neutrophil count ≥1.5 × 109/L (Granulocyte 
colony-stimulating factor [G-CSF] administration is 
not allowed within 1 week prior to screening 
assessment.) 
 White blood cell >2000/mm3 
 Platelet count ≥100 × 109/L (Platelet transfusion is 
not allowed within 1 week prior to screening 
assessment.) 
 Hemoglobin level ≥9.0 g/dL (Red blood cell 
transfusion is not allowed within 1 week prior to 
screening assessment.) 
8. Adequate renal function, defined as: 


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 Creatinine clearance ≥30 mL/min, as calculated 
using the Cockcroft-Gault equation: 
CLcr (mL/min) =  
[140 – age (years)] × weight (kg)    {× 0.85 for females} 
 [72 × serum creatinine (mg/dL)  
 (Section 17.4).  
9. Adequate hepatic function, including mild to moderate 
hepatic impairment defined as the following: 
 Total bilirubin ≤1.5 × upper limit of normal (ULN; 
except subjects with documented Gilbert’s syndrome 
or liver metastases at baseline who must have a total 
bilirubin level of ≤2.0 × ULN). 
 Aspartate aminotransferase/alanine aminotransferase 
values ≤2.5 × ULN (≤5 × ULN in subjects with liver 
metastases or other etiologies).  
10. Adequate blood clotting function, defined as: 
international normalized ratio (INR) and prothrombin 
time (PT)/activated partial thromboplastin time (aPTT) 
or partial thromboplastin time (PTT) ≤1.5 × ULN, unless 
the subject is receiving an anticoagulant therapy, in 
which case INR and PT/aPTT or PTT must be within 
therapeutic range of intended use of anticoagulant.  
11. Adequate treatment washout period before enrollment, 
defined as: 
 Major surgery: ≥4 weeks 
 Radiation therapy: ≥4 weeks (if palliative stereotactic 
radiation therapy, >2 weeks) 
 Systemic anticancer therapy [including 
immunotherapy (non-antibody-based therapy)], 
retinoid therapy, hormonal therapy [metastatic breast 
cancer indication]): ≥3 weeks 
 Small-molecule targeted agents such as 5-
fluorouracil-based agents, folinate agents, weekly 
paclitaxel: ≥2 weeks or 5 half-lives, whichever is 
longer 
 Nitrosoureas or mitomycin C: ≥6 weeks 
 Antibody-based anti-cancer therapy: ≥4 weeks. 
 Chloroquine/Hydroxychloroquine: >14 days 


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12. Male and female subjects of reproductive/childbearing 
potential must agree to use a highly effective form of 
contraception or avoid intercourse during and upon 
completion of the study and for at least 7 months after 
the last dose of study drug. Methods considered as 
highly effective methods of contraception include:  
 Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation: 
 Oral 
 Intravaginal 
 Transdermal 
 Progestogen-only hormonal contraception associated 
with inhibition of ovulation: 
 Oral 
 Injectable 
 Implantable 
 Intrauterine device  
 Intrauterine hormone-releasing system  
 Bilateral tubal occlusion 
 Vasectomized partner 
 Complete sexual abstinence, defined as refraining 
from heterosexual intercourse during and upon 
completion of the study and for at least 7 months 
(females) or 7 months (males) after the last dose of 
study drug.  Periodic abstinence (calendar, 
symptothermal, post-ovulation methods) is not an 
acceptable method of contraception.   
13.  Non-childbearing potential defined as pre-menopausal 
females with a documented tubal ligation or 
hysterectomy; or postmenopausal defined as 12 months 
of spontaneous amenorrhea (in questionable cases, a 
blood sample with simultaneous follicle-stimulating 
hormone >40 mIU/mL and estradiol <40 pg/mL 
[<147 pmol/L] is confirmatory).  Females on hormone 
replacement therapy (HRT) and whose menopausal 
status is in doubt will be required to use one of the 
contraception methods outlined for women of 
childbearing potential if they wish to continue their HRT 


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during the study.  Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status prior to 
study enrollment.  For most forms of HRT, at least 2 to 4 
weeks will elapse between the cessation of therapy and 
the blood draw; this interval depends on the type and 
dosage of HRT.  Following confirmation of their 
postmenopausal status, they can resume use of HRT 
during the study without use of a contraceptive method. 
14. Male subjects must not freeze or donate sperm starting at 
Screening and throughout the study period, and at least 7 
months after the last dose of study drug. Preservation of 
sperm should be considered prior to enrollment in this 
study. 
15. Female subjects must not donate or retrieve ova for their 
own use, from the time of Screening and throughout the 
study treatment period, and for at least 7 months after the 
last dose of study drug. 
16. Life expectancy of at least 3 months. 
Inclusion Criteria Specific to Part 1 
1. Subjects meeting the eligibility criteria set up for any of 
the 4 cohorts in Part 2 would be eligible to enroll in Part 
1. 
Inclusion Criteria Specific to Part 2 
For Cohort 1:  
1. Pathologically documented advanced/metastatic breast 
cancer that has centrally-determined HER2-positive 
expression as per ASCO-CAP guidelines  
2. Prior T-DM1 therapy with documented progression.   
For Cohort 2: 
1. Pathologically documented advanced/metastatic breast 
cancer that has centrally-determined low HER2 
expression (IHC 1+ or IHC 2+/ISH-). 
 
2. Subject must have exhausted treatments that can confer 
any clinically meaningful benefit (e.g., other therapies 
such as hormonal therapy for subjects who are hormone 
receptor positive). 
For Cohort 3: 


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1. Pathologically documented advanced/metastatic 
urothelial carcinoma that has centrally-determined HER2 
expression of IHC 2+ or 3+. 
2. Prior treatment with platinum-based combination 
chemotherapy regimen with documented progression.   
For Cohort 4: 
1. Pathologically documented advanced/metastatic 
urothelial carcinoma that has centrally-determined HER2 
expression of IHC 1+. 
2. Prior treatment with platinum-based combination 
chemotherapy regimen with documented progression.   
 
Key Exclusion Criteria: 
1. Has received prior treatment with nivolumab or 
trastuzumab deruxtecan.  
2. Medical history of myocardial infarction (MI) within 6 
months before enrollment, symptomatic congestive heart 
failure (New York Heart Association Class II to IV). 
Subjects with troponin levels above ULN at screening 
(as defined by the manufacturer), and without any MI 
related symptoms, should have a cardiologic consultation 
before enrollment to rule out MI. 
3. Has a corrected QT interval by Fredericia (QTcF) 
prolongation to >470 ms (females) or >450 ms (males) 
based on an average of the screening triplicate 12-lead 
electrocardiogram. 
4. Has a history of interstitial lung disease (ILD) 
/pneumonitis (non-infectious) that required steroids, has 
current ILD/pneumonitis, or where suspected ILD 
/pneumonitis cannot be ruled out by imaging at 
screening. 
5. Subjects with a condition requiring systemic treatment 
with either corticosteroids (>10 mg daily prednisone 
equivalent) or other immunosuppressive medications 
within 14 days of start of study treatment. Inhaled or 
topical steroids, and adrenal replacement steroid doses 
>10 mg daily prednisone equivalent, are permitted in the 
absence of active autoimmune disease. 
6. Has spinal cord compression or clinically active central 
nervous system metastases, defined as untreated and 


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symptomatic, or requiring therapy with corticosteroids or 
anticonvulsants to control associated symptoms. Subjects 
with clinically inactive brain metastases may be included 
in the study. Subjects with treated brain metastases that 
are no longer symptomatic and do not require treatment 
with corticosteroids or anticonvulsants may be included 
in the study if they have recovered from the acute toxic 
effect of radiotherapy. A minimum of 2 weeks must have 
elapsed between being symptomatic or requiring therapy 
with corticosteroids or between the end of whole brain 
radiotherapy and study enrollment.  
7. Known carcinomatous meningitis. 
8. Has received a live vaccine within 30 days prior to the 
first dose of study drug.   
9. Subjects with an active, known or suspected autoimmune 
disease. Subjects with Type I diabetes mellitus, 
hypothyroidism only requiring hormone replacement, 
skin disorders (such as vitiligo, psoriasis, or alopecia) 
not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are 
permitted to enroll.   
10. Uncontrolled adrenal insufficiency. 
11. Has had prior anti-PD-1, anti-PD-L1, anti-PD-L2, or 
anti-CTLA-4 antibody, or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint 
pathways. 
12. Prior anti-HER2 therapy is not permitted except for 
subjects with HER2-positive breast cancer as per ASCO-
CAP guidelines.   
13. Note: Subjects with HER2 negative residual disease 
treated with adjuvant anti HER2 therapy as per standard 
practice may be eligible.  Has multiple primary 
malignancies within 3 years, except adequately resected 
non-melanoma skin cancer, curatively treated in-situ 
disease, other solid tumors curatively treated, or 
contralateral breast cancer (metastatic breast cancer 
indication). 
14. Clinically severe pulmonary compromise resulting from 
intercurrent pulmonary illnesses including, but not 
limited to, any underlying pulmonary disorder (i.e. 
pulmonary emboli within three months of the study 
enrollment, severe asthma, severe COPD, restrictive lung 


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disease, pleural effusion etc.), and any autoimmune, 
connective tissue or inflammatory disorders with 
pulmonary involvement (i.e. Rheumatoid arthritis, 
Sjogren's, sarcoidosis etc.), or prior pneumonectomy. 
15. Has history of severe hypersensitivity reactions to other 
monoclonal antibodies and/or to either the drug 
substances or inactive ingredients in the drug product. 
16. Has known psychiatric, substance abuse, or any other 
medical conditions that would increase the safety risk to 
the subject or interfere with participation of the subject 
or evaluation of the clinical study in the opinion of the 
investigator. 
17. Has known human immunodeficiency virus (HIV) 
infection, or active hepatitis B or C infection.  Subjects 
positive for hepatitis C (HCV) antibody are eligible only 
if polymerase chain reaction is negative for HCV RNA. 
Subjects should be tested for HIV prior to enrollment if 
required by local regulations or Institutional Review 
Board (IRB)/Ethics Committee (EC). 
18. Has a history or current evidence of any condition, 
therapy, or laboratory abnormality that might confound 
the results of the study, interfere with the subject's 
participation for the full duration of the study, or is not in 
the best interest of the subject to participate, in the 
opinion of the treating Investigator. 
19. Has unresolved toxicities from previous anticancer 
therapy, defined as toxicities (other than alopecia) not 
yet resolved to Grade ≤1 or baseline.  Subjects with 
chronic Grade 2 toxicities may be eligible per the 
discretion of the investigator after consultation with the 
Medical Monitor or designee (e.g., Grade 2 
chemotherapy-induced neuropathy). 
20. Is pregnant, breastfeeding, or planning to become 
pregnant.  
21. History of previous organ transplantation, including stem 
cell allograft. 
22. Has an uncontrolled infection requiring intravenous (IV) 
antibiotics, anti-virals, or anti-fungals. Uncontrolled 
infection is inclusive of active tuberculosis. 
23. Otherwise considered inappropriate for the study by the 
investigator. 


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24. Subject must not be a family member of study site 
personnel working for the investigator or of Sponsor 
personnel. 
Dosage Form, Dose and Route 
of Administration: 
Trastuzumab deruxtecan as a lyophilized powder for 
reconstitution (trastuzumab deruxtecan for injection 100 mg) to 
be administered at doses of 3.2 mg/kg or 5.4 mg/kg IV for Part 1 
of the trial. The dose for Part 2 will be determined based on 
results from Part 1. 
Nivolumab as an aqueous solution formulated at 10 mg/mL, to 
be administered at a flat dose of 360 mg IV over 30 minutes.  
Trastuzumab deruxtecan and nivolumab will be administered on 
Day 1 of each 21-day cycle.   
Study Endpoints: 
Primary Endpoint: 
 DLT to assess MTD or RDE (Part1) 
 Objective response rate (ORR) as assessed by the 
Independent Central Review (ICR) Committee based 
on RECIST Version 1.1 (Part 2) 
Secondary Endpoints: 
 Key safety endpoints will include assessment of 
serious adverse events (SAEs), treatment emergent 
adverse events (TEAEs): TEAEs leading to 
discontinuation, and adverse events of special 
interest and immune-mediated AEs.  
 Other safety endpoints include:  hematology and 
chemistry laboratory parameters, physical 
examination, vital signs, left ventricular ejection 
fraction (LVEF) by echocardiogram 
(ECHO)/multigated acquisition/(MUGA) scan. 
 PK and biomarker endpoints including serum 
concentrations of trastuzumab deruxtecan, MAAA-
118a and total anti-HER2 antibody and nivolumab (if 
analyzed)   
 Duration of response (DOR), Disease control rate 
(DCR), progression-free survival (PFS), time to 
response (TTR) based on ICR Committee 
 ORR as assessed by the investigator based on 
RECIST Version 1.1 (Part 2) 
 Overall survival (OS) 


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Exploratory endpoints: 
 ORR by immune Response Evaluation Criteria in 
Solid Tumors (iRECIST) guidelines as assessed by 
the investigator (Part 2) 
 Clinical benefit rate (CBR) in breast cancer cohorts, 
defined as proportion of subjects who achieved 
complete response (CR), or partial response (PR), or 
had stable disease (SD) for at least 6 months per 
RECIST Version 1.1 
 Biomarker analyses related to the combination (i.e. 
PD-L1, microsatellite instability status, tumor 
mutation burden) to understand the mechanism of 
action and resistance based on pretreatment, post-
treatment, and on-treatment new biopsies 
 Evaluation of serum concentration of trastuzumab 
deruxtecan and nivolumab (if analyzed) anti-drug 
antibodies (ADAs) 
Planned Sample Size: 
The estimated total number of subjects planned is between 99 to 
108 subjects.   
Statistical Analyses: 
The primary database lock will occur 6 months after the last 
subject’s first visit or when 80% of subjects experience disease 
progression or discontinue study treatment, whichever occurs 
first.  An interim analysis is planned to be initiated for all breast 
cancer subjects in the study, including those from Part 1.  
Efficacy and safety interim analyses will be performed when all 
subjects enrolled into Cohorts 1 and 2 in Part 2 had at least 12 
weeks of follow up after initiation of study treatment or have 
discontinued study treatment.  For each cohort, the analyses for 
efficacy outcomes will be repeated adding the corresponding 
subject populations from Part 1 of the study.  
The estimate of DCR and ORR assessed by the ICR Committee 
based on RECIST Version 1.1 and their 2-sided 95% exact 
confidence interval will be provided.  DOR, PFS, and OS will 
be summarized with median event times using Kaplan Meier 
method and their 2-sided 95% confidence intervals using 
Brookmeyer and Crowley method.  
Safety analysis will be performed using the Full Analysis Set 
(FAS).  (The Safety Analysis Set is the same as the FAS). 
Safety analyses in general will be descriptive and will be 
presented in tabular format with the appropriate summary 


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statistics. Listings of safety data will be provided and details will 
be specified in the Statistical Analysis Plan. 
Descriptive statistics will be provided for serum concentration 
data at each time point for each dose level for trastuzumab 
deruxtecan and nivolumab (if analyzed). 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
DOCUMENT HISTORY.................................................................................................................3 
SUMMARY OF CHANGES ...........................................................................................................4 
PROTOCOL SYNOPSIS ................................................................................................................8 
LIST OF ABBREVIATIONS ........................................................................................................31 
1. 
INTRODUCTION ...........................................................................................................35 
1.1. 
Background ......................................................................................................................35 
1.2. 
Study Rationale ...............................................................................................................36 
1.2.1. 
Part 1 Safety Data (with a data-cutoff date of 22 July 2019) and Rationale to 
Support the RDE for Part 2 .............................................................................................38 
2. 
STUDY OBJECTIVES, HYPOTHESIS, AND ENDPOINTS .......................................39 
2.1. 
Study Objectives ..............................................................................................................39 
2.1.1. 
Primary Objectives ..........................................................................................................39 
2.1.2. 
Secondary Objectives ......................................................................................................39 
2.1.3. 
Exploratory Objectives ....................................................................................................39 
2.2. 
Study Hypotheses ............................................................................................................39 
2.3. 
Study Endpoints ...............................................................................................................39 
2.3.1. 
Primary Endpoints ...........................................................................................................39 
2.3.2. 
Secondary Endpoint(s) ....................................................................................................40 
2.3.3. 
Exploratory Endpoints .....................................................................................................40 
3. 
STUDY DESIGN ............................................................................................................41 
3.1. 
Overall Design .................................................................................................................41 
3.2. 
Discussion of Study Design .............................................................................................41 
3.2.1. 
Duration of the Study ......................................................................................................43 
3.2.2. 
Duration of Study Participation .......................................................................................43 
3.2.2.1. Nivolumab Treatment Beyond Progression ....................................................................44 
3.2.3. 
Dose-Limiting Toxicity Definition ..................................................................................44 
3.2.4. 
Maximum Tolerated Dose and Recommended Expansion Dose Definition ...................46 
3.2.5. 
Dose Escalation to MTD .................................................................................................46 
4. 
STUDY POPULATION ..................................................................................................47 
4.1. 
Inclusion Criteria .............................................................................................................47 


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4.1.1. 
Key Inclusion Criteria .....................................................................................................47 
4.1.2. 
Inclusion Criteria Specific to Part 1 ................................................................................49 
4.1.3. 
Inclusion Criteria Specific to Part 2 ................................................................................49 
4.2. 
Exclusion Criteria ............................................................................................................50 
5. 
STUDY TREATMENT(S) ..............................................................................................53 
5.1. 
Assigning Subjects to Treatments and Blinding .............................................................53 
5.1.1. 
Treatment Group(s)/Sequences .......................................................................................53 
5.1.2. 
Method of Treatment Allocation .....................................................................................53 
5.1.3. 
Blinding ...........................................................................................................................53 
5.1.4. 
Emergency Unblinding Procedure ..................................................................................53 
5.2. 
Study Drug(s) ..................................................................................................................53 
5.2.1. 
Description ......................................................................................................................53 
5.2.2. 
Labeling and Packaging ..................................................................................................53 
5.2.3. 
Preparation .......................................................................................................................54 
5.2.4. 
Administration .................................................................................................................54 
5.2.4.1. Maximum Duration of Treatment with Nivolumab ........................................................55 
5.2.5. 
Storage .............................................................................................................................55 
5.2.6. 
Drug Accountability ........................................................................................................56 
5.3. 
Control Treatment ...........................................................................................................56 
5.4. 
Dose-Limiting Toxicity or Maximum Tolerated Dose ...................................................56 
5.5. 
Dose Modification (Delay, Reduction, and/or Discontinuation) for Trastuzumab 
Deruxtecan and Nivolumab .............................................................................................56 
5.5.1. 
Guidelines for Delay, Reduction and/or Discontinuation for Trastuzumab 
Deruxtecan and Nivolumab .............................................................................................56 
5.5.2. 
Toxicity Management for Immune-Related Adverse Events Associated With 
Nivolumab .......................................................................................................................58 
5.5.2.1. Criteria to Resume Nivolumab Treatment ......................................................................77 
5.5.2.2. Pregnancy ........................................................................................................................77 
5.6. 
Method of Assessing Treatment Compliance ..................................................................77 
5.7. 
Prior and Concomitant Medications ................................................................................77 
Prohibited Therapies/Products .......................................................................................................78 
5.8. 
Subject Withdrawal/Discontinuation ...............................................................................79 
5.8.1. 
Reasons for Withdrawal ..................................................................................................79 


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5.8.1.1. Reasons for Withdrawal of Study Drug ..........................................................................79 
5.8.1.2. Reasons for Discontinuation of Study Participation .......................................................80 
5.8.2. 
Withdrawal Procedures ...................................................................................................80 
5.8.3. 
Subject Replacement .......................................................................................................81 
5.8.4. 
Subject Re-prescreening Procedures ...............................................................................81 
5.8.5. 
Subject Re-screening Procedures ....................................................................................81 
6. 
STUDY PROCEDURES .................................................................................................82 
6.1. 
Screening .........................................................................................................................82 
6.1.1. 
Central Laboratory HER2 (Pre-Screening) .....................................................................82 
6.1.2. 
Screening .........................................................................................................................82 
6.2. 
Enrollment .......................................................................................................................84 
6.3. 
Treatment Period .............................................................................................................85 
6.3.1. 
Cycle 1 .............................................................................................................................86 
6.3.1.1. Cycle 1, Day 1 .................................................................................................................86 
6.3.1.2. Cycle 1, Days 8 and 15 (± 1 Day) ...................................................................................88 
6.3.2. 
Cycle 2, Day 1 .................................................................................................................88 
6.3.3. 
Cycle 3, Day 1 .................................................................................................................89 
6.3.4. 
Cycle 4 and Subsequent Cycles, Day 1 ...........................................................................91 
6.3.5. 
End of Combination Treatment (See Section 6.4): Optional Biopsy and 
Biomarker Blood Samples ...............................................................................................92 
6.4. 
End of Treatment .............................................................................................................93 
6.5. 
Follow-up ........................................................................................................................94 
6.5.1. 
40-Day Follow-up (+7 Days) ..........................................................................................94 
6.5.2. 
Long-term Follow-up (±7/±14 Days) ..............................................................................95 
6.5.3. 
100-Day Follow-up .........................................................................................................96 
6.5.4. 
Assessment of Disease ....................................................................................................96 
6.5.4.1. RECIST Version 1.1 Assessment of Disease ..................................................................96 
6.5.4.2. iRECIST Assessment of Disease .....................................................................................96 
6.6. 
Additional PK assessments due to SARS-CoV-2 infection ............................................98 
7. 
EFFICACY ASSESSMENTS .........................................................................................99 
7.1. 
Assessments for Efficacy Endpoint(s) .............................................................................99 
7.2. 
Appropriateness of Selected Efficacy Assessment(s) ...................................................100 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS .........................101 


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8.1. 
Pharmacokinetic Assessment(s) ....................................................................................101 
8.2. 
Biomarker Assessment(s) ..............................................................................................102 
8.2.1. 
Additional Biomarker Assessments ..............................................................................103 
8.3. 
Immunogenicity .............................................................................................................103 
8.4. 
Pharmacogenomic Analysis ..........................................................................................104 
8.4.1. 
Genomic or Genetic Banking and Analysis ..................................................................104 
8.4.1.1. Disclosure of the Results of Genomic or Genetic Analysis ..........................................104 
8.4.1.2. Storage and Disposal of Specimens for Genomic or Genetic Analysis ........................105 
9. 
SAFETY EVALUATION AND REPORTING ............................................................106 
9.1. 
Assessment of Safety Endpoint(s) .................................................................................106 
9.2. 
Adverse Event Collection and Reporting ......................................................................106 
9.3. 
Adverse Events of Special Interest ................................................................................107 
9.3.1. 
Interstitial Lung Disease ................................................................................................107 
9.3.1.1. Clinical Summary ..........................................................................................................107 
9.3.1.2. Management Guidance ..................................................................................................107 
9.3.1.3. Interstitial Lung Disease Adjudication Committee .......................................................108 
9.3.2. 
LVEF Decrease .............................................................................................................108 
9.3.2.1. Clinical Summary ..........................................................................................................108 
9.3.2.2. Management Guidance ..................................................................................................108 
9.4. 
Adverse Events ..............................................................................................................109 
9.4.1. 
Definition of Adverse Event ..........................................................................................109 
9.4.2. 
Serious Adverse Event ..................................................................................................109 
9.4.3. 
Severity Assessment ......................................................................................................110 
9.4.4. 
Causality Assessment ....................................................................................................111 
9.4.5. 
Action Taken Regarding Study Drug(s) ........................................................................111 
9.4.6. 
Other Action Taken for Event .......................................................................................111 
9.4.7. 
Adverse Event Outcome ................................................................................................112 
9.5. 
Serious Adverse Events and Adverse Event of Special Interest Reporting–
Procedure For Investigators ...........................................................................................112 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee ...............................................................................................113 
9.7. 
Exposure in Utero during Clinical Studies ....................................................................114 
9.8. 
Clinical Laboratory Evaluations ....................................................................................114 


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9.9. 
Electrocardiograms ........................................................................................................116 
9.10. 
Physical Examinations ...................................................................................................116 
9.11. 
Other Examinations .......................................................................................................116 
10. 
OTHER ASSESSMENTS .............................................................................................117 
11. 
STATISTICAL METHODS .........................................................................................118 
11.1. 
General Statistical Considerations .................................................................................118 
11.2. 
Analysis Sets .................................................................................................................118 
11.3. 
Study Population Data ...................................................................................................118 
11.4. 
Efficacy Analyses ..........................................................................................................119 
11.4.1. Primary Efficacy Analyses ............................................................................................119 
11.4.2. Secondary Efficacy Analyses ........................................................................................119 
11.4.3. Other Secondary Efficacy Analyses ..............................................................................120 
11.4.4. Exploratory Efficacy Analyses ......................................................................................120 
11.4.5. Pharmacokinetic/Pharmacodynamic/Biomarker Analyses............................................120 
11.4.5.1. Pharmacokinetic Analyses .............................................................................................120 
11.4.5.2. Pharmacodynamic Analyses ..........................................................................................120 
11.4.5.3. Biomarker Analyses ......................................................................................................120 
11.4.5.4. Pharmacogenomic Analyses ..........................................................................................121 
11.4.5.5. Immunogenicity (Anti-Drug Antibody) Analyses .........................................................121 
11.5. 
Safety Analyses .............................................................................................................121 
11.5.1. Adverse Event Analyses ................................................................................................121 
11.5.2. Clinical Laboratory Evaluation Analyses ......................................................................122 
11.5.3. Vital Sign Analyses .......................................................................................................122 
11.5.4. Electrocardiogram Analyses ..........................................................................................122 
11.5.5. Physical Examination Analysis .....................................................................................122 
11.5.6. Exploratory Safety Analyses .........................................................................................122 
11.5.7. Other Endpoint Analysis ...............................................................................................122 
11.6. 
Interim Analysis ............................................................................................................123 
11.7. 
The results from this interim analysis will not be used to change the conduct of 
the study. Data Monitoring Committee .........................................................................123 
11.8. 
Sample Size Determination ...........................................................................................124 
11.9. 
Statistical Analysis Process ...........................................................................................124 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ................................................125 


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12.1. 
Monitoring and Inspections ...........................................................................................125 
12.2. 
Data Collection ..............................................................................................................125 
12.3. 
Data Management ..........................................................................................................126 
12.4. 
Study Documentation and Storage ................................................................................126 
12.5. 
Record Keeping .............................................................................................................127 
13. 
FINANCING AND INSURANCE ................................................................................128 
13.1. 
Finances .........................................................................................................................128 
13.2. 
Reimbursement, Indemnity, and Insurance ...................................................................128 
14. 
PUBLICATION POLICY .............................................................................................129 
14.1. 
Publication and Public Disclosure of Clinical Trial Information ..................................129 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION .................................130 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance ........................................130 
15.2. 
Subject Confidentiality ..................................................................................................130 
15.3. 
Informed Consent ..........................................................................................................130 
15.4. 
Regulatory Compliance .................................................................................................131 
15.5. 
Protocol Deviations .......................................................................................................132 
15.6. 
Supply of New Information Affecting the Conduct of the Study .................................132 
15.7. 
Protocol Amendments ...................................................................................................133 
15.8. 
Study Termination .........................................................................................................133 
15.9. 
Data and Safety Monitoring Board ................................................................................133 
15.10. 
Address List ...................................................................................................................133 
16. 
REFERENCES ..............................................................................................................134 
17. 
APPENDICES ...............................................................................................................136 
17.1. 
Appendix 1: Schedule of Events ...................................................................................136 
17.2. 
Appendix 2: Eastern Cooperative Oncology Group Performance Status (ECOG 
Performance Status) .......................................................................................................141 
17.3. 
Appendix 3: Response Evaluation Criteria in Solid Tumors Version 1.1 .....................142 
17.3.1. Measurability of Tumor at Baseline ..............................................................................142 
17.3.1.1. Definitions .....................................................................................................................142 
17.3.1.2. Specifications by Methods of Measurements ................................................................143 
17.3.2. Tumor Response Evaluation ..........................................................................................143 
17.3.2.1. Assessment of Overall Tumor Burden and Measurable Disease ..................................143 
17.3.2.2. Baseline Documentation of “Target” and “Non-target” Lesions ..................................144 


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17.3.2.3. Response Criteria ...........................................................................................................144 
17.3.2.4. Evaluation of Best Overall Response ............................................................................147 
17.3.2.5. Frequency of Tumor Re-evaluation ...............................................................................148 
17.4. 
Appendix 4: Cockcroft-Gault Equation .........................................................................150 
17.5. 
Appendix 5: Description of the iRECIST Process for Assessment of Disease 
Progression ....................................................................................................................151 
17.5.1. Assessment at Screening and Prior to RECIST 1.1 Progression ...................................151 
17.5.2. Assessment and Decision at RECIST 1.1 Progression ..................................................151 
17.5.3. Assessment at the Confirmatory Imaging .....................................................................152 
17.5.4. Confirmation of Progression .........................................................................................152 
17.5.5. Persistent iUPD .............................................................................................................152 
17.5.6. Resolution of iUPD .......................................................................................................153 
17.5.7. Management Following the Confirmatory Imaging ......................................................153 
17.5.8. Detection of Progression at Visits After Pseudo-progression Resolves ........................153 
17.6. 
Appendix 6: New York Heart Association Functional Classification ...........................155 
17.7. 
Appendix 7: Immune-Mediated Adverse Event Management Algorithms 
(Nivolumab) ..................................................................................................................156 
17.8. 
Appendix 8: Instructions Related to Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2) ......................................................................................165 
SARS-CoV-2 Assessment(s) .......................................................................................................166 
 
 


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LIST OF TABLES 
Table 3.1: Trastuzumab Deruxtecan Dose Escalation .................................................................42 
Table 5.1: Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab ...........59 
Table 6.1: End of Combination Treatment (EOCT) Assessments ...............................................93 
Table 6.2: Imaging and Treatment with Nivolumab After First Radiologic Evidence of 
Progressive Disease ....................................................................................................98 
Table 8.1: Sampling Times for Pharmacokinetic Assessments .................................................101 
Table 8.2: Schedule of PK Sample Collection in Case of Chloroquine or 
Hydroxychloroquine Treatment ................................................................................102 
Table 8.3: Biomarker Blood Sampling Time Points (HER2ECD, cfDNA) ..............................103 
Table 17.1: Schedule of Events ...................................................................................................136 
Table 17.2: Eastern Cooperative Oncology Group Performance Status Scale ............................141 
Table 17.3: Overall Response: Subjects with Target (+/–Non-target) Disease ...........................147 
Table 17.4: New York Heart Association Functional Classification ...........................................155 
Table 17.5: SARS-CoV-2 infection Dose Modification Criteria .................................................165 
 


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LIST OF FIGURES 
Figure 3.1: Study Design Schema .................................................................................................41 
Figure 3.2: 3+3+3 Clinical Study Design .....................................................................................46 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ADA 
Anti-drug Antibody 
ADL  
Activities of Daily Living 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BI 
Before Infusion 
BSA 
Body Surface Area 
CAP 
College of American Pathologists 
CART 
Cell-free and Concentrated Ascites Reinfusion Therapy 
Cavgss 
Concentration Average at Steady State 
CBR 
Clinical Benefit Rate 
cfDNA 
Cell-free DNA 
COVID-19 
Coronavirus Disease 2019 
CR 
Complete Response 
CrCl 
Creatinine Clearance Rate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSPV 
Clinical Safety and Pharmacovigilance 
CT 
Computed Tomography 
Ctx 
Platinum-based chemotherapy 
DCR 
Disease Control Rate 
DILI 
Drug-induced Liver Injury 
DOR 
Duration of Response 
DLT 
Dose-limiting Toxicity 
DSI 
Daiichi Sankyo Inc. 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 


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ABBREVIATION 
DEFINITION 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EIU 
Exposure in Utero 
EOCT 
End of Combination Treatment 
EOI 
End of Infusion 
EOT 
End of Treatment 
EU 
European Union 
FAS 
Full Analysis Set 
FFPE 
Formalin-fixed Paraffin-Embedded 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice  
HBsAg 
Hepatitis B Surface Antigen 
HER2 
Human Epidermal Growth Factor 2 
HER2ECD 
HER2 Extracellular Domain 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICR 
Independent Central Review 
ICH 
International Council for Harmonisation 
ICMJE 
International Council of Medical Journal Editors  
ID 
Infectious Disease 
IHC 
Immunohistochemistry 
ILD 
Interstitial Lung Disease 
I-O 
Immuno-oncology 
irAEs 
Immune related Adverse Events 
IRB 
Institutional Review Board 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumors 
IV 
Intravenous 


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ABBREVIATION 
DEFINITION 
IXRS 
Interactive Web/Voice Response System 
LFT 
Liver Function Test 
LLN 
Lower Limit of Normal  
LVEF 
Left Ventricular Ejection Fraction 
MAAA-1181a 
The drug component of trastuzumab deruxtecan – a derivative of exatecan, a 
topoisomerase I inhibitor, free form 
MAAA-1181c 
Additive form of MAAA-1181a(3/10MeCN. 2/5MeOH.3/10 H20) 
MAAL-9001 
The antibody component of trastuzumab deruxtecan – a recombinant 
humanized anti-HER2 IgG1 monoclonal antibody produced in-house with 
reference to the same amino acid sequence of trastuzumab 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major Histocompatibility 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated Acquisition 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NE 
Not Evaluable 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-1 
Programmed Death-1 
PD-L1 
Programmed Death-Ligand 1 
PFS 
Progression-free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
Q3M  
Every 3 Months 
Q6W 
Every 6 Weeks 
QTc 
Corrected QT Interval 
QTcF 
Corrected QT Interval by Fredericia 
RDE 
Recommended Expansion Dose 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RES 
Response Evaluable Set 
SAE 
Serious Adverse Event 


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ABBREVIATION 
DEFINITION 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SAVER 
Serious Adverse Event Report  
SD 
Stable Disease 
SE 
Standard Error 
SID 
Subject Identifier 
SJS 
Stevens-Johnson Syndrome 
SMT 
Safety Management Team 
SpO2 
Peripheral Oxygen Saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T3 
Triiodothyronine 
T-DM1 
Trastuzumab Emtansine 
TEAE 
Treatment-emergent Adverse Event 
TEN 
Toxic Epidermal Necrolysis 
TSH 
Thyroid Stimulating Hormone 
TTR 
Time to Response 
Tx 
Treatment 
ULN 
Upper Limit of Normal 
US 
United States 
 


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1. 
INTRODUCTION 
1.1. 
Background 
Breast cancer remains the most common cancer and the second leading cause of cancer mortality 
in women in developed countries and the first cause of death in developing countries.  In 2015, 
there were 2.4 million new cancer cases leading to 523,000 deaths worldwide.  Breast cancer was 
also the leading cause of morbidity in women, resulting in an estimated burden of 15.1 million 
disability-adjusted life years.1   
In approximately 20% of breast cancer cases, overexpression of human epidermal growth factor 
receptor 2 (HER2) is considered the molecular oncologic alteration resulting in a historically 
aggressive disease with poor outcomes.  Although HER2-targeted drugs have been developed as 
individualized molecularly targeted therapies, locally advanced and metastatic tumors invariably 
relapse with time.1   
HER2-positive breast cancer has historically been associated with more aggressive disease and 
worse outcomes compared to HER2-negative breast cancer except for triple negative breast 
cancer.  Although anti-HER2 targeted therapies have improved outcomes, they are not curative 
in the metastatic setting.  Treatment options for patients who have progressed after 2 lines of 
anti-HER2 therapy remain unclear and limited.  Current options include lapatinib + capecitabine, 
trastuzumab + capecitabine, trastuzumab + lapatinib, or trastuzumab + other agents.  Reported 
response rates for these regimens when given as second lines of anti-HER2 therapy range from 
10% to 22%.2,3,4,5  It is expected that these response rates would be lower when given in a later 
line of therapy. 
The only trial to report outcomes after 2 lines of anti-HER2 therapy was the THERESA trial, 
which compared trastuzumab emtansine (T-DM1) in the third-line setting to physician’s choice 
therapies.  The 2 prior lines of anti-HER2 therapy in this case were regimens containing 
trastuzumab and lapatinib.  In this setting, although 81% of physician’s choice treatments 
consisted of combining an anti-HER2 agent with chemotherapy, the objective response rate 
(ORR) for the physician’s choice treatment was only 9%, and the median progression-free 
survival (PFS) was 3.3 months.6  Treatment options for HER2-positive breast cancer, therefore, 
remain limited, with no targeted therapy specifically approved following trastuzumab, 
pertuzumab, and T-DM1 failure.6  In this setting, recommended treatment options include 
continuation of an anti-HER2 therapy in combination with a standard chemotherapy agent.  Due 
to the lack of clear superiority, no specific combination is currently endorsed in established 
guidelines, and consideration of palliative care is recommended after 3 lines of targeted therapy.  
Therefore, a high unmet medical need exists, and new treatment options need to be developed to 
improve outcomes for patients with disease progression following the failure of trastuzumab, 
pertuzumab, and T-DM1 regimens.   
Urothelial bladder cancer is the ninth most common malignancy in the world.7  In the United 
States, approximately 79,000 new cases and 17,000 deaths occur each year due to bladder 
cancer.8  In Europe, there were an estimated 118,000 cases and 52,000 deaths in 2012.9  In 
developed regions such as North America and Europe, bladder cancer is predominantly 
urothelial. 


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At the time of diagnosis, approximately 80% of urothelial bladder carcinomas are superficial and 
20% of them will become invasive.  The treatment of locally advanced or metastatic disease is 
currently based on the M-VAC regimen (methotrexate, vinblastine, doxorubicin, cisplatin), or 
gemcitabine and cisplatin.10  Approximately half of patients with bladder cancer do not respond 
to their initial, or first-line therapy, and only 10% to 15% of those patients respond to second-line 
chemotherapy.  Recently, programmed death 1 (PD-1)/PD-L1 antibodies have been approved for 
the treatment of patients with locally advanced or metastatic bladder cancer whose disease has 
progressed during or after first-line, adjuvant, or neoadjuvant therapy with platinum-containing 
chemotherapy.11 
The HER2 is known to contribute to physiologic mechanisms of cell proliferation by an intrinsic 
tyrosine kinase activity.  The assessment of HER2 status is a crucial in breast cancer patient 
management.12  In invasive urothelial bladder carcinomas, HER2 overexpression was also found. 
However, the true incidence of HER2 overexpression remains uncertain ranging from 12% to 
80% for overexpression.10  
Unlike breast cancer, where the role of HER2-targeting agents has been well established in both 
metastatic and adjuvant settings, the experimental use of HER2-targeting agents has only 
emerged recently in bladder cancer clinical research. A possible involvement of the HER2 
receptor in the proliferation of invasive urothelial bladder cancer has led to initiate 
HER2-targeted therapy trials in locally advanced or metastatic disease.10 
Earlier trials of HER2 targeted therapies (monotherapy or in combination with chemotherapy) in 
HER2 overexpressing urothelial cancer have failed to show evidence of efficacy.11  National 
Comprehensive Cancer Network guidelines recommends participation in clinical trials for new 
agents in patients that failed first line therapy indicating a high unmet medical need and a need to 
develop new treatment options for patients with this disease.12 
1.2. 
Study Rationale 
Trastuzumab deruxtecan is an anti-HER2 antibody drug conjugate incorporating a novel linker 
with a target number of 7 to 8 drug linker to 1 antibody molecule using a novel topoisomerase I 
inhibitor warhead different from currently approved tubulin inhibitors.  In preclinical models as 
well as preliminary results from Phase 1 trials performed in the salvage line setting, trastuzumab 
deruxtecan has shown efficacy across a broad array of tumor types as well as in both HER2 high 
and low expressing models and tumors. 
Preliminary evidence of clinical efficacy of trastuzumab deruxtecans monotherapy was seen in 
several tumor types at various levels of HER2 expression in the J101 study.13   
The immune checkpoints prevent autoimmunity by down-regulating T-cell activation or effector 
function.  By engaging immune checkpoints, tumors evade the immune system.  
Programmed death 1 plays a key role in regulating and maintaining the balance between T-cell 
activation and immune tolerance.  The PD-1 receptor, which is expressed on activated T-cells, is 
engaged by ligands PD-L1 and PD-L2, which are expressed by tumor cells and infiltrating 
immune cells.  Tumor PD-L1 expression is prevalent in many tumor cells, and the interaction of 
PD-1 with the PD-L1 and PD-L2 ligands inhibits T-cell activation and promotes tumor immune 


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escape (i.e., the mechanism by which tumor cells escape recognition and elimination by the 
immune system).14 
Nivolumab is a fully human IgG4 PD-1 immune-checkpoint–inhibitor antibody that disrupts 
PD-1–mediated signaling and restores antitumor immunity.11,12,14  In vitro, nivolumab 
(BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and inhibits the binding 
of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ± 1 nM).15 
Nivolumab is currently approved for use in several solid tumors including urothelial cancer.  
Immune checkpoint inhibitor efficacy depends on expression levels of major histocompatibility 
(MHC)-class I on tumor cell.  The MHC-class I recovery approaches might synergize with 
complementary forms of immunotherapy.  Trastuzumab deruxtecan causes cancer cell death and 
release of antigen and drug molecule (DX-8951 derivative), leading to MHC-class I 
up-regulation (bystander effect).  The dendritic cell activation and increased MHC-class I 
expression on cancer cell in turn increases T-cell recognition of cancer cell.  
In preclinical studies trastuzumab deruxtecan showed antitumor effect in an immunocompetent 
mouse model with human HER2-expressing CT26.WT cells (syngeneic mouse model) and 
formation of immunological memory.  Combination of trastuzumab deruxtecan with an 
anti-PD-1 antibody exhibited significantly better survival prolongation compared with each 
single treatment in preclinical testing due to activating dendritic cell and MHC-class I markers 
and up-regulating PD-L1.16   
Therefore, trastuzumab deruxtecan has potential synergistic effect with anti-PD-1therapy.   
Extensive details on the safety profile of nivolumab are available in the Investigator’s Brochure 
(IB).13  
Overall, the safety profile of nivolumab monotherapy is manageable and generally consistent 
across completed and ongoing clinical trials with no maximum tolerated dose (MTD) reached at 
any dose tested up to 10 mg/kg.  Most adverse events (AEs) were low-grade (Grade 1 to 2) with 
relatively few related high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, 
severity, or causality of AEs with respect to nivolumab dose level.  A pattern of immune-related 
AEs has been defined, for which management algorithms have been developed; these are 
discussed further in Section 9.2 and Section 17.7.  Most high-grade events were manageable with 
the use of corticosteroids or hormone replacement therapy (HRT; (endocrinopathies) as 
instructed in these algorithms.  Additional details on the safety profile of nivolumab, including 
results from other clinical studies, are also available in the nivolumab IB. 
The observed preclinical data and clinical data from the monotherapy trials of trastuzumab 
deruxtecan and nivolumab and the mechanisms of action of the 2 drugs provide scientific 
rationale for a clinical trial with this combination.  The efficacy of trastuzumab deruxtecan at 
dose levels ranging from 0.8 to 8.0 g/kg of trastuzumab deruxtecan was observed in J101.  
Nivolumab 360 mg every 3 weeks is currently under investigation in monotherapy and 
combination oncology studies.  The less frequent dosing regimens are designed to afford more 
convenience to the target patient populations and allow combination of nivolumab with other 
agents using alternative dosing regimens versus every 2 weeks.  This nivolumab dose was 
selected using PK and exposure-response analyses modeling and simulation approaches such that 
it is predicted to provide approximately equivalent exposures (Cavgss) following administration 


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of nivolumab 3 mg/kg every 2 weeks.17  In addition, to mitigate the safety risk of the 
combination in study subjects, the U105 trial design starts with a lower dose of trastuzumab 
deruxtecan (3.2 mg/kg).  This design allows early assessment of safety risk of the combination 
prior to escalating to a recommended expansion dose (RDE) of trastuzumab deruxtecan as a 
combination or prior to enrolling a higher number of subjects in dose expansion cohorts. 
1.2.1. 
Part 1 Safety Data (with a data-cutoff date of 22 July 2019) and Rationale to 
Support the RDE for Part 2 
A total of 7 subjects were enrolled in Part 1 (4 subjects in cohort 1 and 3 subjects in cohort 2). No 
DLTs were declared among the DLT evaluable subjects (3 in each cohort). Therefore, based on 
the safety data of Part 1, the recommended dose for expansion [RDE] (phase 2) was declared at: 
trastuzumab deruxtecan 5.4 mg/kg and nivolumab 360 mg every three weeks. The data will be 
further detailed in the final Clinical Study Report (CSR). 


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2. 
STUDY OBJECTIVES, HYPOTHESIS, AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
 To determine the MTD or the RDE of trastuzumab deruxtecan when used in 
combination with nivolumab (Part 1). 
 To evaluate the efficacy of combination treatment of trastuzumab deruxtecan and 
nivolumab in HER2-expressing advanced breast cancer as well as HER2-expressing 
advanced urothelial cancer (Part 2). 
2.1.2. 
Secondary Objectives 
 To assess the safety and tolerability of the combination of trastuzumab deruxtecan 
and nivolumab. 
 To determine the pharmacokinetics (PK) of trastuzumab deruxtecan when dosed 
concomitantly with nivolumab.  To further evaluate the efficacy of the combination 
of trastuzumab deruxtecan and nivolumab. 
2.1.3. 
Exploratory Objectives 
 To evaluate the efficacy of the combination of trastuzumab deruxtecan and 
nivolumab by by using the immune Response Evaluation Criteria in Solid Tumors 
(iRECIST) guidelines as assessed by the study investigator (Part 2) 
 To further evaluate the efficacy of the combination of trastuzumab deruxtecan and 
nivolumab in terms of clinical benefit rate (CBR) in breast cancer cohorts 
 To perform biomarker analyses related to the combination to understand the 
mechanism of action and resistance based on pretreatment, post-treatment, and 
on-treatment biopsies 
 To evaluate the immunogenicity of trastuzumab deruxtecan and nivolulmab (if 
analyzed). 
2.2. 
Study Hypotheses 
Trastuzumab deruxtecan plus nivolumab at the tolerated dose level will confer significant 
clinical benefit as reported by ORR and other efficacy endpoints. 
2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoints 
 DLT to assess MTD or RDE (Part1) 
 ORR as assessed by the ICR Committee based on RECIST Version 1.1 (Part 2) 


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2.3.2. 
Secondary Endpoint(s) 
 Key safety endpoints will include assessment of SAEs, TEAEs: TEAEs leading to 
discontinuation, adverse events of special interest, and immune-mediated AEs.  
 Other safety endpoints include:  hematology and chemistry laboratory parameters, 
physical examination, vital signs, left ventricular ejection fraction (LVEF) by 
echocardiogram (ECHO)/multigated acquisition/(MUGA) scan. 
 PK and biomarker endpoints including serum concentrations of trastuzumab 
deruxtecan, MAAA- 118a and total anti-HER2 antibody and nivolumab (if analyzed). 
 Duration of response (DOR), disease control rate (DCR), PFS, time to response 
(TTR) based on ICR Committee 
 ORR as assessed by the investigator based on RECIST Version 1.1 (Part 2)  
 Overall survival (OS). 
2.3.3. 
Exploratory Endpoints 
 ORR by iRECIST guidelines as assessed by the investigator (Part 2) 
 CBR in breast cancer cohorts, defined as proportion of subjects who achieved CR, or 
PR, or had SD for at least 6 months per RECIST Version 1.1  
 Biomarker analyses related to the combination (i.e. PD-L1, microsatellite instability 
status, tumor mutation burden) to understand the mechanism of action and resistance 
based on pretreatment, post-treatment, and on-treatment new biopsies. 
 Evaluation of serum concentration of trastuzumab deruxtecan and nivolumab (if 
analyzed) anti-drug antibodies (ADAs)  


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a Phase 1b, open-label, 2-part, multicenter, non-randomized, multiple-dose, study of 
trastuzumab deruxtecan in combination with nivolumab.  This 2-part study will include both a 
dose escalation part, to identify the RDE of trastuzumab deruxtecan in combination with a fixed 
dose of nivolumab, and a dose expansion part, to evaluate efficacy, safety, and tolerability. 
A schema of the study design is provided in Figure 3.1. 
Figure 3.1: 
Study Design Schema 
 
Ctx = platinum-based chemotherapy; HER2 = human epidermal growth factor 2; IHC = immunohistochemistry; 
T-DM1 = trastuzumab emtansine; Tx = treatment 
3.2. 
Discussion of Study Design 
Part 1 is a dose escalation phase for trastuzumab deruxtecan to determine RDE for Part 2 and 
Part 2 is a dose expansion phase as discussed in Section 3.1.  Nivolumab will be infused over 
approximately 30 minutes on Day 1 of each cycle prior to the administration of trastuzumab 
deruxtecan with no less than a 30-minute gap between the 2 infusions.  The initial dose of 
trastuzumab deruxtecan will be infused intravenously into each subject for approximately 
90 minutes on Day 1 of Cycle 1.  If no infusion reaction is observed, infusion may occur over 
30 minutes on subsequent cycles. 
 
 
 
 
 
 


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Part 1 (Dose Escalation) 
Part 1 will enroll subjects meeting the eligibility criteria set up for any of the 4 cohorts of Part 2 
using a 3 + 3 + 3 design.  Escalating doses of trastuzumab deruxtecan (Table 3.1) in combination 
with nivolumab will be assessed.  Trastuzumab deruxtecan and nivolumab will be administered 
on Day 1 of each 21-day cycle. 
Table 3.1: 
Trastuzumab Deruxtecan Dose Escalation 
Dose Level 
Trastuzumab 
Deruxtecan 
Nivolumab 
1 
3.2 mg/kg Q3W 
360 mg Q3W 
2 
5.4 mg/kg Q3W 
360 mg Q3W 
The starting dose of trastuzumab deruxtecan will be 3.2 mg/kg and a fixed dose of 360 mg for 
nivolumab combination given every 3 weeks. Escalation/de-escalation to the next dose will be 
based on acceptable safety signal from the earlier dose cohort. Intrasubject dose escalations are 
not allowed. Note: If the maximum dose of 5.4 mg/kg for trastuzumab deruxtecan is lower than 
MTD, the RDE of 5.4 mg/kg will be taken as RDE.  
The DLT observation period will be the first 2 cycles (6 weeks). Upon completion of the DLT 
observation period, subjects may continue to receive study treatment in subsequent cycles as 
previously described, until the occurrence of unacceptable toxicity, progressive disease (PD), or 
withdrawal of consent. Subjects may continue to receive nivolumab beyond progression if the 
investigator believes this will provide clinical benefit to the subject (See Section 3.2.3 for 
specification of DLT). 
Part 2 (Dose Expansion) 
Upon completion of dose escalation (Part 1) with determination of RDE, the dose expansion part 
will begin.   
Part 2 will consist of 4 cohorts as follows: 
Cohort 1 (n=30):  
Pathologically documented advanced/metastatic breast cancer that has centrally-determined 
HER2-positive expression as per ASCO-CAP guidelines. Subjects who have received prior 
trastuzumab emtansine (T-DM1) with documented progression.   
Cohort 2 (n=15):  
Pathologically documented advanced/metastatic breast cancer that has centrally-determined low 
HER2 expression (IHC 1+ or IHC 2+/ISH-). Subjects who have exhausted treatments that can 
confer any clinically meaningful benefit (e.g., other therapies such as hormonal therapy for 
subjects who are hormone receptor positive). 
Cohort 3 (n=30):  
Pathologically documented advanced/metastatic urothelial carcinoma that has 
centrally-determined HER2 expression of IHC 2+ or 3+. Subjects who received prior 
platinum-based therapy with documented progression.  


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Cohort 4 (n=15):  
Pathologically documented advanced/metastatic urothelial carcinoma that has 
centrally-determined HER2 expression of IHC 1+. Subjects who have received prior 
platinum-based therapy with documented progression.  
The estimated total number of subjects planned is between 99 to 108 subjects. 
Approximately 5 sites are planned for Part 1 and 25 sites for Part 2 in the United States (US) and 
Europe. 
3.2.1. 
Duration of the Study 
Enrollment for both Part 1 and Part 2 combined is planned to occur over approximately 
18 months.  An efficacy and safety interim analysis will be performed when all subjects enrolled 
into Cohorts 1 and 2 in Part 2 have had at least 12 weeks of follow-up after initiation of study 
treatment or have discontinued study treatment.  Anticipated total duration of the study is 
approximately 24 months.  The primary database lock will occur 6 months from the last subject 
enrolled in the study or when 80% of the subjects have experienced disease progression or 
discontinued study treatment, whichever occurs first.   
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.   
There will be a 40-Day Follow-up Visit (± 7 days), and a 100-Day safety follow up, followed by 
Long-term Follow-up Visits.  Subjects who discontinue study treatment for any other reason than 
disease progression will be followed as described in Section 6.3 for tumor assessment until 
disease progression or start of new anticancer therapy.  Subjects who discontinue study treatment 
due to disease progression will be followed every 3 months (±14 days) from the date of 40-Day 
Follow-up Visit until death, withdrawal of consent, loss to follow-up, or study closure, 
whichever occurs first. 
Safety and survival information will be collected via a 100-Day Telephone Follow-up. 
Subjects will continue trastuzumab deruxtecan and nivolumab until they have disease 
progression or meet any other criteria for treatment discontinuation.  Nivolumab treatment 
beyond progression is allowed only if the potential benefits of treatment outweigh the risks in the 
opinion of the investigator.  A maximum of 35 cycles/2 years of nivolumab can be administered 
to a subject.  Trastuzumab deruxtecan may be administered until occurrence of disease 
progression as per RECIST 1.1. 
Sponsor may terminate the study at any time due to administrative reason or at request from 
competent regulatory authorities. 
3.2.2. 
Duration of Study Participation 
The screening period is up to 28 days.  Upon commencing, subjects may continue receiving 
study drug until the occurrence of unacceptable toxicity, PD, or withdrawal of consent.  Each 
treatment cycle will be 21 days. 
Subjects who discontinued both study treatments due to any reason other than disease 
progression will continue Long-term Follow-up for tumor assessment until disease progression 


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or start of additional anticancer treatment as described in Section 6.3 and every 3 months 
(±14 days) thereafter, from the date of 40-Day Follow-up Visit/last tumor assessment until death, 
withdrawal of consent, loss to follow-up, or study closure, whichever occurs later.  Subjects who 
discontinued study treatments due to disease progression would be followed every 3 months 
(±14 days), to obtain information about subsequent treatment(s) and survival status from the date 
of 40-Day Follow-up Visit until death, withdrawal of consent, loss to follow-up, or study closure, 
whichever occurs later. 
3.2.2.1. 
Nivolumab Treatment Beyond Progression 
Accumulating evidence indicates that a minority of patients with solid tumors treated with 
immunotherapy may derive clinical benefit despite initial evidence of PD.  Patients will be 
permitted to continue on nivolumab treatment beyond initial RECIST Version 1.1-defined PD 
for up to a maximum of 24 months from date of first dose as long as they meet the following 
criteria:  
 Investigator-assessed clinical benefit and without rapid disease progression.  
 Continue to meet all other study protocol eligibility criteria.  
 Continues to tolerate study drug.  
 Patient has stable ECOG performance status.  
 Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (e.g., central nervous system 
metastases).  
The assessment of clinical benefit should take into account whether the patient is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. All decisions to 
continue treatment beyond initial progression must be discussed with the Medical Monitor, and 
an assessment of the risk/benefit of continuing with study therapy must be documented in the 
study records.  
For patients who stay on nivolumab treatment beyond RECIST Version 1.1-defined PD, all study 
procedures (Section 6, Study Procedures) should be performed continuously, including 
radiographic assessment by computed tomography (CT) (preferred) or magnetic resonance 
imaging (MRI) as described in Section 6.3. Patients will be discontinued from the treatment upon 
further evidence of disease progression, as per iRECIST criteria.  If a subject has confirmed 
radiographic progression (iCPD) as defined by iRECIST, nivolumab should be discontinued.  
Treatment with nivolumab can only be administered for 24 months regardless of tumor 
progression. 
3.2.3. 
Dose-Limiting Toxicity Definition 
A DLT is defined as any TEAE not attributable to disease or disease-related processes that 
occurs during the DLT evaluation period (2 complete cycles during Part 1) and is Grade 3 or 
above according to National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) version 5.0.  The list of potential DLTs and exceptions are defined below:  


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For hematological toxicities, a potential DLT is defined as follows:  
 Grade 4 neutrophil count decreased lasting >7 days  
 Grade ≥3 febrile neutropenia  
 Grade 4 anemia  
 Grade 4 platelet count decreased  
 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:  
 Grade ≥3 total bilirubin increased 
 Subject without baseline liver metastases: Grade 3 aspartate aminotransferase (AST) 
or alanine aminotransferase (ALT) increased 
 Subject with liver metastases:  AST or ALT >5 × upper limit of normal (ULN) if the 
baseline level was ≤3 × ULN or AST or ALT >8 × ULN if the baseline level was 
>3 × ULN 
 AST or ALT >3 × ULN (in subjects with baseline liver metastases, AST or ALT >5 × 
ULN) if accompanied by Grade ≥2 blood bilirubin increased 
For non-hematological, non-hepatic major organ toxicities, a potential DLT is defined as 
follows:  
 Symptomatic congestive heart failure   
 LVEF decline to <40% or >20% drop from baseline  
 Grade ≥2 interstitial lung disease (ILD)   
 Any Grade ≥2 drug-related uveitis, eye pain, or blurred vision that does not respond 
to topical therapy and does not improve to Grade 1 severity within the re-treatment 
period OR requires systemic treatment 
 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 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  


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Sponsor will collaborate with investigator/principal investigator to determine whether a specific 
toxicity observed during DLT period would qualify as a DLT taking into account the criteria 
above as well as other circumstances around the toxicity observed such as evidence of disease 
progression. 
3.2.4. 
Maximum Tolerated Dose and Recommended Expansion Dose Definition 
The MTD or RDE is determined in Part 1.  The RDE may be either the MTD/RDE determined in 
Part 1, or an alternative dose, pending discussions between the Sponsor and the investigator(s).  
Once the RDE has been determined, enrollment to Part 2 will begin. 
3.2.5. 
Dose Escalation to MTD 
The 3 + 3 + 3 design uses the dose escalation/de-escalation rules as shown in Figure 3.2 below.  
Figure 3.2: 
3+3+3 Clinical Study Design 
 
MTD: Maximum tolerated dose 
The MTD is determined as follows: 
 At a trastuzumab deruxtecan dose, if 2 DLTs out of 3 subjects, or ≥3 DLTs out of 
6 subjects or 9 subjects, then the previous dose is the MTD unless the current dose is 
3.2 mg/kg, which means that 3.2 mg/kg of trastuzumab deruxtecan is above the MTD.  
The Sponsor will determine the next step in consultation with the investigator. 
 At 5.4 mg/kg trastuzumab deruxtecan dose, if 0 DLTs out of 3 subjects, or ≤1 DLT 
out of 6 subjects, or ≤2 DLTs out of 9 subjects, then 5.4 mg/kg is the RDE, although 
MTD has not been reached. 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Prior to the start of any study-specific qualification procedures, all subjects must sign and date 
the informed consent form (ICF), which will be provided to them by the study site.  
Subjects must satisfy all of the following criteria to be included in the study: 
4.1.1. 
Key Inclusion Criteria 
1. Adults ≥18 years old. (Please follow local regulatory requirements if the legal age of 
consent for study participation is >18 years old.) 
2. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Section 17.2). 
3. Pathologically documented HER2-expressing locally advanced/metastatic breast cancer 
or urothelial cancer that is unresectable, and refractory to or intolerant of existing 
therapy(ies) known to provide clinical benefit and as specified in each study cohort. 
Note: Subjects with urothelial cancer eligible to receive anti PD-1/PD-L1 treatment as per 
the approved local label may be considered eligible for the study. 
4. Subjects must have an adequate archival tumor sample available for determination of 
HER2 status by the central laboratory (most recent tumor tissue preferred).  Subjects are 
eligible to participate if they meet HER2 status criteria based on results from the central 
laboratory. 
5. Presence of at least 1 measurable lesion per RECIST Version 1.1. as assessed by the 
Investigator.  Lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions (Section 1.1). 
6. Has adequate cardiac function, as defined by LVEF ≥50% within 28 days before 
enrollment.  
7. Adequate bone marrow function, defined as: 
 Absolute neutrophil count ≥1.5 × 109/L (Granulocyte colony-stimulating factor 
[G-CSF] administration is not allowed within 1 week prior to screening assessment.) 
 White blood cell >2000/mm3 
 Platelet count ≥100 × 109/L (Platelet transfusion is not allowed within 1 week prior to 
screening assessment.) 
 Hemoglobin level ≥9.0 g/dL (Red blood cell transfusion is not allowed within 1 week 
prior to screening assessment.) 
8. Adequate renal function, defined as: 
 Creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault equation 
CLcr (mL/min) =  [140 - age (years)] × weight (kg) /72 × serum creatinine (mg/dL)    
{× 0.85 for females} (Section 17.4).  


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9. Adequate hepatic function, including mild to moderate hepatic impairment defined as the 
following: 
 Total bilirubin ≤1.5 × ULN (except subjects with documented Gilbert's syndrome or 
liver metastases at baseline who must have a total bilirubin level of ≤2.0 × ULN).  
 AST/ALT values ≤2.5 × ULN (≤5 × ULN in subjects with liver metastases or other 
etiologies).   
10. Adequate blood clotting function, defined as: international normalized ratio (INR) and 
prothrombin time (PT)/activated partial thromboplastin time (aPTT) or partial 
thromboplastin time (PTT) ≤1.5 × ULN unless the subject is receiving anticoagulant 
therapy, in which case INR and PT/aPTT or PTT must be within therapeutic range of 
intended use of anticoagulant.  
11. Adequate treatment washout period before enrollment, defined as: 
 Major surgery: ≥4 weeks 
 Radiation therapy including palliative stereotactic radiation to chest: ≥4 weeks 
( palliative stereotactic radiation therapy to other areas, ≥2 weeks) 
 Systemic anticancer therapy including immunotherapy (non-antibody-based therapy), 
retinoid therapy, hormonal therapy (metastatic breast cancer indication): ≥3 weeks 
  Small-molecule targeted agents such as 5-fluorouracil-based agents, folinate agents, 
weekly paclitaxel: ≥2 weeks or 5 half-lives, whichever is longer 
 Nitrosoureas or mitomycin C:>6 weeks) 
  Antibody-based anti-cancer therapy: ≥4 weeks.  
 Chloroquine/Hydroxychloroquine: >14 days 
12. Male and female subjects of reproductive/childbearing potential must agree to use a 
highly effective form of contraception or avoid intercourse during and upon completion 
of the study and for at least 7 months after the last dose of study drug. Methods 
considered as highly effective methods of contraception include:  
 Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
a. Oral 
b. Intravaginal 
c. Transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
a. Oral 
b. Injectable 
c. Implantable 
 Intrauterine device  
 Intrauterine hormone-releasing system  


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 Bilateral tubal occlusion 
 Vasectomized partner 
 Complete sexual abstinence, defined as refraining from heterosexual intercourse 
during and upon completion of the study and for at least 7 months (males and 
females) after the last dose of study drug.  Periodic abstinence (calendar, 
symptothermal, post-ovulation methods) is not an acceptable method of 
contraception.   
13. Non-childbearing potential defined as pre-menopausal females with a documented tubal 
ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous 
amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating 
hormone >40 mIU/mL and estradiol <40 pg/mL [<147 pmol/L] is confirmatory). Females 
on HRT and whose menopausal status is in doubt will be required to use 1 of the 
contraception methods outlined for women of childbearing potential if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status prior to study enrollment.  For most forms of 
HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood 
draw; this interval depends on the type and dosage of HRT.  Following confirmation of 
their postmenopausal status, they can resume use of HRT during the study without use of 
a contraceptive method. 
14. Male subjects must not freeze or donate sperm starting at Screening and throughout the 
study period, and at least 7 months after the final study drug administration.  Preservation 
of sperm should be considered prior to enrollment in this study.  
15. Female subjects must not donate or retrieve ova for their own use from the time of 
Screening and throughout the study treatment period, and for at least 7 months after the 
final study drug administration.   
16.  Life expectancy of at least 3 months. 
4.1.2. 
Inclusion Criteria Specific to Part 1 
Subjects meeting the eligibility criteria set up for any of the 4 cohorts in Part 2 would be eligible 
to enroll in Part 1. 
4.1.3. 
Inclusion Criteria Specific to Part 2 
For Cohort 1:  
1. Pathologically documented advanced/metastatic breast cancer that has 
centrally-determined HER2-positive expression as per ASCO-CAP guidelines. 
2. Prior T-DM1 therapy with documented progression. 
For Cohort 2: 
1. Pathologically documented advanced/metastatic breast cancer that has 
centrally-determined low HER2 expression (IHC 1+ or IHC 2+/ISH-). 


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2. Subject must have exhausted treatments that can confer any clinically meaningful benefit 
(e.g., other therapies such as hormonal therapy for patients who are hormone receptor 
positive). 
For Cohort 3:  
1. Pathologically documented advanced/metastatic urothelial carcinoma that has 
centrally-determined HER2 expression of IHC 2+ or 3+. 
2. Prior treatment with a platinum-based combination chemotherapy regimen with 
documented progression.   
For Cohort 4: 
1. Pathologically documented advanced/metastatic urothelial carcinoma that has 
centrally-determined HER2 expression of IHC 1+. 
2. Prior treatment with a platinum-based combination chemotherapy regimen with 
documented progression.   
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 
1. Has received prior treatment with nivolumab or trastuzumab deruxtecan.  
2. Medical history of myocardial infarction within 6 months before enrollment, 
symptomatic congestive heart failure (New York Heart Association Class II to IV). 
Subjects with troponin levels above ULN at screening (as defined by the manufacturer), 
and without any MI related symptoms should have a cardiologic consultation before 
enrollment to rule out MI.  
3. Has a QTcF prolongation to >470 ms (females) or >450 ms (males) based on an average 
of the screening triplicate12-lead electrocardiograms ECGs. 
4. Has a history of ILD/pneumonitis (non-infectious) that required steroids, has current 
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at 
screening.  
5. Subjects with a condition requiring systemic treatment with either corticosteroids 
(>10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement 
steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease. 
6. Has spinal cord compression or clinically active central nervous system metastases, 
defined as untreated and symptomatic, or requiring therapy with corticosteroids or 
anticonvulsants to control associated symptoms. Subjects with clinically inactive brain 
metastases may be included in the study. Subjects with treated brain metastases that are 
no longer symptomatic and do not require treatment with corticosteroids or 
anticonvulsants may be included in the study if they have recovered from the acute toxic 
effect of radiotherapy. A minimum of 2 weeks must have elapsed between being 


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symptomatic or requiring therapy with corticosteroids or between the end of whole brain 
radiotherapy and study enrollment. 
7. Known carcinomatous meningitis. 
8. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin, and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are 
live attenuated vaccines and are not allowed. 
9. Subjects with an active, known or suspected autoimmune disease.  Participants with type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions 
not expected to recur in the absence of an external trigger are permitted to enroll. 
10. Uncontrolled adrenal insufficiency. 
11. Has had prior anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other 
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. 
12. Prior anti-HER2 therapy is not permitted except for subjects with HER2-positive breast 
cancer as per ASCO-CAP guidelines.  Note: Subjects with HER2 negative residual 
disease treated with adjuvant anti HER2 therapy as per standard practice may be eligible. 
13. Has multiple primary malignancies within 3 years, except adequately resected 
non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors 
curatively treated, or contralateral breast cancer (metastatic breast cancer indication). 
14. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses 
including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary emboli 
within three months of the study enrollment, severe asthma, severe COPD, restrictive 
lung disease, pleural effusion etc.), and any autoimmune, connective tissue or 
inflammatory disorders with pulmonary involvement (i.e. Rheumatoid arthritis, Sjogren's, 
sarcoidosis etc.), or prior pneumonectomy. 
15. Has history of severe hypersensitivity reactions to other monoclonal antibodies and/or to 
either the drug substances or inactive ingredients in the drug product. 
16. Has known psychiatric, substance abuse, or any other medical conditions such as 
clinically significant cardiac or psychological conditions, that may, in the opinion of the 
investigator, interfere with the subject’s participation in the clinical study or evaluation of 
the clinical study results.   
17. Has known human immunodeficiency virus (HIV) infection, or active hepatitis B or C 
infection.  Subjects positive for hepatitis C (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA.  Subjects should be tested for HIV 
prior to enrollment if required by local regulations or Institutional Review Board 
(IRB)/Ethics Committee (EC). 


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18. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject's participation for 
the full duration of the study, or is not in the best interest of the subject to participate, in 
the opinion of the treating Investigator. 
19. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other 
than alopecia) not yet resolved to Grade ≤1 or baseline.  Subjects with chronic Grade 2 
toxicities may be eligible per the discretion of the investigator after consultation with the 
Medical Monitor or designee (e.g., Grade 2 chemotherapy-induced neuropathy). 
20. Is pregnant, breastfeeding, or planning to become pregnant.  
21. History of previous organ transplantation, including stem cell allograft. 
22. Has an uncontrolled infection requiring intravenous (IV) antibiotics, anti-virals, or 
anti-fungals. Uncontrolled infection is inclusive of active tuberculosis. 
23. Otherwise considered inappropriate for the study by the investigator. 
24. Subject must not be a family member of study site personnel working for the investigator 
or of Sponsor personnel. 


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5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
Treatment Group(s)/Sequences 
This study consists of 2 dose levels of trastuzumab deruxtecan with a flat dose of nivolumab for 
dose escalation (Part 1) and 4 expansion cohorts (Part 2).  All subjects will be receiving 
nivolumab and trastuzumab deruxtecan.  Nivolumab will be administered prior to trastuzumab 
deruxtecan.  Part 2 enrollment will start after Part 1 is completed and an RDE has been 
established.   
5.1.2. 
Method of Treatment Allocation 
For Part 1, treatment allocation is based on available dose combination following the 3 + 3 + 3 
design.  Details of dose escalation are provided in Section 3.2.5.  For Part 2, subjects of all 
4 expansion cohorts will be treated with RDE of trastuzumab deruxtecan plus nivolumab. 
5.1.3. 
Blinding 
Not applicable due to single-arm study design (no comparator arm). 
5.1.4. 
Emergency Unblinding Procedure 
Not applicable due to single-arm study design (no comparator arm). 
5.2. 
Study Drug(s) 
5.2.1. 
Description 
The trastuzumab deruxtecan drug product will be provided as a lyophilized powder containing 
100 mg of trastuzumab deruxtecan in a glass vial.  Each glass vial should be reconstituted with 
sterile water to a concentration of 20.0 mg/mL.  Each vial is designed for single use only and is 
not to be used to treat more than 1 subject. 
Nivolumab injection, 100 mg/10 mL (10 mg/mL) or 40 mg/4 mL (10 mg/mL) is a clear to 
opalescent, colorless to pale yellow liquid, which may contain light (few) particulates.  It is 
supplied in 10-mL Type I flint glass vials, stoppered with butyl rubber stoppers and sealed with 
aluminum seals.  Each vial is designed for single use only and is not to be used to treat more than 
1 subject. 
5.2.2. 
Labeling and Packaging 
Trastuzumab deruxtecan and nivolumab will be supplied by the Sponsor.  Both drugs will be 
labeled in compliance with regulatory requirements and packaged.  The packaging will clearly 
display the name of the study drug, the lot number, storage condition, and other required 
information in accordance with local regulations. 


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5.2.3. 
Preparation 
The study drug (DS-8201) for IV infusion is prepared by the study site pharmacist by 
reconstitution with sterile water for injection and dilution of the required volume of the study 
drug calculated based on the subject’s body weight in a volume of 100 mL.  Prepared study drug 
solutions should be used as directed in the Pharmacy Manual.  The preparation will be conducted 
in accordance with the Pharmacy Manual provided by the Sponsor.  Procedures for proper 
handling and disposal of anticancer drugs should be followed in compliance with the standard 
operating procedures of the study site. 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron 
pore size, low-protein binding (polyethersulfone membrane) in-line filter at the 
protocol-specified doses and infusion times. It is not to be administered as an IV push or bolus 
injection.  Nivolumab injection can be infused undiluted or diluted so as not to exceed a total 
infusion volume of 120 mL. 
During drug product preparation and handling, vigorous mixing or shaking is to be avoided.  
Instructions for dilution and infusion of nivolumab injection are provided in the Pharmacy 
Manual.  Care must be taken to assure sterility of the prepared solution as the product does not 
contain any antimicrobial preservative or bacteriostatic agent.  Nivolumab infusions are 
compatible with glass bottles and polyvinyl chloride or polyolefin containers and infusion sets. 
5.2.4. 
Administration 
Nivolumab will be infused over approximately 30 minutes on Day 1 of each cycle prior to the 
administration of trastuzumab deruxtecan with no less than a 30-minute gap between the 
infusions of the 2 study drugs.  Do not co-administer the 2 drugs through the same IV line.  Flush 
the IV line after infusion of each drug.  Since nivolumab contains only human immunoglobulin 
protein sequences, it is unlikely to be immunogenic and induce infusion or hypersensitivity 
reactions. However, if such a reaction were to occur, it might manifest with fever, chills, rigors, 
headache, rash, pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other 
allergic-like reactions. All Grade 3 or 4 infusion reactions should be reported within 24 hours to 
the study medical monitor/designee and reported as an SAE if it meets the criteria. Infusion 
reactions should be graded according to NCI CTCAE version 5.   
The study drug (trastuzumab deruxtecan) will be administered initially as an IV infusion over 
30 or 90 minutes every 3 weeks.  The initial dose of trastuzumab deruxtecan will be infused over 
approximately 90 minutes.  If there is no infusion-related reaction, after the initial dose, the next 
dose of trastuzumab deruxtecan will be infused for approximately 30 minutes.  The prophylactic 
premedication can be administered as per investigator’s discretion and as per institutional 
guidelines for subjects who have experienced potential Grades 1-2 infusion-related reactions 
during the previous infusion.  The subject’s weight at screening (baseline) will be used to 
calculate the initial dose.  During the course of treatment, if the subject’s weight changes by 
± 10% of the baseline weight, then recalculate the trastuzumab deruxtecan dose based on the 
subject’s updated weight.  Refer to the pharmacy instructions for detailed information about 
administration of study drug. 
It is recommended that study sites provide basic life support and advanced life support with 
necessary equipment and appropriate and available emergency medications to manage any 


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potential hypersensitivity/infusion-related reactions in/or close proximity to the infusion area.  At 
least an oxygen tank, nasal prongs, and an oxygen mask must be available to manage respiratory 
symptoms.  Access to other respiratory equipment is also critical in all settings of care and would 
include an ambu bag, oral airway, and suction apparatus in case a subject becomes unconscious.  
Large-gauge IV catheters are recommended to enable administration of normal saline and 
emergency medications.  A cardiopulmonary resuscitation board is not necessary as long as the 
treatment chairs are low enough for a subject to be eased to the floor if necessary.  
5.2.4.1. 
Maximum Duration of Treatment with Nivolumab 
The optimal duration of immunotherapy is currently unknown.  However, because 
immunotherapy engages the immune system to control the tumor, continuous treatment as is 
required with targeted agents or cytotoxic therapy may not be necessary.  
Accumulating evidence from different clinical trials in different tumor types with nivolumab, or 
nivolumab combined to ipilimumab, indicates that most of the responses are generally occurring 
early, with a median TTR of 2 to 4 months, including in patients with NSCLC,18,19 and a recent 
analysis in a melanoma study suggests the majority of patients who discontinue nivolumab 
and/or ipilimumab for toxicity maintain disease control in the absence of further treatment.20 
For these reasons, in study DS8201-A-U105, treatment with nivolumab will be administered for 
up to 35 cycles/approximately 24 months in the absence of disease progression or unacceptable 
toxicity.  Trastuzumab deruxtecan will be given as per the study dosing schedule (Table 17.1). 
Treatment with nivolumab could be reinitiated as per the initial schedule for subsequent disease 
progression and administered for up to 1 additional year. 
5.2.5. 
Storage 
Drug supplies must be stored in a secure, limited-access storage area under the recommended 
storage conditions. 
Trastuzumab Deruxtecan 
 Stored at 2°C to 8°C (protected from light) 
Nivolumab 
 Vials of nivolumab injection must be stored at 2°C to 8°C (36°F to 46°F) and 
protected from light and freezing. 
If storage conditions are not maintained per specified requirements, the Sponsor or Clinical 
Research Organization (CRO) should be contacted. 
The administration of nivolumab infusion must be completed within 24 hours of preparation. If 
not used immediately, the infusion solution may be stored under refrigeration conditions (2°C to 
8°C [36°F to 46°F]) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at 
room temperature (20°C to 25°C [68°F to 77°F]) and room light. The maximum of 8 hours under 
room temperature and room light conditions includes the product administration period. 
See the Pharmacy Manual for storage conditions of the infusion solution. 


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5.2.6. 
Drug Accountability 
When a drug shipment is received, the investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label, check the drug expiration 
date, and sign the Receipt of Shipment Form provided.   
The Receipt of Shipment Form should be faxed as instructed on the form unless receipt is 
controlled by an Interactive Web/Voice Response System.  The original will be retained at the 
study site.   
In addition, the investigator or designee shall contact the Sponsor as soon as possible if there is a 
problem with the shipment. 
A Drug Accountability Record will be provided for the study drugs, active drugs, and diluents or 
products of regulatory concern.  The record must be kept current and should contain; 
 The dates and quantities of study drug received,  
 Subject’s identification number and/or initials or supply number, as applicable, (for 
whom the study drug was dispensed).  
 The date and quantity of study drug dispensed and remaining.  
 The initials of the dispenser. 
At the end of the study, a final study drug reconciliation statement must be completed by the 
investigator or designee and provided to the Sponsor.  Unused drug supplies may be destroyed 
by the investigator when approved in writing by the Sponsor and the Sponsor has received copies 
of the study site’s drug handling and disposition standard operating procedures and it is ensured 
that the Sponsor will receive copies of the certificate of destruction that is traceable to the study 
drug. 
All study drug inventory forms must be made available for inspection by a Sponsor authorized 
representative or designee and regulatory agency inspectors. 
5.3. 
Control Treatment 
Not applicable due to single-arm study design. 
5.4. 
Dose-Limiting Toxicity or Maximum Tolerated Dose 
See Section 3.2.3, Section 3.2.4, and Section 3.2.5. 
5.5. 
Dose Modification (Delay, Reduction, and/or Discontinuation) for 
Trastuzumab Deruxtecan and Nivolumab 
5.5.1. 
Guidelines for Delay, Reduction and/or Discontinuation for Trastuzumab 
Deruxtecan and Nivolumab 
All dose modifications (interruption, reduction, and/or discontinuation) should be based on the 
worst preceding toxicity (CTCAE version 5.0) as shown in Table 5.1 Specific criteria for 
interruption, re-initiation, dose reduction and/or discontinuation of trastuzumab deruxtecan are 
listed in the table below, which is applicable only to TEAEs that are assessed as related to use of 


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trastuzumab deruxtecan by the investigator.  For non-drug related TEAEs, follow standard 
clinical practice.  Appropriate clinical experts should be consulted as deemed necessary.   
Dose increases are not permitted for trastuzumab deruxtecan. In the event that a dose reduction 
of trastuzumab deruxtecan is required, only 2 dose reductions are allowed:  dose level -1: 
4.4mg/kg, and dose level -2: 3.2mg/kg.  Dose reductions below 3.2 mg/kg are strictly prohibited.  
Once the dose of trastuzumab deruxtecan has been reduced because of toxicity, all subsequent 
cycles should be administered at that lower dose level unless further dose reduction is required.  
If toxicity continues after 2 dose reductions, the subject will be withdrawn from the study 
treatment. 
Dose reductions or increases for nivolumab are not permitted. 
All interruptions or modifications must be recorded on the case report form (CRF). Appropriate 
clinical experts should be consulted as deemed necessary.  
For Grade 3 or Grade 4 events, monitoring (including local laboratory tests when appropriate) 
should be performed at intervals no greater than 7 days until AE is determined to be resolving or 
back to baseline.  Monitoring of Grade 3 or 4 AEs will also be performed for subjects who 
discontinued study treatment (s). 
Prophylactic or supportive treatment for expected toxicities will be as per the treating physician’s 
discretion and institutional guidelines. 
If a specific toxicity can be attributed to only 1 of the study treatments, then the management 
guidelines for that specific treatment should be followed as listed in Table 5.1 below.  
However, if a specific toxicity cannot be attributed to only 1 of the study treatments, the 
management guidelines for each of the study treatments should be followed as listed in Table 5.1 
below. 
In cases of diarrhea/colitis and pulmonary toxicities, management guidelines for each of the 
study treatments should be followed, regardless of the causality assessment.  
NOTE: There will be no dose modifications for Grade 1 or Grade 2 AEs unless specified in 
Table 5.1 below. 
Dose reduction for trastuzumab deruxtecan in Part 2 will be applicable and will be based on the 
RDE dose and available lower dose level(s).  The study treatment (either or both drugs) can be 
delayed up to 7 weeks from the previous dose received beyond which the subject will be 
withdrawn from the study drug.  If the subject will restart/continue on both the study drugs, then 
it is recommended that both drugs are given on the same day whenever possible.  
Future cycles schedule should be based on the date of the last study treatment received.   
All confirmed or suspected Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) 
infection events must be recorded in the eCRF.  Please refer to Section 1.1 for additional 
information on dose modification. 


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5.5.2. 
Toxicity Management for Immune-Related Adverse Events Associated With 
Nivolumab 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice.  Non-inflammatory etiologies should be considered and appropriately 
treated.  Corticosteroids are a primary therapy for immuno-oncology drug-related AEs.  The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity.  The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.  Consultation with a medical or 
surgical specialist, especially prior to an invasive diagnostic or therapeutic procedure, is 
recommended. 
Adverse events associated with nivolumab exposure may represent an immunologic etiology.  
These immune-related AEs (irAEs) may occur shortly after the first dose or several months after 
the last dose of nivolumab treatment and may affect more than 1 body system simultaneously.  
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of nivolumab, administration of corticosteroids, and/or other supportive care.  For 
suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes.  
Additional procedures or tests such as bronchoscopy and endoscopy may be included as part of 
the evaluation.  Based on the severity of irAEs, withhold or permanently discontinue nivolumab 
and administer corticosteroids.  Dose modification and toxicity management guidelines for 
immune-mediated AEs associated with nivolumab are provided in Appendix 17.7. 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (unless 
otherwise specified): Dose or Schedule Modification for 
Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (unless otherwise 
specified): Dose or Schedule Modification for Nivolumab 
Infusion Reaction 
 
Grade 1 
If infusion-related reaction (such as fever and chills, with 
and without nausea/vomiting, pain, headache, dizziness, 
dyspnea, hypotension) is observed during administration, 
the infusion 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 1 
Infusion interruption not indicated. 
Intervention not indicated. 
Remain at bedside and monitor subject until recovery from 
symptoms. 
The following prophylactic pre-medications are recommended for 
future infusions: diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes 
before additional nivolumab administrations 
 
Grade 2  
Interrupt the infusion. 
Symptomatic treatment started (e.g., antihistamines, 
nonsteroidal anti-inflammatory drugs, narcotics, 
intravenous [IV] fluids). 
If the event resolves or improves to Grade 1, infusion can 
be re-started at a 50% reduced infusion rate. 
Subsequent administrations should be conducted at the 
reduced rate. 
Use of prophylactic premedication is recommended as per 
investigator’s discretion and as per institutional guidelines 
for subjects who had Grade 2 (or above) infusion-related 
reactions during the previous infusion. 
Grade 2  
Stop the infusion. 
Begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 
to 1000 mg (acetaminophen). 
Remain at bedside and monitor subject until resolution of symptoms. 
When symptoms resolve, restart at 50% of the original infusion rate. 
If no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate.   
Monitor participant closely. If symptoms recur, then no further study 
medication will be administered at that visit. 
For future infusions, the following prophylactic pre-medications are 
recommended: 
Diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg should be administered 
at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be 
used. 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (unless 
otherwise specified): Dose or Schedule Modification for 
Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (unless otherwise 
specified): Dose or Schedule Modification for Nivolumab 
 
Grade 3-4 
Discontinue immediately and permanently.  
Urgent intervention needed. 
Grade 3-4 
Immediately discontinue infusion of study drug. Begin an IV 
infusion of normal saline and treat the participant as follows: 
Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000 
solution for subcutaneous administration or 0.1 to 0.25 mg of a 
1:10,000 solution injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or 
equivalent), as needed. Participant should be monitored until the 
Investigator is comfortable that the symptoms will not recur. Study 
drug will be permanently discontinued. Investigators should follow 
their institutional guidelines for the treatment of anaphylaxis. Remain 
at bedside and monitor participant until recovery of the symptoms. 
In case of late-occurring hypersensitivity symptoms (eg, appearance 
of a localized or generalized pruritus within 1 week after treatment), 
symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).   
 
 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (unless 
otherwise specified): Dose or Schedule Modification for 
Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (unless otherwise 
specified): Dose or Schedule Modification for Nivolumab 
Hematologic Toxicity 
Neutrophil Count 
Decreased and/or 
White Blood Cell 
Count Decreased 
Grade 3 
Delay dose until resolved to ≤Grade 2, then maintain dose. 
 
Grade 4  
Delay dose until resolved to ≤Grade 2; reduce dose 1 level. 
Grade 1-2   
No dose modification. 
Grade 3  
First occurrence: withhold dose - resume treatment when improves to 
Grade 0 or 1  
Recurrence of same Grade 3:  permanently discontinue 
Grade 4  
Permanently Discontinue 
Febrile Neutropenia  
Delay dose until resolved; reduce dose 1 level. 
Grade 3 
First occurrence: withhold dose – resume treatment when it improves 
to grade 0. 
Recurrence of same grade 3: permanently discontinue 
Grade 4:  
Permanently discontinue 
Lymphocyte Count 
Decreased 
Grade 1-3 
No dose modification. 
 
Grade 4  
Delay dose until resolved to ≤ Grade 2. 
If resolved in ≤14 days from day of onset, maintain dose. 
If resolved in >14 days from day of onset, reduce dose 1 
level. 
Grade 1-2  
No dose modification. 
 
Grade 3  
First occurrence: withhold dose - resume treatment when improves to 
Grade 0 or 1  
Recurrence of same Grade 3:  permanently discontinue 
 
Grade 4  
Permanently discontinue.   
 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (unless 
otherwise specified): Dose or Schedule Modification for 
Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (unless otherwise 
specified): Dose or Schedule Modification for Nivolumab 
Anaemia 
Grade 3  
Delay dose until resolved to Grade ≤2, then maintain dose. 
Grade 4  
Delay dose until resolved to Grade ≤2; reduce dose 1 level. 
Grade 1-2 
No dose modification. 
Grade 3   
First occurrence: withhold dose - resume treatment when improves to 
Grade 0 or 1  
Recurrence of same Grade 3:  permanently discontinue 
Grade 4  
Permanently discontinue. 
 
Platelet Count 
Decreased  
Grade 1-2 
No dose modification. 
Grade 3  
Delay dose until resolved to ≤Grade 1. 
If resolved in ≤7 days from day of onset, maintain dose. 
If resolved in >7 days from day of onset, reduce dose 1 
level. 
 
Grade 4  
Delay dose until resolved to ≤Grade 1, then reduce dose 1 
level. 
 
Grade 1-2  
No dose modification. 
Grade 3   
First occurrence: withhold dose - resume treatment when improves to 
Grade 0 or 1  
Recurrence of same Grade 3:  permanently discontinue 
Grade 4  
Permanently discontinue. 
 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless 
Otherwise Specified): Dose Or Schedule Modification 
For Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless Otherwise 
Specified): Dose Or Schedule Modification For Nivolumab 
Renal Toxicity 
Blood Creatinine 
Increased 
Grade 3 (>3.0 to 6.0 × ULN)  
Delay dose until resolved to ≤Grade 2 or baseline.  
Reduce dose 1 level. 
 
Grade 4 (>6.0 × ULN) 
Discontinue subject from study treatment. 
Grade 2 and 3  
Delay dose. Resume treatment when it improves to Grade 0 or 1. 
 
Grade 4  
Discontinue. 
 
Hepatic Toxicity 
AST/ALT ≥3.0 × ULN 
with Simultaneous 
Total Bilirubin >2.0 × 
ULN 
 
Delay study medication until drug-induced liver injury can 
be ruled out.  
If drug-induced liver injury is ruled out, the subject should 
be treated accordingly, and resumption of study drug may 
occur after discussion between the Investigator and 
Sponsor.  
If drug-induced liver injury cannot be ruled out from 
diagnostic workup, permanently discontinue study 
treatment. 
Monitor AST/ALT and total bilirubin twice weekly until 
resolution or return to baseline. 
 
Discontinue if:  
Concurrent AST or ALT >3 × ULN and total bilirubin >2 × ULN. 
 
 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless 
Otherwise Specified): Dose Or Schedule Modification 
For Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless Otherwise 
Specified): Dose Or Schedule Modification For Nivolumab 
AST/ALT 
 
 
 
 
Grade 2 (>3.0 - 5.0 × ULN if baseline was normal; >3.0 - 
5.0 × baseline if baseline was abnormal) 
No action 
  
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 ≤3 × ULN: 
Repeat testing within 3 days. Delay dose until resolved to 
≤Grade 1, if baseline ≤ 3 x ULN, otherwise delay dose until 
resolved to ≤ baseline then: 
If resolved in ≤7 days from day of onset, maintain dose. 
If resolved in >7 days from day of onset, reduce dose 1 
level. 
Grade 3 (>8.0 - 20.0 × ULN if baseline was normal; >8.0 
- 20.0 × baseline if baseline was abnormal).  In subjects 
with liver metastases, if the baseline level was >3 × 
ULN: 
Repeat testing within 3 days. Delay dose until resolved to 
≤baseline level, then: 
If resolved in ≤7 days from day of onset, maintain dose. 
If resolved in >7 days from day of onset, reduce dose 1 
level. 
 
Grade 4(>20.0 × ULN if baseline was normal; >20.0 × 
baseline if baseline was abnormal)  
Discontinue subject from study treatment. 
 
For subjects without baseline liver metastases: 
Grade 2 (>3.0 - 5.0 × ULN if baseline was normal; >3.0 - 5.0 × 
baseline if baseline was abnormal):  
Delay dose. Resume treatment when it improves to Grade 0 or 1. 
 
Grade 3 (>5.0 - 20.0 × ULN if baseline was normal; >5.0 - 20.0 × 
baseline if baseline was abnormal) or higher:  
Permanently discontinue  
 
Note: In most cases of Grade 3 AST or ALT elevation, study drug(s) 
will be permanently discontinued. If the investigator determines a 
possible favorable benefit/risk ratio that warrants continuation of 
study drug(s), a discussion between the investigator and the Sponsor 
Medical Monitor/designee must occur. 
 
For subjects with baseline liver metastases  
Grade 2 & 3 (up to 10 times the ULN): 
Withhold dose. Resume treatment when it improves to Grade 0 or 1 
 
Grade 3 (from 10 - 20 times the ULN) and grade 4 AST or ALT: 
Permanently discontinue 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless 
Otherwise Specified): Dose Or Schedule Modification 
For Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless Otherwise 
Specified): Dose Or Schedule Modification For Nivolumab 
Blood Alkaline 
Phosphatase Increased 
Grade 3 (>5.0 - 20.0 × ULN if baseline was normal; >5.0 
- 20.0 × baseline if baseline was abnormal) 
or 
Grade 4 (>20.0 × ULN if baseline was normal; >20.0 × 
baseline if baseline was abnormal): 
 
No modification unless determined by the Investigator to 
be clinically significant or life-threatening. 
 
 
Grade 2 – 4  
Withhold if clinically significant or life-threatening determined by 
the investigator. Resume treatment when it improves to Grade 0 or 1  
 
 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless 
Otherwise Specified): Dose Or Schedule Modification 
For Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless Otherwise 
Specified): Dose Or Schedule Modification For Nivolumab 
Total Bilirubin 
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 dose until resolved to ≤ Grade 1: 
If resolved in ≤ 7 days from day of onset, maintain dose 
If resolved in > 7 days from day of onset, reduce dose 1 
level 
If documented Gilbert’s syndrome or liver metastases at 
baseline, continue study treatment 
Grade 3 (>3.0 - 10.0 × ULN if baseline was normal; >3.0 
- 10.0 × baseline if baseline was abnormal) 
If no documented Gilbert’s syndrome or liver metastases at 
baseline, repeat testing within 3 days, delay dose until 
resolved to ≤ Grade 1: 
If resolved in ≤ 7 days from day of onset, reduce dose 1 
level 
If resolved in > 7 days from day of onset, discontinue 
trastuzumab deruxtecan 
If documented Gilbert’s syndrome or liver metastases at 
baseline, repeat testing within 3 days. Delay dose until 
resolved to ≤Grade 2: 
If resolved in ≤ 7 days from day of onset, reduce dose 1 
level 
If resolved in > 7 days from day of onset, discontinue 
trastuzumab deruxtecan 
Grade 4 (>10.0 × ULN if baseline was normal; >10.0 × 
baseline if baseline was abnormal) 
Discontinue subject from study treatment. 
Grade 2 
Withhold. Resume treatment when it improves to Grade 0 or 1. 
 
Grade  3 Total Bilirubin 
Permanently discontinue. 
 
 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless 
Otherwise Specified): Dose Or Schedule Modification 
For Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless Otherwise 
Specified): Dose Or Schedule Modification For Nivolumab 
Gastrointestinal 
Nausea 
 
Grade 3  
Delay dose until resolved to ≤Grade 1 
If resolved in ≤7 days from day of onset, maintain dose. 
If resolved in >7 days from day of onset, reduce dose 1 
level. 
 
Refer to “Other Non-laboratory Adverse Events” for Nivolumab. 
Diarrhea/Colitis  
Regardless of the causality assessment, also follow the 
diarrhea/colitis treatment guidelines for nivolumab. 
 
Grade 3  
Delay dose until resolved to Grade 1. 
If resolved in ≤3 days from day of onset, maintain dose. 
If resolved in >3 days from day of onset, reduce dose 1 
level. 
Grade 4 
Discontinue subject from study treatment. 
 
Regardless of the causality assessment, also follow the 
diarrhea/colitis treatment guidelines for trastuzumab deruxtecan. 
 
Grade 2 & 3 
Withhold dose. Resume treatment when it improves to Grade 0 or 1. 
 
 
Grade 4 
Permanently discontinue. 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless 
Otherwise Specified): Dose Or Schedule Modification For 
Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless Otherwise 
Specified): Dose Or Schedule Modification For Nivolumab 
Pulmonary Toxicity 
Regardless of the causality assessment, also follow the 
pulmonary toxicity treatment guidelines for nivolumab. 
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 the AE is confirmed to have an etiology other than 
ILD/pneumonitis, follow the management guidance outlined 
in the “Other Non-laboratory Adverse Events” dose 
modification section below. 
If the AE is suspected to be ILD/pneumonitis, treatment with 
study drug should be interrupted pending further evaluations.  
Evaluations should include: 
High resolution CT  
Pulmonologist consultation (Infectious Disease consultation 
as clinically indicated)  
Blood culture and CBC. Other BLOOD tests could be 
considered as needed 
Consider bronchoscopy and bronchoalveolar lavage if 
clinically indicated and feasible 
Pulmonary function tests and pulse oximetry (SpO2) 
Arterial blood gases if clinically indicated 
One blood sample collection for PK 
(central) analysis as soon as ILD/pneumonitis is 
suspected, if feasible.  
Other tests could be considered, as needed.  
If the AE is confirmed to be ILD/pneumonitis, follow the 
ILD/pneumonitis management guidance as outlined below. 
 
Regardless of the causality assessment, also follow the pulmonary 
toxicity treatment guidelines for trastuzumab deruxtecan. 
 
Grade 1 (radiological changes only) 
Consider dose delay. 
Monitor symptoms every 2-3 days. 
Consider pulmonary and infectious disease consults. 
Re-image as clinically indicated. 
 
Grade 2 (mild to moderate new symptoms) 
Delay dose. 
Pulmonary and infectious disease consults. 
Monitor symptoms daily; consider hospitalization. 
Systemic corticosteroids. 
Consider lung biopsy, bronchoscopy. 
Re-image as clinically indicated. 
 
Grade 3-4 
Permanently discontinue study therapy.  
Pulmonary and infectious disease consults. 
Systemic corticosteroids. 
Consider lung biopsy, bronchoscopy. 
Add prophylactic antibiotics. 
If worsening: add additional immunosuppression. 
 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless 
Otherwise Specified): Dose Or Schedule Modification For 
Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless Otherwise 
Specified): Dose Or Schedule Modification For Nivolumab 
Pulmonary Toxicity 
(Cont’d) 
 
All events of ILD/pneumonitis regardless of severity or 
seriousness will be followed until resolution including after 
drug discontinuation. 
Confirmed study drug-induced ILD  
Grade 1 
The administration of trastuzumab deruxtecan must be 
interrupted for any ILD/pneumonitis events regardless of grad 
Monitor and closely follow-up in 2 to 7 days for onset of 
clinical symptoms and pulse oximetry 
Consider follow-up imaging in 1-2 weeks (or as clinically 
indicated). 
Consider starting systemic steroids (e.g. 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 should still be 
considered as Grade 1 even if steroid treatment is given  
 
For Grade 1 events, trastuzumab deruxtecan 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  
 
 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless 
Otherwise Specified): Dose Or Schedule Modification For 
Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless Otherwise 
Specified): Dose Or Schedule Modification For Nivolumab 
 
Grade 2 
Permanently discontinue subject from study treatment. 
Promptly start and treat with systemic steroids (e.g., at least 
1mg/kg/day prednisone or equivalent) for at least 14 days or 
until complete resolution of clinical and chest CT findings, 
then followed by a gradual taper over at least 4 weeks.   
Monitor symptoms closely. 
Re-image as clinically indicated. 
If worsening or no improvement in clinical or diagnostic 
observations in 5 days,  
Consider increasing dose of steroids (e.g., 2 mg/kg/day 
prednisone or equivalent) and administration may be switched 
to intravenous (e.g. methylprednisolone). 
Re-consider additional work-up for alternative etiologies as 
described above. 
Escalate care as clinically indicated. 
Grade 3 and 4 
Permanently discontinue subject from study treatment.   
Hospitalization required. 
Promptly initiate empiric high-dose methylprednisolone IV 
treatment (e.g., 500-1000 mg/day for 3 days), followed by at 
least 1.0 mg/kg/day of prednisone (or equivalent) for at least 
14 days or until complete resolution of clinical and chest CT 
findings, then followed by a gradual taper over at least 4 
weeks. 
Re-image as clinically indicated. 
If still no improvement within 3 to 5 days,  
Re-consider additional work-up for alternative etiologies as 
described above. 
Consider other immuno-suppressants and/or treat per local 
practice. 
 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless 
Otherwise Specified): Dose Or Schedule Modification For 
Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless Otherwise 
Specified): Dose Or Schedule Modification For Nivolumab 
Ocular 
 
Grade 3 
Delay dose until resolved to ≤ Grade 1: 
If resolved in ≤ 7 days from day of onset, maintain dose 
If resolved in > 7 days from day of onset, reduce dose 1 level 
Grade 4  
Discontinue subject from study treatment 
 
Grade 2  
Withhold. Resume treatment when it improves to Grade 0 or 1. 
 
Grade 3-4: 
Permanently discontinue 
 
Cardiac Toxicity 
Symptomatic 
congestive heart 
failure  
 
Discontinue subject from study treatment. 
 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless 
Otherwise Specified): Dose or Schedule Modification For 
Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (Unless Otherwise 
Specified): Dose Or Schedule Modification For Nivolumab 
 
Left Ventricular 
Ejection Fraction 
(LVEF) 
 
LVEF >45% and decrease in LVEF by 10% to 20% 
(absolute value) 
Continue treatment with trastuzumab deruxtecan.  
 
LVEF 40% to ≤45% and decrease is <10% (absolute 
value) from baseline 
Continue treatment with trastuzumab deruxtecan. 
Repeat LVEF assessment within 3 weeks. 
 
LVEF 40% to ≤45% and decrease is 10-20% (absolute 
value) from baseline 
Interrupt trastuzumab deruxtecan dosing. 
Repeat LVEF assessment within 3 weeks. 
If LVEF has not recovered to within 10% (absolute value) 
from baseline, discontinue subject from study treatment.  If 
LVEF recovers to within 10% from baseline, resume study 
drug treatment 
 
LVEF <40% or >20% (absolute value) drop from baseline 
Interrupt trastuzumab deruxtecan dosing. 
Repeat LVEF assessment within 3 weeks. 
If LVEF <40% or >20% drop from baseline is confirmed, 
discontinue subject from study treatment. 
 
Grade 3 & 4  
Permanently discontinue. 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (unless otherwise 
specified): Dose or Schedule Modification for trastuzumab 
deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (unless otherwise 
specified): Dose or Schedule Modification for Nivolumab 
 Electrocardiogram 
QTcF Prolonged 
Grade 3 (QTc >500 ms on 2 separate ECGs, or >60 ms 
change from baseline) 
 
Delay dose until resolved to ≤Grade 1 (QTc ≤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 attributed to trastuzumab deruxtecan, reduce dose 1 level. 
 
Grade 4 (Torsade de pointes, polymorphic ventricular 
tachycardia, or signs/symptoms of serious arrhythmia) 
Discontinue subject from study treatment. 
Refer to “Other Non-laboratory Adverse Events” for 
Nivolumab. 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (unless 
otherwise specified): Dose or Schedule Modification for 
Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (unless otherwise 
specified): Dose or Schedule Modification for Nivolumab 
Endocrinopathy 
Grade 3 
Delay dose until resolved to ≤Grade 1 or baseline.  
If resolved in ≤7 days from day of onset, maintain dose. 
If resolved in >7 days from day of onset, reduce dose 1 
level. 
 
Grade 4  
Permanently discontinue subject from study treatment. 
Hypophysitis: 
Withhold (Grade 2* or 3*). 
Permanently discontinue (Grade 4). 
Adrenal Insufficiency: 
Withhold (Grade 2*). 
Permanently Discontinue (Grade 3 or 4).  
Type 1 Diabetes Mellitus: 
Withhold (Grade 3*). 
Permanently discontinue (Grade 4). 
Hypothyroidism/Hyperthyroidism: 
Withhold (Symptomatic Grade 2* or 3*). 
Permanently Discontinue (Grade 4). 
 
*Withhold dose(s) until symptoms resolve and management with 
corticosteroids (if needed for symptoms of acute inflammation) is 
complete.  Resume treatment when adverse reaction improves to 
Grade 0 or 1 
Treatment should be continued in the presence of hormone 
replacement therapy as long as no symptoms are present. 
 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (unless 
otherwise specified): Dose or Schedule Modification for 
Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (unless otherwise 
specified): Dose or Schedule Modification for Nivolumab 
Skin Adverse Event 
Grade 3 
Delay dose until resolved to ≤Grade 1 or baseline.  
If resolved in ≤7 days from day of onset, maintain dose. 
If resolved in >7 days from day of onset, reduce dose 1 
level. 
Grade 4 
Discontinue subject from study treatment. 
 
Grade 3 rash or suspected Stevens-Johnson syndrome (SJS) or 
toxic epidermal necrolysis (TEN) 
Withhold dose. Resume treatment when adverse reaction improves to 
Grade 0 or 1.   
 
Grade 4 rash or confirmed SJS or TEN: 
Permanently discontinue. 
 
Other Laboratory 
Adverse Events 
Grade 3 
Delay dose until resolved to ≤Grade 1 or baseline level.  
If resolved in ≤7 days from day of onset, maintain dose. 
If resolved in >7 days from day of onset, reduce dose 1 
level. 
 
Grade 4 
Permanently discontinue subject from study treatment. 
Grades 1-2:  
No modification required 
 
Grade 3:  
First occurrence – withhold treatment. Resume treatment once 
recovered to Grade 0 or 1. 
Recurrence of same grade 3: 
Permanently discontinue 
 
Grade 4  
Permanently discontinue subject from study treatment except for the 
following events which do not require discontinuation: 
Grade 4 asymptomatic amylase or lipase. 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not 
associated with clinical sequelae and are corrected with 
supplementation/appropriate management within 72 hours of their 
onset. 


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Table 5.1: 
Criteria for Dose Modification for Trastuzumab Deruxtecan and Nivolumab (Continued) 
Criteria 
Worst Toxicity NCI-CTCAE Version 5.0 (unless 
otherwise specified): Dose or Schedule Modification for 
Trastuzumab Deruxtecan 
Worst Toxicity NCI-CTCAE Version 5.0 (unless otherwise 
specified): Dose or Schedule Modification for Nivolumab 
Other Non-laboratory 
Adverse Events 
Grade 3 
Delay dose until resolved to ≤ Grade 1 or baseline:  
If resolved in ≤ 7 days from day of onset, maintain dose. 
If resolved in > 7 days from day of onset, reduce dose 1 
level. 
 
Grade 4  
Permanently discontinue subject from study treatment. 
Encephalitis: 
Withhold dose for new-onset moderate or severe neurologic signs or 
symptoms. Resume treatment when adverse reaction improves to 
Grade 0 or 1. 
Permanently discontinue for immune-mediated encephalitis. 
Myocarditis: 
Grade 2: Withhold dose. Follow adverse event management in 
appendix 17.7 
Grade ≥ 3: Permanently discontinue. 
 
Other Non-laboratory Adverse Events: 
Grade 1-2 
No modification required  
Grade 3 
Withhold (first occurrence). Resume treatment when it improves to 
Grade 0 or 1. 
Grade 4 or recurrent Grade 3 
Permanently Discontinue. 
 
Discontinue Nivolumab:  
If require 10 mg per day or greater 
prednisone or equivalent for more than 12 weeks. 
If persistent Grade 2 or 3 adverse reactions lasting 12 weeks or 
longer. 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT = computed tomography; DILI = drug-induced liver injury, ECG = 
electrocardiogram; ILD = interstitial lung disease; NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; ULN = upper 
limit of normal 
 


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5.5.2.1. 
Criteria to Resume Nivolumab Treatment 
If nivolumab dosing has been delayed due to an AE, the subject may resume treatment when the 
drug-related AE resolves to Grade ≤1 or baseline, with the following exceptions: 
 Participants may resume treatment in the presence of Grade 2 fatigue 
 Participants who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity 
 For participants with Grade 2 AST, ALT and/or total bilirubin abnormalities, dosing 
may resume when laboratory values return to baseline and management with 
corticosteroids, if needed, is complete. 
 Participants with combined Grade 2 AST/ALT and total bilirubin values meeting 
discontinuation parameters (Section 5.5.1) should have treatment permanently 
discontinued.  
 Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline 
before treatment is resumed. Participants with persistent Grade 1 pneumonitis after 
completion of a steroid taper over at least 1 month may be eligible for retreatment if 
discussed with and approved by Medical Monitor. 
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the Medical Monitor.  
5.5.2.2. 
Pregnancy 
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of 
this event.  In most cases, the study drug will be permanently discontinued in an appropriate 
manner (e.g., dose tapering if necessary, for participant safety).  Please contact the Sponsor or 
designee within 24 hours of awareness of the pregnancy. If the investigator determines a possible 
favorable benefit/risk ratio that warrants continuation of study drug, a discussion between the 
investigator and the Sponsor or designee must occur. 
5.6. 
Method of Assessing Treatment Compliance 
Trastuzumab deruxtecan and nivolumab will be administered IV only to subjects participating in 
the study and under the supervision of clinical study personnel at the study site. Therefore, 
treatment compliance will be guaranteed as long as the subject attends each visit for 
administration of the study treatment. Start and stop date/time of injection, amount of drug 
administered, and reason for change or interruption (if applicable) must be recorded in medical 
record by clinical study personnel. These data will be recorded in the electronic CRF (eCRF). 
5.7. 
Prior and Concomitant Medications 
Medications used from the time the subject signs the ICF for study participation to the Follow-up 
40 Day Visit (+ 7 days) after the last administration of trastuzumab deruxtecan or nivolumab will 
be recorded.  Prophylactic treatment for the study treatment and all concomitant medications will 
be recorded in the eCRF. Concomitant medications will be collected 40 days after both study 
drugs discontinued. 


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Prohibited Therapies/Products 
The following medications and products will be prohibited during the treatment period. The 
Sponsor must be notified if a subject receives any of these during the study: 
 Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy (other 
than study drug nivolumab), antibody, retinoid, or anticancer hormonal treatment. 
Concurrent use of hormones for noncancer-related conditions (e.g. insulin for 
diabetes and hormone replacement therapy) is acceptable. 
Live vaccines must be avoided during the course of the study and for a period of 
3 months after the last dose of study drug(s). 
 Other investigational therapeutic agents. 
 Radiotherapy (except for palliative radiation to known metastatic sites as long as it 
does not affect assessment of response or interrupt treatment for more than the 
maximum time specified in dose modification Section 5.5. Radiation therapy to a 
symptomatic solitary lesion or to the brain may be allowed at the Investigator's 
discretion. 
 Radiotherapy to the thorax. 
 Concomitant use of chronic systemic (IV or oral) corticosteroids or other 
immunosuppressive medications except for managing AEs.  (Inhaled steroids or 
intra-articular steroid injections are permitted in this study.) 
 Chloroquine or hydroxychloroquine:  
 if treatment with chloroquine or hydroxychloroquine is required for SARS-CoV-2 
infection (ie, COVID-19), trastuzumab deruxtecan must be interrupted and a 
wash-out period of >14 days is required before restarting trastuzumab deruxtecan. 
Permitted Products: 
 Subjects are permitted to use topical, intraocular, intra-articular, intranasal, and 
inhaled corticosteroids (with minimal systemic absorption).  Physiologic replacement 
doses of systemic corticosteroids are permitted, even if >10 mg/day prednisone or 
equivalent. 
 A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy, 
chemotherapy induced nausea) or for treatment of non-autoimmune conditions (e.g., 
delayed-type hypersensitivity reaction caused by contact allergen) is permitted. 
 Subjects with bronchopulmonary disorders who require intermittent use of 
bronchodilators (such as albuterol) will not be excluded from this study. 
 Hematopoietic growth factors may be used for prophylaxis or treatment based on the 
clinical judgment of the investigator. 
 Concomitant use of dietary supplements, medications not prescribed by the 
investigator, and alternative/complementary treatments is discouraged, but not 
prohibited. 


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 Prophylactic or supportive treatment of study-drug induced AE will be as per 
investigator’s discretion and the institutional guidelines unless specified in this 
protocol. 
 Based on the currently available clinical safety data, it is recommended that subjects 
receive prophylactic anti-emetic agents prior to infusion of trastuzumab deruxtecan 
and on subsequent days. Antiemetics such as 5-hydroxytryptamine receptor (5-HT3) 
antagonists or Neurokinin-1 (NK1) receptor antagonists and/or steroids (e.g. 
dexamethasone) should be considered and administered in accordance with the 
prescribing information or institutional guidelines. 
Restricted Products: 
 Use of e-cigarettes and vaping is strongly discouraged but not prohibited 
Subjects who, in the assessment of the Investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study. 
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.  
All concomitant medication will be recorded on the eCRF including all prescriptions, 
over-the-counter products, herbal supplements, and IV medications and fluids.  If changes occur 
during the study period, documentation of drug dosage, frequency, route, and date should also be 
included on the eCRF. 
All concomitant medications received within 28 days prior to the first dose of study treatment 
and up to 40 days after the last dose of study treatment should be recorded. Concomitant 
medications administered 40 days after the last dose of study treatment should be recorded for 
SAEs and AESIs as defined in Section 9.4.2.  
5.8. 
Subject Withdrawal/Discontinuation 
Any subject who is withdrawn from the study treatment or from the study for any reason will 
have their reasons for withdrawal recorded. 
5.8.1. 
Reasons for Withdrawal 
5.8.1.1. 
Reasons for Withdrawal of Study Drug 
Any subject who is withdrawn from the study treatment for any reason will have their reasons for 
withdrawal recorded.  Subject may withdraw from both study drugs at the same time or 1 study 
drug at a time.   
Some examples include: 
 PD per RECIST Version 1.1 (Section 1.1) assessed by the investigator; 
 Clinical progression (definitive clinical signs of disease progression, but a recent 
radiographic assessment did not meet the criteria for PD according to RECIST 
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 AE; 
 Death; 
 Pregnancy; 
 Withdrawal by subject; 
 Lost to follow-up; 
 Physician decision; 
 Study terminated by Sponsor; 
 Protocol deviation 
 Other, specify. 
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 the Medical Monitor.  
All subjects who are withdrawn from the study treatment should complete protocol-specified 
withdrawal procedures (Section 5.8.2) and follow-up procedures (Section 6.5). Discontinued 
subjects will be followed for survival, either through direct contacts or by collecting public 
records (e.g., death certificates) as allowed by local laws. 
5.8.1.2. 
Reasons for Discontinuation of Study Participation 
The duration of subject participation in the study will be until 1 of the following occurs: 
 Death; 
 Study terminated by Sponsor; 
 Withdrawal by subject; 
 Lost to follow-up; 
 Other, specify (for e.g., If subject becomes a prisoner during the study, the subject 
should be withdrawn from the study). 
Note: All subjects will be followed for survival status even after consent for study procedures is 
withdrawn.  Subjects discontinued from the study because of withdrawal of consent will be 
followed for survival by collecting public records (e.g., death certificates) unless prohibited by 
local laws. 
5.8.2. 
Withdrawal Procedures 
If a subject is withdrawn from the study treatment, 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.  Investigator should make all efforts to retain subject in 
the study for survival follow-up after withdrawal from study treatment.   


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If the subject is withdrawn from the study treatment due to an AE, the investigator will follow 
the subject until the AE has resolved or stabilized and perform the study procedures as per 
Section 6.5.2. 
All subjects who are withdrawn from the study treatment should complete protocol-specified 
withdrawal procedures. Protocol-specified withdrawal procedures will be conducted during the 
End of Treatment (EOT) Visit (+ 7 days) and the 40-Day Follow-up Visit (+ 7 days) [Section 6 
and Table 17.1]. 
5.8.3. 
Subject Replacement 
Subjects will be replaced in Part 1 at the same dose level if they discontinued study treatment 
due to any other reason than DLT prior to the completion of the DLT period.  Subjects enrolled 
and administered study medication in Part 2 will not be replaced.  However, it is allowable to 
replace a subject that was screen-failed but not administered any study medication. 
5.8.4. 
Subject Re-prescreening Procedures 
Re-prescreening is permitted for any subject that had initial tumor sample sent for analysis to 
central lab and the report states that the subject is ineligible (i.e. IHC score 0). The limit of 
re-prescreening is 1. At re-prescreening, sites can send newer additional archival tissue or 
perform a new tumor biopsy.  Subjects that perform re-prescreening would need to sign a new 
prescreening ICF. 
Subjects that had initial tumor sample sent but central lab reports that there was an analytical 
failure (i.e. quality control samples fail, tissue with quality issues (including no staining, no 
tumor, or equivocal cases)) then site can send additional tissue, archival or by performing a new 
tumor biopsy. NOTE: this is not a re-prescreening, this is part of the same prescreening 
procedure. 
5.8.5. 
Subject Re-screening Procedures 
Re-screening is permitted for any subject who failed to meet the eligibility criteria in the initial 
screening. The limit of re-screening is 1 time. The site subject identifier must remain the same at 
the time of re-screening. The initial screening information and the reason why the subject was 
ineligible for the initial evaluation will be recorded in the Screening Log. 


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6. 
STUDY PROCEDURES 
Study procedures as described below are presented in schematic form in Table 17.1. 
6.1. 
Screening 
6.1.1. 
Central Laboratory HER2 (Pre-Screening) 
To determine eligibility, subjects must meet tumor biomarker criteria.   
Note: If an archival tissue sample is provided at pre-screening, subjects may continue on prior 
therapy while tissue testing takes place.   
Please refer to the Laboratory Manual for required tumor sample shipping instructions.  
The following procedures will be conducted: 
 Obtain a signed and dated written consent from the subject to collect tissue and/or 
perform a biopsy as needed. This may be done 14 days prior to tissue collection. 
 The sample must be a formalin-fixed paraffin embedded (FFPE) block and not stored 
slides cut previously from such a FFPE block.   
 If an archived tumor tissue sample is not available or is inadequate, new tumor biopsy 
is required for HER2 screening. 
 Prepare and send the tissue samples to the Central Laboratory. 
  The central laboratory will assess the HER2 status and provide results to 
Investigators and Daiichi Sankyo Inc (DSI). 
 If a tumor biopsy is performed, report any SAEs directly related to tissue screening 
procedure (i.e., tumor biopsy) along with any associated treatment.  Unless 
documentation of other AEs is required by local law, only SAEs directly related to 
tumor biopsy will be recorded during tissue screening. 
 Additional slides for exploratory biomarker assessment are requested.  
6.1.2. 
Screening 
The duration of the screening/baseline period is up to 28 days (+7 days).  Informed consent will 
be obtained from the subject before any study-specific procedures are initiated.  
The following activities and/or assessments will be performed within 28 days (+ 7 days) before 
enrollment during the screening period: 
 Obtain written (i.e., signed and dated) informed consent. 
 Assign subject identifier. 
 Obtain ophthalmologic assessments: visual acuity testing, slit lamp examination, and 
fundoscopy. 
 Obtain HIV antibody test (as required by local regulations). 
 Obtain Hepatitis B surface antigen/hepatitis C antibody. 


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Perform Baseline tumor measurement per RECIST Version 1.1 (spiral CT or MRI 
with ≤5 mm cuts).  Existing radiographic scans can be used as baseline if scan was 
performed within 4 weeks prior to the first scheduled day of treatment.  The baseline 
scan will include the chest, abdomen, and pelvis.  Brain MRI/CT is required if the 
subject has a history of brain metastases and/or symptoms suggestive of brain 
metastases at baseline.  Any existing brain metastases must have been effectively 
treated and shown to be stable at the baseline scan over an interval of at least 4 weeks. 
The method of tumor assessment used must remain consistent at each assessment.  
MRI is the strongly preferred modality for imaging the brain.  If brain imaging is 
performed to document the stability of existing metastases, MRI should be used if 
possible. If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative.  The same imaging technique regarding modality, ideally the same 
scanner, and the use of contrast should be used in a subject throughout the study to 
optimize the reproducibility of the assessment of existing and new tumor burden and 
improve the accuracy of the assessment of response or progression based on imaging.  
For the purposes of assessing tumor imaging, the term “Investigator” refers to the 
local Investigator at the site and/or the radiological reviewer located at the site or at 
an offsite facility.  The method of tumor assessment used must remain consistent at 
each assessment.   
Any supplemental imaging done such as plain X-rays that may be acquired for 
correlation, should be submitted to the central imaging vendor.   
 Record prior and concomitant medications.  
 Assess the subject for AEs. 
 Record hospitalization-related records 
 If the subject is a screen failure, deactivate the subject in the interactive response 
technology. 
Unless otherwise noted, the following activities and/or assessments will be performed at/during 
Screening and within 14 days (except as indicated) before starting study treatment: 
 Review inclusion and exclusion criteria and confirm subject’s eligibility when the 
results of all screening procedures have been obtained. 
 Collect blood samples for the other biomarker analyses (only if new tissue sample is 
collected at screening). 
 Details regarding shipping instructions to the central laboratory will be provided in 
the Laboratory Manual. 
 Record demographic and history information. 
 Perform a complete physical examination. 
 Obtain vital sign measurements (e.g., systolic and diastolic blood pressure, heart rate, 
and body temperature). 
 Height and weight. 


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 Obtain peripheral oxygen saturation (SpO2). 
 Assess functional status using the ECOG Performance Status.  
 Obtain a blood sample for hematology. 
 Obtain two blood samples (one for local lab test and one for central lab test) for 
troponin (preferably high-sensitivity troponin-T).  Eligibility assessment will be based 
on the local lab result.  If at any time a subject reports signs or symptoms suggesting 
congestive heart failure, myocardial infarction, or other causes of myocyte necrosis: 
 Perform ECG in triplicate.  
 If ECG is abnormal, follow institutional guidelines.  
 Obtain a blood sample for serum chemistry and coagulation. 
 Obtain a urine sample for urinalysis. 
 Obtain a blood or urine sample to perform a serum or urine pregnancy test for female 
subjects of childbearing potential within 72 hours before enrollment.  Test must be 
confirmed negative within 72 hours prior to drug administration. A positive urine 
pregnancy test result must immediately be confirmed using a serum test. 
 Obtain an ECHO or MUGA scan for LVEF.  
 Obtain a 12-lead ECG in triplicate.  ECGs to be taken ≤3 minutes apart, with the 
subject in a supine/semi-recumbent position. 
 After eligibility is confirmed, register subject to Interactive Web/Voice Response 
System (IXRS) as eligible or ineligible. 
6.2. 
Enrollment 
This is a single-arm open-label trial consisting of 2 parts: Part 1 (Dose Escalation) and Part 2 
(Dose Expansion).  Part 2 includes 4 different cohorts.  Part 1 will enroll before Part 2.  First 
eligible subjects will be directly registered in Part 1 at the lowest dose level.  The first group of 
3 subjects can be registered simultaneously or sequentially.  Enrollment of the next 3 subjects 
will occur after the first 3 subjects have completed the DLT observation period and safety data 
have been reviewed by the Sponsor team and investigator(s).  Based on their recommendations, 
the next 3 eligible subjects will be registered at the same or next dose level.  Up to 9 subjects will 
be registered at a dose level until an MTD is reached or subjects have been registered and have 
successfully completed the DLT observation period at both dose levels.  At each dose level, 
subjects will be considered DLT evaluable if they were able to complete 2 cycles of treatment of 
both study drugs (trastuzumab deruxtecan and nivolumab) and had completed DLT assessment 
or discontinued from study due to a DLT.  A subject will be replaced if discontinued from the 
study during the DLT period due to any other reason than DLT (refer to Section 5.8.3).   
No subject shall receive study drug until approved by the Sponsor or designee.  The Sponsor or 
designee will notify the other sites of the inclusion of a new subject and will inform study sites 
about the next possible enrollment date. Subjects must be registered in IXRS prior to the 
beginning of treatment as IXRS is used to manage dispensing of material.  


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6.3. 
Treatment Period 
Study procedures as described below are presented in schematic form in Table 17.1. 
Subjects must be registered in IXRS prior to the beginning of treatment as IXRS is used to 
manage dispensing of material.   
The first on-study imaging assessment should be performed per RECIST Version 1.1 (spiral CT 
or MRI with ≤5 mm cuts) at 6 weeks (42 days ±7 days) from Cycle 1, Day 1.  Subsequent tumor 
imaging should be performed every 6 weeks (±7 days) from Day 1 of Cycle 1 or more frequently 
if clinically indicated.  After 52 weeks (365 days ±7 days), subjects who remain on treatment 
will have imaging performed every 12 weeks (±14 days) until disease progression or start of new 
anticancer treatment.  Imaging timing should follow calendar days.  Imaging time points should 
not be adjusted for delays in cycle starts.  Imaging should continue to be performed until disease 
progression is identified by the Investigator or notification by the Sponsor, whichever occurs 
first.  All supplemental imaging must be submitted to the central imaging vendor.  Tumor 
assessment at 40 days follow up is no longer required, because subjects who discontinue study 
treatment due to progression, should not have any additional tumor assessment performed. 
However, subjects that discontinue due to reasons other than disease progression, will continue 
assessment as per initial schedule until start of new anticancer therapy.  In cases where EOT and 
40-Day Follow-up Visit fall within 7 days, then both of these visits’ requirements can be 
completed during the same visit. 
Objective response should be confirmed by a repeat imaging assessment.  Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a response is 
observed.  Subjects will then return to regular scheduled imaging, starting with the next 
scheduled imaging time point.  Subjects who receive additional imaging for confirmation do not 
need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging 
may resume at the subsequent scheduled imaging time point. Response does not typically need to 
be verified in real time by the central imaging vendor. 
Per iRECIST, disease progression should be confirmed by the site 4 to 8 weeks after the site 
assessed first radiologic evidence of PD in a clinically stable subject.  Subjects who have 
unconfirmed disease progression may continue on treatment at the discretion of the Investigator 
until progression is confirmed by the site, provided they have met the conditions detailed in 
Section 17.5.2 Subjects who receive confirmatory imaging do not need to undergo the next 
scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may resume at the 
subsequent scheduled imaging time point, if clinically stable.  Subjects who have confirmed 
disease progression by iRECIST, as assessed by the site, will discontinue study treatment.   
Tumor measurement per RECIST version 1.1 (spiral CT or MRI with ≤5 mm cuts) is to be 
performed every 6 weeks (±7 days) in the first year after Day 1 of Cycle 1 and thereafter every 
12 weeks (±14 days) until disease progression or start of new anticancer treatment.  CT or MRI 
(spiral CT or MRI with ≤5 mm cuts) of brain, chest, abdomen, and pelvis should be used for 
tumor assessment unless another modality of disease assessment is necessary for the lesions at 
screening period.  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, 
brain CT or MRI should only be done if symptoms associated with brain metastasis appear 
during the study period.  If no clinical symptoms are observed, brain CT or MRI is not 


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mandatory during the study period.  Treatment decision will be based on the investigator-based 
assessment.  If the investigator decides to continue the treatment post-progression, the study site 
should continue to scan the subject after initial progression has been identified to continue tumor 
assessment by iRECIST. 
All scans, scheduled or unscheduled, should be submitted to the central imaging vendor for 
review as soon as possible.   
Concomitant medication, AEs, and hospitalization (except hospitalization for study drug 
infusion) should be recorded at each visit. 
Thyroid function testing is required every 6 weeks while on nivolumab treatment.  Thyroid panel 
should include: 
 Triiodothyronine (T3) or free triiodothyronine (FT3) 
 Free thyroxine (FT4)  
 TSH 
If TSH <0.5 × lower limit of normal (LLN) or TSH >2 × ULN, or consistently out of range in 
2 subsequent measurements: FT4 is required to be tested at subsequent cycles as clinically 
indicated, and an endocrinology consult should be considered. 
6.3.1. 
Cycle 1 
Treatment and procedures performed on Day 1 of Cycle 1 and beyond are specified in Table 17.1 
and further described below.  Procedures are to be performed within -3 days of the Day 1 visit of 
each cycle unless otherwise specified.   
6.3.1.1. 
Cycle 1, Day 1 
Before Dosing: Between -3 Days through immediately Before Infusion (note: if these 
assessments are done -3 Days through immediately Before Infusion for screening purposes, then 
these may not be repeated at Day 1 of Cycle 1): 
 Record ECOG performance status. 
 Record triplicate 12-lead ECG. 
 Record concomitant medications and AEs. 
 Record physical examination. 
 Record vital signs and weight. 
 Obtain SpO2. 
 Collect blood samples for hematology. 
 Collect blood samples for chemistry. 
 Collect blood samples for coagulation. 
 Urinalysis test is to be performed at screening and as clinically indicated throughout 
the study. 


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 Collect blood samples for serum amylase and lipase testing. 
 Obtain a blood or urine sample to perform a serum or urine pregnancy test for female 
subjects of childbearing potential within 72 hours prior to study drug infusion.  A 
positive urine pregnancy test result must immediately be confirmed using a serum 
test. 
 Collect blood sample for pharmacogenomic analysis (if the subject has consented to 
provide a pharmacogenomic sample). 
 Collect a blood sample for biomarker analysis and/or banking 
Day 1 Before Infusion 
 Record triplicate 12-lead ECG (if not done within 3 days before Day 1). 
 Collect blood sample for pharmacogenomics and biomarker analysis and/or banking 
(if the subject has consented to provide a pharmacogenomic sample). 
 Collect blood samples for 
 PK assessments (Table 8.1).  
 Anti-drug antibodies (ADAs). Section 8.3.  
 Thyroid function tests: While on nivolumab, the subject must have thyroid panel 
including TSH testing every 6 weeks. If TSH <0.5 × LLN or TSH >2 × ULN, or 
consistently out of range in 2 subsequent measurements: FT4 is required to be 
tested at subsequent cycles as clinically indicated, and an endocrinology consult 
should be considered. 
 Collect serum samples for SARS-CoV-2 testing.  For subjects with suspected or 
confirmed SARS-CoV-2 infections, follow the dose modifications in Section 17.8 
Record concomitant medications and AEs. 
Study Drug Administration (refer to Section 5.2.4) 
 Nivolumab will be infused over approximately 30 minutes on Day 1 of each cycle 
prior to the administration of trastuzumab deruxtecan with no less than a 30-minute 
gap between the infusions of 2 study drugs.   
 Collect blood samples for PK assessment (Table 8.1).  Samples should be collected 
according to the schedule in Table 8.1.  At the time of PK sampling, record PK 
sampling times). 
 Allow 30 minutes between the end of nivolumab infusion and start of trastuzumab 
deruxtecan infusion. 
 Administer trastuzumab deruxtecan IV infusion: approximately 90 minutes for the 
initial dose and, if no infusion-related reaction after the initial dose, infuse subsequent 
doses over approximately 30 minutes.  Record start and stop times of any study drug.  
trastuzumab deruxtecan is to be administered every 3 weeks ± 2 days.  Nivolumab 
will be administered in cycles of every 3 weeks ± 2 days. 


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 Record each study drug’s start and end time for infusion.  Record any infusion 
interruptions.  
 Record concomitant medications and AEs. 
After Infusion 
 Assess vital signs within 30 minutes of completing the infusion of each study drug. 
More frequent examinations may be performed at the discretion of the investigator 
and if medically indicated. 
 For Part 1 subjects only: Assess DLTs.  
 Record concomitant medications and AEs. 
 Obtain SpO2. 
 Collect blood samples for troponin 2 to 3 hours after end of infusion (EOI) of 
trastuzumab deruxtecan to be submitted for central laboratory testing only.  Local 
troponin testing should be performed only if clinically indicated. 
 Collect blood samples for post dose PK analysis.  Samples should be collected 
according to the schedule in Table 8.1. At the time of PK sampling, record the PK 
sampling time. 
6.3.1.2. 
Cycle 1, Days 8 and 15 (± 1 Day) 
 Record vital signs. 
 Record SpO2. 
 Collect blood for hematology. 
 Collect blood for chemistry. 
 For Part 1 subjects only: Assess DLTs.  
 Record concomitant medications and AEs. 
 Record hospitalization-related records. 
 Collect samples for urinalysis and coagulation only if clinically indicated. 
 Collect blood samples for PK analysis.  Samples should be collected according to the 
schedule in Table 8.1.  At the time of PK sampling, record the PK sampling time. 
6.3.2. 
Cycle 2, Day 1 
Treatment and procedures performed on Day 1 of Cycle 2 and beyond are specified in Table 17.1 
and further described below.  Procedures are to be performed within -3 days of the Day 1 visit of 
each cycle unless otherwise specified.   
Before Treatment 
 Obtain a blood or urine sample to perform a serum or urine pregnancy test for female 
subjects of childbearing potential within 72 hours prior to study drug infusion.  A 


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positive urine pregnancy test result must immediately be confirmed using a serum 
test. 
 For Part 1 subjects only: Assess DLTs. 
 Record ECOG performance status. 
 Record triplicate 12-lead ECG. 
 Record concomitant medications and AEs. 
 Record hospitalization-related records 
 Record physical examination. 
 Record vital signs and weight.  
 Record SpO2. 
 Collect blood samples for PK analysis.  Samples should be collected according to the 
schedule in Table 8.1.  At the time of PK sampling, record the PK sampling time. 
 Collect blood samples for hematology. 
 Collect blood samples for chemistry. 
 Collect samples for urinalysis and coagulation only if clinically indicated. 
 Collect blood sample for ADAs. 
 Collect blood samples for serum amylase and lipase testing. 
Study Drug Administration 
 Administer second doses of study drugs at the study site as in Section 6.3.1.1. Record 
the study drug administration time. 
 Record concomitant medications and AEs. 
After Infusion 
 Assess vital signs as in Section 6.3.1.1. 
 Collect blood sample for central lab troponin testing as in Section 6.3.1.1. Local 
troponin testing should be performed only if clinically indicated. 
 Collect blood samples for PK analysis.  Samples should be collected according to the 
schedule in Table 8.1.   
 Record concomitant medications and AEs. 
 Obtain SpO2. 
6.3.3. 
Cycle 3, Day 1 
Before Treatment 
 Obtain a blood or urine sample to perform a serum or urine pregnancy test for female 
subjects of childbearing potential within 72 hours prior to study drug infusion.  A 


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positive urine pregnancy test result must immediately be confirmed using a serum 
test. 
 Tumor assessment at 6 weeks (± 7 days) from Cycle 1, Day 1. 
 For Part 1 subjects only: Assess DLTs. 
 Record ECOG performance status. 
 Record triplicate 12-lead ECG. 
 Record concomitant medications and AEs. 
 Record hospitalization-related records 
 Record physical examination. 
 Record vital signs and weight. 
 Obtain SpO2. 
 Collect blood samples for hematology. 
 Collect blood samples for chemistry. 
 Collect samples for urinalysis and coagulation only if clinically indicated. 
 Collect blood sample for ADAs (Section 8.3). 
 Thyroid function tests: While on nivolumab, the subject must have thyroid panel 
including TSH testing every 6 weeks. If TSH <0.5 × LLN or TSH >2 × ULN, or 
consistently out of range in 2 subsequent measurements: FT4 is required to be tested 
at subsequent cycles as clinically indicated, and an endocrinology consult should be 
considered. 
 Collect blood samples for serum amylase and lipase testing. 
 Collect blood samples for PK analysis (Table 8.1). At the time of PK sampling, 
record PK sampling times. 
 Collect blood samples for biomarker analysis (Table 8.3) and every 4 cycles starting 
on Cycle 3 (e.g., Cycle 3, 7, 11...). 
 Collect on-treatment tissue sample (optional new biopsy). 
Study Drug Administration 
 Administer third doses of study drugs at the study site.  Record the study drug 
administration time. 
After Infusion 
 Record vital signs. 
 Collect blood samples for central lab troponin testing as in Section 6.3.1.1. Local 
troponin testing should be performed only if clinically indicated 


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 Record concomitant medications and AEs as in Section 6.3.1.1.  
 Obtain SpO2. 
6.3.4. 
Cycle 4 and Subsequent Cycles, Day 1 
Before Treatment 
 Obtain a blood or urine sample to perform a serum or urine pregnancy test for female 
subjects of childbearing potential within 72 hours prior to study drug infusion.  A 
positive urine pregnancy test result must immediately be confirmed using a serum 
test. 
 Tumor assessment every 6 weeks (± 7 days) in the first year after Day 1 of Cycle 1 
and thereafter every 12 weeks (± 14 days). 
 Record ECOG performance status. 
 Record triplicate 12-lead ECG. 
 Record concomitant medications and AEs. 
 Record hospitalization-related records 
 Record physical examination. 
 Record vital signs and weight. 
 Record SpO2. 
 Collect blood samples for hematology. 
 Collect blood samples for chemistry. 
 Collect samples for urinalysis and coagulation only if clinically indicated. 
 Collect serum samples for SARS-CoV-2 testing on Day 1 of Cycle 5 and every 
4 cycles thereafter (i.e C5D1, C9D1 etc).  For subjects with suspected or confirmed 
SARS-CoV-2 infections, follow the dose modifications in Section 17.8  
 Collect blood sample for ADAs (Section 8.3) ADA samples will be obtained prior to 
study treatment on Day 1 of Cycles, 1, 2, and 3 and thereafter every 4 cycles and at 
the 40 Day Follow-Up visit. Additional serum ADA samples may be collected at the 
Long-term Follow-Up visits as follows: 
 Every 3 months (± 14 days) up to 1 year after the last dose of the study drug, or 
until the ADA becomes negative, or until the ADA titer becomes less than 
baseline (applicable when pre-existing ADA was observed), or until the subject 
starts another anti-cancer therapy or withdraws consent from the study, whichever 
occurs first.  
 Thyroid function tests: While on nivolumab, the subject must have thyroid panel 
including TSH testing every 6 weeks. If TSH <0.5 × LLN or TSH >2 × ULN, or 
consistently out of range in 2 subsequent measurements: FT4 is required to be tested 


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at subsequent cycles as clinically indicated, and an endocrinology consult should be 
considered. 
 Collect blood samples for serum amylase and lipase testing on the first day of each 
treatment cycle. 
 Obtain ECHO or MUGA scan for LVEF.  This assessment will be performed at 
screening and before infusion on Day 1 of Cycle 5 and then every 4 cycles (± 7 days 
[e.g., Cycles 5, 9, 13, etc]). The same test must be used for a given subject throughout 
the study.   
After Infusion 
• 
Record vital signs. 
• 
Collect blood samples for central lab troponin testing as in Section 6.3.1.1. Local troponin 
testing should be performed only if clinically indicated. 
• 
Obtain SpO2. 
Study Drug Administration 
 Administer scheduled doses of study drugs at the study site as in Section 6.3.1.1. 
Record the study drug administration time. 
 Record concomitant medications and AEs. 
After Infusion 
 Record vital signs as in Section 6.3.1.1. 
 Collect blood sample for troponin as in Section 6.3.1.1. 
 Record concomitant medications and AEs. 
 Obtain SpO2. 
6.3.5. 
End of Combination Treatment (See Section 6.4): Optional Biopsy and 
Biomarker Blood Samples 
End of Combination Treatment (EOCT) is defined as the date of discontinuation of one of the 
study drugs. 
 Obtain an optional new tumor specimen at discontinuation of any 1 of the study 
drugs, either trastuzumab deruxtecan or nivolumab, if amenable. Tumor tissue will be 
sent to the central laboratory for an exploratory biomarker analysis.   
 Collect blood samples for biomarker analysis according to the schedule in Table 8.3. 


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Table 6.1: 
End of Combination Treatment (EOCT) Assessments 
EOCT Assessments 
where trastuzumab 
deruxtecan or 
nivolumab is 
discontinued 
EOT Assessments 
where trastuzumab 
deruxtecan or 
nivolumab has been 
discontinued previously 
and the remaining study 
drug is completed 
EOT Assessments where 
trastuzumab deruxtecan and 
Nivolumab are discontinued 
concurrently 
Collect Blood Samples 
for: 
Optional Tumor 
Sample 
Exploratory 
Biomarkers 
HER2ECD 
cfDNA 
All EOT assessments 
found in the Schedule 
of Events Table (See 
Table 17.1) with the 
exception of the 
biomarkers that were 
previously collected 
when trastuzumab 
deruxtecan or 
nivolumab was 
discontinued 
All EOT assessments found 
in the Schedule of Events 
table (See Table 17.1)  
6.4. 
End of Treatment 
End of Treatment (EOT) on a subject level is defined as the date investigator decides to 
discontinue study treatment (+7 days).  Subjects who permanently discontinue the study 
treatment should be scheduled for an EOT visit within approximately +7 days following the date 
study treatment is permanently discontinued. If the decision to discontinue the subject occurs at a 
regularly scheduled visit, that visit may serve as the EOT visit rather than having the subject 
return for an additional visit. At EOT visit, all the following assessments will be performed: 
Record ECOG performance status (Section 17.2). 
 Record triplicate 12-lead ECG. 
 Record physical exam. 
 Record vital signs and weight. 
 Obtain SpO2. 
 Collect blood samples for hematology. 
 Collect blood samples for chemistry. 
 Collect blood samples for coagulation 
 Collect samples for urinalysis if clinically indicated. 
 Obtain two blood samples (one for local lab test and one for central lab test) for 
troponin (preferably high-sensitivity troponin-T). 
 Collect blood samples for serum amylase and lipase testing. 
 Obtain blood samples for exploratory biomarkers (Table 8.3). 


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 Obtain a blood or urine sample to perform a serum or urine pregnancy test for female 
subjects of childbearing potential.  A positive urine pregnancy test result must 
immediately be confirmed using a serum test.  
 Tumor assessments should include all sites of disease identified at screening and any 
other locations if PD is suspected (e.g., MRI of the brain if brain metastases are 
suspected) should also be imaged, per RECIST Version 1.1 (Section 1.1).  If the 
previous scan was within the last 6 weeks (within 12 weeks if the subject completed 
first year of tumor assessments), the tumor assessment at the EOT Visit does not need 
to be performed.  If the investigator makes a clinical diagnosis that there has been 
progression, imaging examinations should be performed as promptly as possible, and 
effort should be made to obtain an image-based assessment of PD. 
 An MRI of the brain is mandatory for all subjects included with baseline stable brain 
metastases.  Subjects without brain metastases do not need brain scan for tumor 
assessment unless clinically indicated.  
 Ophthalmologic assessments including visual acuity testing, slit lamp examination, 
and fundoscopy.  
 Obtain ECHO or MUGA scan for LVEF.  The same test must be used for a given 
subject throughout the study. 
 Obtain an optional new tumor biopsy after discontinuation of combination treatment 
(i.e., at discontinuation of either trastuzumab deruxtecan or nivolumab). Tumor tissue 
will be sent to the central laboratory for exploratory biomarker analyses.   
 Record concomitant medications and AEs.  Grade 3 or Grade 4 AEs ongoing at the 
discontinuation of study drug(s) will be monitored (including local laboratory tests 
when appropriate) at intervals no greater than 7 days until the AE is determined to be 
resolving or back to baseline. 
 Record hospitalization-related records. 
6.5. 
Follow-up 
6.5.1. 
40-Day Follow-up (+7 Days) 
Forty days (+7 days) after the last study drug administration (when both study drugs are either 
discontinued together) or before starting new anticancer treatment, whichever comes first, the 
following procedures will be performed as specified in the Schedule of Events.  If EOT is 
>40 days (+7 days) after last treatment, then the EOT assessments can also function as the 
Follow-up Visit. 
 Perform and record complete physical examination. 
 Record ECOG performance status. 
 Record vital signs (sitting systolic and diastolic blood pressure, heart rate, and body 
temperature) and weight. 
 Obtain SpO2. 


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 Take blood samples for hematology and chemistry. 
 Take blood samples for ADAs.  For subjects with positive ADA at the 40-Day 
Follow-up Visit, additional serum ADA samples may be collected every 3 months 
(± 14 days) up to 1 year after the last dose of the study drug, or until the ADA 
becomes negative, or until the ADA titer becomes less than baseline (applicable when 
pre-existing ADA was observed), or until the subject starts another therapy for 
cancer, or withdraws consent from the study, whichever occurs later. 
 Record AEs and treatments (drug and non-drug) given for AEs, and 
hospitalization-related records.  Grade 3 or Grade 4 AEs ongoing at the 
discontinuation of study drug(s) will be monitored (including local laboratory tests 
when appropriate) at intervals no greater than 7 days until the AE is determined to be 
resolving or back to baseline. 
 Record concomitant medications, including subsequent anticancer treatment. 
 In cases where EOT and 40-Day Follow-up Visit fall within 7 days, then both of these 
visits’ requirements can be completed during the same visit. 
6.5.2. 
Long-term Follow-up (±7/±14 Days) 
 Subjects who discontinued both study treatments due to any other reason than disease 
progression will continue Long-term Follow-up for tumor assessment as per scan 
schedule (i.e., every 6 weeks ± 7 days in the first year and every 12 weeks ± 14 days 
thereafter) by radiological imaging to monitor disease status until PD or start of new 
anticancer treatment. 
Once subject progresses or starts additional anticancer treatment, survival follow-up 
is performed every 12 weeks (± 14 days) by telephone to assess for survival status 
until death, withdrawal of consent, loss to follow-up, or study closure, whichever 
occurs first. 
 Subjects who discontinued study treatments due to disease progression will be 
followed every 3 months (± 14 days) from the date of 40-Day Follow-up Visit, until 
death, withdrawal of consent, loss to follow-up, or study closure, whichever occurs 
first.   
The following activities will take place during Long-term/Survival follow-up at the study site or 
by telephone contact: 
 Tumor assessments only during Long-term Follow-up (if discontinued study 
treatment due to any other reason than disease progression). 
 Record subsequent anticancer treatments and their outcomes, and survival.  
 Further follow-up may be required for ongoing AEs.  
 Record concomitant medications and AEs. 
 Survival status. 


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 Subjects with positive ADAs at 40-Day Follow-up Visit, additional serum samples 
may be collected at Long-term Follow-up visits as follows: Every 3 months 
(± 14 days) up to 1 year after the last dose of the study drug, until the ADA becomes 
negative, until the ADA titer becomes less than baseline (applicable when 
pre-existing ADA was observed), or until the subject starts another anticancer therapy 
or withdraws consent from the study. 
If direct contacts are not possible due to withdrawal of consent or because the subject becomes 
lost to follow-up, the study site must make every effort to collect survival status from public 
records (e.g., death certificates) in accordance with local laws. 
6.5.3. 
100-Day Follow-up 
The 100-Day Follow-up Visit will occur at 100 days from the last study treatment of nivolumab.  
The following activities will take place during 100-Day Follow-up by telephone contact: 
 Record subsequent anticancer treatments and their outcomes, and survival.  
 Further follow-up may be required for ongoing AEs.  
 Record concomitant medications and AEs. 
 Survival status. 
If direct contacts are not possible due to withdrawal of consent or because the subject becomes 
lost to follow-up, the study site must make every effort to collect survival status from public 
records (e.g., death certificates) in accordance with local laws. 
6.5.4. 
Assessment of Disease 
6.5.4.1. 
RECIST Version 1.1 Assessment of Disease 
RECIST version 1.1 (Section 1.1) will be used by independent central imaging review as the 
primary measure for assessment of tumor response, date of disease progression, and as a basis 
for all protocol guidelines related to disease status (e.g., discontinuation of study treatment).  
RECIST version 1.1 references a maximum of 5 target lesions in total and 2 per organ. 
6.5.4.2. 
iRECIST Assessment of Disease 
iRECIST (Section 17.5) is based on RECIST 1.1, but adapted to account for the unique tumor 
response seen with immunotherapeutic drugs. iRECIST will be used by the Investigator to assess 
tumor response and progression and make treatment decisions. When clinically stable, subjects 
should not be discontinued until progression is confirmed by the Investigator, working with local 
radiology, according to the rules outlined in Section 17.5.4. This allowance to continue treatment 
despite initial radiologic PD takes into account the observation that some subjects can have a 
transient tumor flare in the first few months after the start of immunotherapy, and then 
experience subsequent disease response. This data will be captured in the clinical database. 


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Clinical stability is defined as the following:  
 Absence of symptoms and signs indicating clinically significant progression of 
disease 
 No decline in ECOG performance status  
 No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care 
Any subject deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the subject may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment.  Images should continue to be sent in to the central 
imaging vendor for potential retrospective independent review.  
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
subject continues to be clinically stable, study treatment may continue and follow the regular 
imaging schedule.  If PD is confirmed, subjects will be discontinued from study treatment. 
If a subject has confirmed radiographic progression (iRECIST-confirmed progressive disease 
[iCPD]) as defined in Section 17.5, study treatment should be discontinued; however, if the 
subject is achieving a clinically meaningful benefit, an exception to continue study treatment 
may be considered following consultation with the Sponsor.  In this case, if study treatment is 
continued, tumor imaging should continue to be performed following the intervals as outlined in 
Section 17.5 and submitted to the central imaging vendor.  
A description of the adaptations and iRECIST process is provided in Section 17.5, with 
additional details in the iRECIST publication. A summary of imaging and treatment 
requirements after first radiologic evidence of progression is provided in Table 6.2. 


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Table 6.2: 
Imaging and Treatment with Nivolumab After First Radiologic Evidence of 
Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD by 
RECIST version 1.1  
Repeat imaging at 4 
to 8 weeks to 
confirm PD. 
May continue study 
treatment at the 
Investigator’s discretion 
while awaiting 
confirmatory tumor 
imaging by site by 
iRECIST. 
Repeat imaging at 4 
to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor 
imaging confirms PD 
(iCPD) by iRECIST 
per Investigator 
assessment 
No additional 
imaging required. 
Discontinue treatment 
(exception is possible 
upon consultation with 
Sponsor). 
No additional 
imaging required. 
Not applicable 
Repeat tumor 
imaging shows iUPD 
by iRECIST per 
Investigator 
assessment 
Repeat imaging at 4 
to 8 weeks to 
confirm PD.  May 
occur at next 
regularly scheduled 
imaging visit. 
Continue study 
treatment at the 
Investigator’s discretion. 
Repeat imaging at 4 
to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor 
imaging shows iSD, 
iPR, or iCR by 
iRECIST per 
Investigator 
assessment. 
Continue regularly 
scheduled imaging 
assessments. 
Continue study 
treatment at the 
Investigator’s discretion. 
Continue regularly 
scheduled imaging 
assessments. 
May restart study 
treatment if condition has 
improved and/or clinically 
stable per Investigator’s 
discretion.  Next tumor 
imaging should occur 
according to the regular 
imaging schedule. 
iCPD = iRECIST-confirmed progressive disease; iCR = iRECIST-confirmed complete response; iPR = partial response;  
iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST-
confirmed stable disease; iUPD = iRECIST-unconfirmed progressive disease; PD = progressive disease; RECIST version 1.1 = 
Response Evaluation Criteria in Solid Tumors version 1.1   
6.6. 
Additional PK assessments due to SARS-CoV-2 infection 
In case of chloroquine or hydroxychloroquine administration for SARS-CoV-2 infection (ie, 
COVID-19), additional PK serum samples should be collected at the following time points 
(See Table 8.2)  


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7. 
EFFICACY ASSESSMENTS 
7.1. 
Assessments for Efficacy Endpoint(s) 
The clinical activity of trastuzumab deruxtecan and nivolumab combination treatment will be 
assessed by evaluating tumor response.  Tumor response will be evaluated using RECIST 
Version 1.1 (Section 1.1).  Efficacy assessments will be based on tumor assessments (to be 
performed at screening and every 6 weeks (± 7 days) in the first year after Day 1 of Cycle 1 and 
thereafter every 12 weeks (±14 days) until disease progression or initiation of additional 
anticancer therapy) and survival (See Section 6.5.2).  CT or MRI (spiral CT or MRI with ≤5 mm 
cuts) of brain, chest, abdomen, and pelvis should be used for tumor assessment unless another 
modality of disease assessment is necessary for the lesions at screening period.  Every effort 
should be made to use the same assessment modality for all assessments for each subject.  
However, if there is no brain metastases at the time of screening, CT or MRI should only be done 
when symptoms associated with brain metastases appear during the study period.  If no clinical 
symptoms are observed, brain CT or MRI is not mandatory during the study period.  Subjects 
that are treated with nivolumab beyond RECIST 1.1 PD will continue tumor assessments until 
confirmed PD as per iRECIST. 
The following primary efficacy endpoints will be assessed.   
Primary Efficacy Endpoint: 
 ORR (the sum of CR rate and PR rate) assessed by ICR Committee based on RECIST 
Version 1.1 for Part 2.  
Secondary Efficacy Endpoint:   
Secondary endpoint will be assessed based on ICR Committee unless specified otherwise. 
 DCR (the sum of CR, PR, and SD rates). 
 DOR. 
 TTR. 
 PFS.  
 Percent change in target lesion.  
 ORR (the sum of CR rate and PR rate) assessed by investigator based on RECIST 
Version 1.1 for Part 2.  
Exploratory endpoints: 
 ORR by iRECIST guidelines by study investigator (part 2). 
 CBR for breast cancer cohorts, defined as proportion of subjects achieved CR, or PR, 
or had SD for at least 6 months per RECIST Version1.1. 


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7.2. 
Appropriateness of Selected Efficacy Assessment(s) 
All selected efficacy endpoints provide evidence of drug activity.  ORR is defined as the 
proportion of subjects with CR and PR as defined by RECIST Version 1.1 in this trial. ORR is a 
direct measure of drug antitumor activity, which can be evaluated in a single-arm study.  
Because ORR is directly attributable to study drug effect, it is an appropriate measure of efficacy 
in single-arm trials.  
In addition, PFS is not confounded by subsequent therapies compared to OS, and OS is 
considered the “gold standard” for demonstrating clinical benefit. 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
8.1. 
Pharmacokinetic Assessment(s) 
Blood samples for trastuzumab deruxtecan and nivolumab PK analyses will be obtained at the 
time points specified in the Schedule of Events (Table 17.1) 
Table 8.1: 
Sampling Times for Pharmacokinetic Assessments 
Cycle 
Day  
Sampling Time Point (Acceptable Ranges) 
Cycle 1 
Day 1 
BI: (-8 hours) 
• 
Both samples (one for each study drug) taken at the 
same time before nivolumab infusion 
 
EOI: 
• 
Within 15 minutes after EOI of nivolumab 
• 
Within 15 minutes after EOI of trastuzumab 
deruxtecan 
• 
5 hours from start of trastuzumab deruxtecan 
infusion (± 2 hours) 
 
Day 8 and Day 15 
Draw sample on Day 8 (± 1 day) and Day 15 (± 1 day) 
Cycle 2 
Day 1 
BI: (-8 hours) 
• 
Both samples (one for each study drug) taken at the 
same time before nivolumab infusion 
 
EOI: 
• 
Within 15 minutes after EOI of nivolumab 
• 
Within 15 minutes after EOI of trastuzumab 
deruxtecan 
• 
5 hours from start of trastuzumab deruxtecan 
infusion (± 2 hours) 
Cycle 3  
Day 1 
BI: (Within 30 minutes) 
• 
Both samples (one for each study drug) taken at the 
same time before nivolumab infusion 
BI = before infusion; EOI = end of infusion. 
Note: Obtain one blood sample collection for PK as soon as ILD is suspected, if feasible 
In case of chloroquine or hydroxychloroquine administration for SARS-CoV-2 infection (ie, 
COVID-19), additional PK samples should be collected at the following time points 


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Table 8.2: 
Schedule of PK Sample Collection in Case of Chloroquine or 
Hydroxychloroquine Treatment 
Day of Chloroquine or Hydroxychloroquine 
Administration 
Sampling Time Point 
Day 1 
Prior to chloroquine or hydroxychloroquine dose   
Day 3 or 4 
Prior to chloroquine or hydroxychloroquine dose 
(within 4 h)   
EOT with chloroquine or hydroxychloroquine 
Prior to chloroquine or hydroxychloroquine dose 
(within 4 h)  
Prior to re-initiation of trastuzumab deruxtecan 
BI (within 8 hours) 
BI = Before Infusion; EOT = End of Treatment 
At each time point, blood will be collected for nivolumab and trastuzumab deruxtecan analysis. 
The actual times of study drug administrations and the exact time of blood sampling for 
trastuzumab deruxtecan and nivolumab PK analysis must be recorded on the eCRF, including 
those samples collected in case of chloroquine or hydroxychloroquine administration for 
SARS-CoV-2 infection (ie, COVID-19).  For the samples to be taken before infusion at Cycle 1 
Day 1, Cycle 2 Day 1 and Cycle 3 Day 1, both samples (one for each study drug) should be taken 
at the same time before nivolumab infusion, within the acceptable time ranges as per Table 8.1. 
Instructions for the handling of blood samples and shipping of serum samples for trastuzumab 
deruxtecan and nivolumab PK analyses are included in a separate document (i.e., Laboratory 
Manual). The trastuzumab deruxtecan and nivolumab PK samples will be shipped to a central 
laboratory for forwarding to a Sponsor-designated bioanalytical laboratory.  Note that separate 
EOI draw times will be required for trastuzumab deruxtecan and nivolumab to maintain the 
proper time windows.  Samples for nivolumab PK will be retained and analyzed if necessary. 
Serum concentrations of trastuzumab deruxtecan, total anti-HER2 antibody, MAAA-1181a and 
nivolumab will be measured using validated assays at bioanalytical laboratories.  The serum PK 
parameters (listed in Section 2.3.2) for trastuzumab deruxtecan, total anti-HER2 antibody, 
MAAA-1181a and nivolumab for each subject will be estimated using standard 
noncompartmental method. 
Data will be analyzed using a population PK modeling approach and may be reported separately 
from the clinical study report. 
8.2. 
Biomarker Assessment(s) 
Exploratory blood biomarkers will be analyzed with the intent of monitoring the anti-tumor 
impact of treatment with trastuzumab deruxtecan.  Blood samples will be collected for 
HER2ECD and cfDNA analysis at the time points specified in Table 8.3. 
Biomarker samples will be shipped to a central laboratory.  


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Table 8.3: 
Biomarker Blood Sampling Time Points (HER2ECD, cfDNA) 
Cycle 
Sampling Time Point (Acceptable Range) 
Cycle 1, Day 1 
Within 3 days before administration 
Every 4 cycles starting on Cycle 3 (e.g., 
Cycle 3, 7, 11...) 
Within 3 days before administration 
End of Combination Treatment (EOCT) 
The date when the investigator decides on discontinuing one 
of the study treatments 
End of Treatment (EOT) 
End of Treatment (EOT) on a subject level is defined as the 
date investigator decides to discontinue study treatment (+7 
days).  
cfDNA = cell-free DNA; HER2ECD = human epidermal growth factor 2 extracellular domain  
Tumor specimens will be used to assess HER2 and PD-L1 expression using IHC and/or ISH and 
possibly, but not limited to, mRNA expression profile, mutation burden, using next-generation 
sequencing technology or other methods.  Pharmacodynamic biomarkers are planned with intent 
of monitoring the antitumor impact of treatment with trastuzumab deruxtecan.   
8.2.1. 
Additional Biomarker Assessments 
During the study, in addition to the biomarkers specified above, additional exploratory biomarker 
research may be conducted on tissue and/or liquid biopsy samples.  This additional research is 
intended to expand the translational research and development capability at DSI, and will support 
as yet undefined research aims that will advance our understanding of disease and options for 
treatment.  It may also be used to support health authority requests for analysis, and advancement 
of pharmacodiagnostic development to better target drugs to the right subjects.  This may also 
include genetic/genomic exploration aimed at exploring disease pathways, progression and 
response to treatment etc.  These additional investigations would be dependent upon clinical 
outcome, reagent and sample availability.  
The Sponsor will not collect the samples for additional biomarker assessments but will conduct 
the additional research using the remaining samples of biomarker assessments described in 
Section 8.2. 
The remaining biomarker samples (tumor tissue, blood or other specimen obtained in the study) 
may be stored for up to 15 years and further analyzed to address scientific questions related to 
trastuzumab deruxtecan, nivolumab, and/or cancer. 
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the Sponsor’s senior leaders in research and development to ensure the research 
supports appropriate and well-defined scientific research activities. 
8.3. 
Immunogenicity 
Blood samples for ADA analyses will be collected prior to study treatment on Day 1 of Cycles 1, 
2, and 3 and thereafter every 4 cycles, and 40-Day Follow-up (Table 17.1).  A blood sample will 
be drawn at each time point.  Instructions for the handling and shipping of ADA serum samples 


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are included in the Laboratory Manual.  The ADA samples will be shipped to a central 
laboratory for forwarding to a Sponsor-designated bioanalytical laboratory. 
For subjects with positive ADAs at the 40-Day Follow-up Visit, additional serum samples may 
be collected at the Long-term Follow-up visits as follows: 
 Every 3 months (± 14 days) up to 1 year after the last dose of the study drug, until the 
ADA becomes negative, until the ADA titer becomes less than baseline (applicable 
when pre-existing ADA was observed), or until the subject starts another anticancer 
therapy or withdraws consent from the study. 
The immunogenicity testing will be performed using validated ADA assay following tiered assay 
steps including screening, confirmatory as well as titer determination. . In addition to the 
trastuzumab deruxtecan ADA analyses, these blood samples may be used to perform nivolumab 
ADA analyses. Samples confirmed ADA positive maybe analyzed with neutralizing anti-drug 
antibody (NAB) assay.  Serum concentrations of trastuzumab deruxtecan, or total anti-HER2 
antibody, may be measured using the same ADA samples as part of ADA assessment. 
8.4. 
Pharmacogenomic Analysis 
8.4.1. 
Genomic or Genetic Banking and Analysis 
A single blood sample for pharmacogenomics analysis will be collected from each subject who 
consented to this test, predose on Cycle 1, Day 1. Participation in this part of the study is 
optional for all subjects. 
In the event that pharmacogenomics analysis will be carried out in the future, the Sponsor will 
prepare a plan for conducting pharmacogenomics analysis, and it will be deliberated at the 
review committee.  This review committee also participates as a member who has no interest in 
the Sponsor, and scientific and ethical deliberations will be held on the plan for conducting 
pharmacogenomics analysis. 
The following procedures will be used for the long-term preservation (banking) of DNA 
specimens extracted from subjects' blood samples.  Pharmacogenomic samples may be analyzed 
for genes involved in absorption, distribution, metabolism, elimination, safety, and efficacy of 
trastuzumab deruxtecan.  Additionally, samples may be analyzed for genes involved in 
trastuzumab deruxtecan-related signaling pathways, or to examine diseases or physiologic 
processes related to trastuzumab deruxtecan.  DNA samples will not be immortalized or 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. 
Specimen shipping and handling details will be included in the Laboratory Manual. 
8.4.1.1. 
Disclosure of the Results of Genomic or Genetic Analysis 
See ICF for the details on disclosure. 


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8.4.1.2. 
Storage and Disposal of Specimens for Genomic or Genetic Analysis 
Samples will be retained until the genetic material has been exhausted or until Sponsor directs 
the genotyping contractor to destroy the sample (in accordance with laboratory procedures).  
During the period of storage, the genetic samples will not be immortalized or sold to anyone.  
Subjects will have the right to withdraw consent and have their sample destroyed at any time.   
However, the data will not be discarded if genetic analysis has been completed before the subject 
withdraws consent. 


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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Assessment of Safety Endpoint(s) 
Key safety endpoints will include assessment of DLTs, SAEs, TEAEs, TEAEs leading to 
discontinuation, and AESIs. 
9.2. 
Adverse Event Collection and Reporting 
In Part 1 (dose escalation), the (DLT) observation period will be 2 cycles (6 weeks).  DLT is 
defined in Section 3.2.3. 
All clinical non serious AEs and AESI (see Section 9.4.1 for definitions) occurring after the 
subject signs the ICF and a minimum of 47 days after study treatment ends, and should continue 
to be collected until 100 days after the last dose of study medication (i.e., the follow-up period), 
or start of a new anti-cancer therapy, whichever is earlier, whether observed by the investigator 
or reported by the subject, will be recorded on the Adverse Event CRF page.  Grade 3 or Grade 4 
AEs ongoing at the discontinuation of study drug(s) will be monitored (including local 
laboratory tests when appropriate) at intervals no greater than 7 days until the AE is determined 
to be resolving or back to baseline. All SAEs occurring after subject signs the main ICF and up 
to 100 days after the last dose of nivolumab or trastuzumab deruxtecan, must also be reported by 
the Investigator.   
All AEs, SAEs, and AESIs are to be reported according to the procedures in Section 9.5.   
Medical conditions (including laboratory values/vital signs that are out of range) that were 
diagnosed or known to exist prior to signing the informed consent will be recorded as part of 
medical history. All clinical laboratory results, vital signs, and ECG results or findings should be 
appraised by the investigator to determine their clinical significance.  Isolated abnormal 
laboratory results, vital sign findings, or ECG findings (i.e., not part of a reported diagnosis) 
should be reported as AEs if they are symptomatic, lead to study drug discontinuation, dose 
reduction, require corrective treatment, or constitute an AE in the investigator’s clinical 
judgment. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
subject.  Adverse events may be directly observed, reported spontaneously by the subject or by 
questioning the subject at each study visit.  Subjects should be questioned in a general way, 
without asking about the occurrence of any specific symptoms.  The investigator must assess all 
AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 9.4.  The investigator’s assessment must be clearly documented in the 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) 


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procedures or treatments requiring hospitalization for preexisting conditions that do not worsen 
in severity should not be reported as SAEs (see Section 9.4.2 for definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an SAE.   
Disease progression/worsening of breast cancer/urothelial cancer will not be recorded as an AE 
on the Adverse Event eCRF.  However, events associated with disease progression (i.e. 
thrombocytopenia), may be recorded as AEs.  Death due to disease progression should be 
recorded on the Death eCRF.   
Any serious, untoward event that may occur subsequent to the reporting period that the 
investigator assesses as related to study drug should also be reported and managed as an SAE. 
Immune-mediated AEs are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (e.g., infection or tumor 
progression) have been ruled out. Immune-mediated AEs can include events with an alternate 
etiology which were exacerbated by the induction of autoimmunity. Information supporting the 
assessment will be collected on the eCRF. General guidelines for safety management of 
immune-mediated AEs are provided in Appendix 17.7 (Safety Management Algorithms). 
9.3. 
Adverse Events of Special Interest 
For the trastuzumab deruxtecan clinical program, based on the available preclinical data, review 
of the cumulative literature, reported toxicities for the same class of agents and biological 
plausibility, the following events are considered to be AESIs: ILD, and LVEF decrease. 
Relevant information regarding the AESIs ILD, and LVEF decrease for the trastuzumab 
deruxtecan clinical program, regardless of seriousness, is to be collected through the targeted 
questionnaires (TQ) within the applicable eCRFs in the clinical study database.   
9.3.1. 
Interstitial Lung Disease 
9.3.1.1. 
Clinical Summary  
Interstitial lung disease is considered an important identified risk based on a comprehensive 
cumulative review of the available safety data from the clinical development program as well as 
the results of potential ILD cases reviewed by the independent ILD Adjudication Committee, 
available data from recent epidemiology/literature, biological plausibility, and safety information 
from drugs of similar class.  Refer to the current IB13 for a summary of preliminary clinical study 
data. 
9.3.1.2. 
Management Guidance 
Interstitial lung disease/pneumonitis should be ruled out 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. If the 
AE is confirmed to have an etiology other than ILD/pneumonitis, follow the management 
guidance outlined in the designated “Other Non-laboratory Adverse Events” dose modification 
section of this study protocol (Section 5.5.1).  


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If the AE is suspected to be ILD/pneumonitis, treatment with study drug should be interrupted 
pending further evaluations. Evaluations should include high resolution CT, pulmonologist 
consultation (Infectious Disease consultation as clinically indicated), blood culture and CBC, 
other blood tests could be considered as needed. Consider bronchoscopy and bronchoalveolar 
lavage if clinically indicated and feasible, pulmonary function tests and pulse oximetry (SpO2), 
arterial blood gases if clinically indicated, one blood sample collection for PK (central) analysis 
as soon as ILD/pneumonitis is suspected, if feasible.  
If the AE is confirmed to be ILD/pneumonitis, follow the management guidance outlined in the 
designated “Pulmonary Toxicity” dose modification section of this study protocol 
(Section 5.5.1).  
All events of ILD/pneumonitis regardless of severity or seriousness will be followed until 
resolution, including after drug discontinuation. 
9.3.1.3. 
Interstitial Lung Disease Adjudication Committee 
An independent ILD Adjudication Committee for the trastuzumab deruxtecan program 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.  These additional data collections will cover a more 
in-depth relevant medical history (e.g., smoking, radiation, chronic obstructive pulmonary 
disease and other chronic lung conditions), diagnostic evaluation, treatment and outcome of the 
event.  This data collection will be triggered for adverse events reported using selected 
42 Preferred Terms [all from the ILD Standard MedDRA Query (SMQ)] plus 2 PTs of acute 
respiratory failure and respiratory failure.  
9.3.2. 
LVEF Decrease 
9.3.2.1. 
Clinical Summary 
LVEF decrease in association with trastuzumab deruxtecan is considered to be important 
potential risk based on the available pre-clinical data, literature and available safety information 
for drugs of similar class.  Refer to the current IB for a summary of preliminary clinical trial 
data. 
9.3.2.2. 
Management Guidance 
LVEF will be measured at screening, Day 1 of Cycle 5, then every 4 cycles from Cycle 5 and at 
EOT by either ECHO or MUGA scan.  All ECHOs/MUGA scans will be evaluated by the 
investigator or delegated physician for cardiac function monitoring.  
Troponin will be measured centrally as well at screening and EoT. While the subject is receiving 
trastuzumab deruxtecan, troponin will also be measured on day 1 of each cycle 2-3 hours post 
infusion of trastuzumab deruxtecan for retrospective central analysis. Subjects may also have 
local troponin testing as clinically indicated during the treatment phase based on subject reported 
cardiac symptoms. An additional sample will be submitted for central lab troponin-T testing, and 
ECG will be performed in triplicate. If ECG is abnormal, follow institutional guidelines.  


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Triplicate ECGs will be performed and standard ECG parameters will be measured, including 
RR, PR, QT intervals, and QRS duration.  All ECGs must be evaluated by the investigator or 
delegated physician for the presence of abnormalities.  Whether or not measurement is 
performed, the date performed, results, and findings for each parameter are to be recorded in the 
eCRF. 
9.4. 
Adverse Events 
All non-serious AEs and AESI should be collected continuously during the treatment period and 
for a minimum of 47days after the last dose (for non-serious adverse events), and should 
continue to be collected until 100 days following discontinuation of last study treatment or start 
of new anticancer therapy, whichever is earlier, whether related or not to study treatment.  
Grade 3 or Grade 4 AEs ongoing at the discontinuation of study drug(s) will be monitored 
(including local laboratory tests when appropriate) at intervals no greater than 7 days until the 
AE is determined to be resolving or back to baseline.  All SAEs from the time of obtaining a 
signed ICF and up to 100 days after the last dose of nivolumab or trastuzumab deruxtecan, must 
also be reported by the Investigator. 
For subjects enrolled but never treated with study drug, SAEs should be collected for 30 days 
from the date of enrollment.   
Every AE must be assessed by the investigator with regard to whether it is considered 
immune-mediated.  For events that are potentially immune-mediated, additional information will 
be collected. 
9.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have to have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.21  It is the responsibility of 
investigators, based on their knowledge and experience, to determine those circumstances or 
abnormal laboratory findings that should be considered AEs. 
A TEAE is defined as an AE that occurs, having been absent before the first dose of study drug, 
or has worsened in severity or seriousness after initiating the study drug until 47 days after last 
dose of the study drug.  SAEs with an onset or worsening 48 days or more after the last dose of 
study drug, if considered related to the study treatment, are also TEAEs. 
9.4.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity, 


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 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.21  
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. 
 Disease progression is a study endpoint and consequently should not be reported as 
an AE/SAE. However, when a subject dies from disease progression with no other 
immediate cause, disease progression should be reported as an SAE. 
9.4.3. 
Severity Assessment 
All AEs will be graded (1 to 5; see below) according to the latest NCI-CTCAE version 5.0: 
 Grade 1 Mild AE 
 Grade 2 Moderate AE 
 Grade 3 Severe AE 
 Grade 4 Life-threatening consequences; urgent intervention indicated 
 Grade 5 Death related to AE 
Severity versus Seriousness: Severity is used to describe the intensity of a specific event while 
the event itself, however, may be of relatively minor medical significance (such as severe 
headache).  Seriousness of an event is based upon a universal and global regulatory definition for 
reporting SAEs to regulatory agencies.  For example, 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 may or may not be assessed as serious based on the 
seriousness criteria.  Overall, the severity of an event may be graded by the investigator as Grade 
1 or 2, but if the subject presents to the emergency facility for evaluation and is hospitalized 
overnight for observation that immediately makes the event serious based upon hospitalization 
without regard to the investigator assessment of severity. 


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9.4.4. 
Causality Assessment 
The investigator should assess causal relationship between an AE and the study drugs on the 
basis of his/her clinical judgment and the following definitions.  The causality assessment must 
be made based on the available information and can be updated as new information becomes 
available. 
 Related: 
 The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(e.g., disease under study, concurrent diseases, and concomitant medications). 
or 
 The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its chemical group, or is 
predicted by known pharmacology. 
 Not Related: 
 The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the subject’s clinical state or other factors (e.g., 
disease under study, concurrent diseases, and concomitant medications). 
9.4.5. 
Action Taken Regarding Study Drug(s) 
 Dose Not Changed: No change in study drug dosage was made. 
 Drug Withdrawn: The study drug was permanently stopped. 
 Dose Reduced: The dosage of study drug was reduced. 
 Drug Interrupted: The study drug was temporarily stopped. 
 Not Applicable: Subject died, study treatment had been completed prior to 
reaction/event, or reaction/event occurred prior to start of treatment 
9.4.6. 
Other Action Taken for Event 
 None. 
 No treatment was required. 
 Medication required. 
 Prescription and/or over-the-counter medication was required to treat the AE. 
 Hospitalization or prolongation of hospitalization required. 
 Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
 Other. 


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9.4.7. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the AE with no residual effect observed. 
 Recovering/Resolving 
 The AE improved but has not fully resolved. 
 Not Recovered/Not Resolved 
 The AE itself is still present and observable. 
 Recovered/Resolved with Sequelae 
 The residual effects of the AE are still present and observable. 
 Include sequelae/residual effects. 
 Fatal 
 Fatal should be used when death is a direct outcome of the AE. 
 Unknown 
9.5. 
Serious Adverse Events and Adverse Event of Special Interest 
Reporting–Procedure For Investigators 
All AEs, SAEs, and AESIs, will be reported in the eCRF.   
Additional relevant information regarding the AESIs ILD and LVEF, for the trastuzumab 
deruxtecan clinical program regardless of seriousness is to be collected through the targeted 
questionnaires built within the applicable eCRFs in the clinical study database.   
For broad surveillance of LVEF decrease, relevant AEs under the MedDRA SMQs of Cardiac 
Failure and Myocardial Infarction are included for enhanced data collection; additional data for 
these AEs are collected via TQ of heart failure. 
For broad surveillance of ILD/pneumonitis, selected 42 Preferred Terms [all from the ILD 
Standard MedDRA Query (SMQ)] plus 2 PTs of acute respiratory failure and respiratory failure 
are included for enhanced data collections. The following types of events should be reported by 
the investigator in electronic data capture within 24 hours of awareness.  This data entry of an 
SAE in the eCRF is the expedited way of reporting of SAEs to the sponsor. 
 SAEs (see Section 9.4.2 for definition). 
 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 PTs).  
 Hepatic events (both serious and non-serious) 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 either at different time points or simultaneously 


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during the study.  A targeted questionnaire is built within the eCRF to collect relevant 
additional information for these potential cases. 
 Overdose, for trastuzumab deruxtecan and/or nivolumab, defined as the accidental or 
intentional administration of any dose of a product that is considered both excessive 
and medically important. An "excessive and medically important" overdose includes 
any overdose in which either a serious adverse event, a non-serious adverse event, or 
no adverse event occurs and is considered by the Investigator as clinically relevant, 
i.e. poses an actual or potential risk to the subject.  
- 
Overdose is always serious. By definition an overdose is medically important, 
which meets the seriousness criterion of important medical event. An 
overdose can occur with or without an AE. AEs can either be serious or 
non-serious. Details of the overdose including trastuzumab deruxtecan and/or 
nivolumab dosage, clinical course, associated AEs, and outcome must be 
captured in the Narrative form of the CRF within eDC. 
All events (serious and non-serious) must be reported with investigator’s assessment of the 
event’s seriousness, severity, and causality to the study drugs.  A detailed narrative summarizing 
the course of the event, including its evaluation, treatment, and outcome should be provided.  
Specific or estimated dates of event onset, treatment, and resolution should be included when 
available.  Medical history, concomitant medications, and laboratory data that are relevant to the 
event should also be summarized in the narrative.  For fatal events, the narrative should state 
whether an autopsy was or will be performed, and include the results if available.  Source 
documents (including medical reports) will be retained at the study site and should not be 
submitted to the Sponsor for SAE reporting purposes. 
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  In the event that the eCRF is unavailable, report 
SAEs by faxing the paper Serious Adverse Event Report (SAVER) Form to the CRO using the 
provided fax cover sheet and the appropriate fax number provided for your country.  Once the 
eCRF becomes available, please enter SAEs reported on the SAVER Form into the eCRF as 
soon as possible.  Please refer to the eCRF Completion Guide for additional instructions. 
See the Study Site Manual for contact information for SAE reporting.  Please call the local SAE 
Hotline (see the Study Site Manual) or your Medical Monitor for any questions on SAE 
reporting.   
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee 
Daiichi Sankyo Inc. (DSI) and/or CRO will inform investigators, IRBs/ECs, and regulatory 
authorities of any suspected unexpected serious adverse reactions (SUSARs) occurring at other 
study sites or in other studies of the investigational drug, as appropriate per local reporting 
requirements.  DSI and/or the CRO will comply with any additional local safety reporting 
requirements. 


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In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the study 
drug, unless delegated to the Sponsor, it is the investigator’s responsibility to inform the IRB per 
Sponsor’s instruction. 
In the European Economic Area states, it is the Sponsor’s responsibility to report SUSARs to all 
ECs. 
9.7. 
Exposure in Utero during Clinical Studies 
DSI must be notified of any subject who becomes pregnant while receiving study treatment or 
within 7 months of end of study treatment for female participants and 7 months for partners of 
male participants 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 male subject’s female partner using the Exposure in Utero (EIU) Reporting 
Form.  Please contact your study Medical Monitor to receive the EIU Reporting Form upon 
learning of a pregnancy.  The investigator should make every effort to follow the subject until 
completion of the pregnancy and complete the EIU Reporting Form with complete pregnancy 
outcome information, including normal delivery and induced abortion.  The adverse pregnancy 
outcome, either serious or non-serious, should be reported in accordance with study procedures.  
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., 
post-partum complications, spontaneous or induced abortion, stillbirth, neonatal death, or 
congenital anomaly, including that in an aborted fetus), the investigator should follow the 
procedures for reporting SAEs outlined in Section 9.5.  
For reports of pregnancy in the female partner of a male subject, the EIU Reporting Form (or 
SAE Form if associated with an adverse outcome) should be completed with the subject’s 
identification number, initials, and date of birth, and details regarding the female partner should 
be entered in the narrative section. 
9.8. 
Clinical Laboratory Evaluations 
The following items will be measured.  For clinical laboratory parameters, the reference range of 
the institution that performs the measurements will be used. 
Information will be collected on whether or not measured, date of measurement, and 
measurement results for the following items.   
Blood samples for laboratory tests (hematology and blood chemistry, as follows) will be 
obtained at screening (-14 days), and on Day 1 (-3 days), Days 8 and 15 of Cycle 1(± 1 day).  On 
subsequent cycles blood samples for hematology and chemistry will be obtained on Day 1 
(-3 days) of each cycle.  Samples will also be obtained at EOT and Follow-Up. 
1. Pregnancy test will be performed within 72 hours before enrollment and at each cycle 
before study drug infusion for all female subjects of childbearing potential.  A positive 
urine pregnancy test result must immediately be confirmed using a serum test. 
2. HIV antibody test: (as required by local laws, hepatitis B surface antigen/hepatitis C 
antibody will be done at screening. 


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3. Hematology tests: 
 Red blood cell count, hemoglobin, hematocrit, white blood cell count, differential 
white blood cell count (neutrophils, lymphocytes, monocytes, eosinophils, basophils 
to be recorded as absolute ± percentage differential values), and platelet count. 
4. Blood chemistry tests: 
 Total protein, albumin, total bilirubin (direct/indirect), AST, ALT, alkaline 
phosphatase, lactate dehydrogenase, creatinine kinase, blood urea nitrogen/urea, 
glucose, serum creatinine, uric acid, sodium, potassium, chloride, calcium, and 
magnesium.   
 Creatinine clearance (mL/min) will be calculated using the Cockcroft-Gault equation 
(Section 17.4). 
 A coagulation test will be performed (prothrombin time, activated partial 
thromboplastin time or partial thromboplastin time, and international normalized 
ratio). 
 Troponin will be analyzed at the local level at Screening and EOT.  During the 
treatment period, (while the subject is receiving trastuzumab deruxtecan), troponin 
will be analyzed at the central laboratory retrospectively. Local lab values will be 
used to assess eligibility, and the central lab values will be stored within the central 
database. Collect blood samples for troponin testing by local lab, if at any time a 
subject reports signs or symptoms suggesting congestive heart failure, myocardial 
infarction, or other causes of myocyte necrosis.  Whenever a local troponin testing is 
performed (during the study treatment period), an additional sample will be submitted 
for central lab troponin-T testing and ECG performed in triplicate. If ECG is 
abnormal, follow institutional guidelines. 
5. ADA samples will be obtained within 8 hours before infusion on Day 1 of Cycles 1, 2, 3, 
and 4, then every 4 cycles and 40-Day Follow-up (Section 8.3 for details). For subjects 
with positive ADA at the 40-Day F/U Visit, additional serum ADA samples may be 
collected at the Long-term F/U visits as follows: 
 Every 3 months (± 14 days) up to 1 year after the last dose of the study drug, or until 
the ADA becomes negative, or until the ADA titer becomes less than baseline 
(applicable when pre-existing ADA was observed), or until the subject starts another 
anti-cancer therapy or withdraws consent from the study, whichever occurs first. 
6. Urinalysis:  Urinary glucose, urinary protein, urinary occult blood, urinary ketone bodies, 
urinary bilirubin, urinary urobilinogen, urine pH, and urine sediments (red blood cells, 
white blood cells, and urinary casts) will be obtained at screening and if clinically 
indicated at subsequent visits.  
7. Thyroid function tests: While on nivolumab, the subject must have thyroid panel 
including TSH testing every 6 weeks. If TSH <0.5 × LLN or TSH >2 × ULN, or 
consistently out of range in 2 subsequent measurements: FT4 is required to be tested at 
subsequent cycles as clinically indicated, and an endocrinology consult should be 
considered. 


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8.  Amylase and lipase testing before infusion on the first day of each treatment cycle and at 
EOT. 
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, relevant procedures must be followed (see 
Section 9.5).  Abnormal laboratory values (NCI-CTCAE Grade 3 or 4) occurring during the 
clinical study will be followed until repeat test results return to normal (or baseline), stabilize, or 
are no longer clinically significant. 
9.9. 
Electrocardiograms 
Triplicate 12-lead ECGs, in close succession, will be taken with the subject in a supine/semi-
recumbent position at screening and before infusion, on Day 1 of all cycles and at EOT. 
The ECG will be measured after the subject has rested in a recumbent position for 5 minutes or 
more.  Whether or not measurement is performed, date performed, results, and findings for the 
following parameters will be recorded in the CRF: 
Heart rate, PR interval, RR interval, QRS amplitude, and QT interval (QTc). 
9.10. 
Physical Examinations 
Physical exam, SpO2, weight, and ECOG performance status will be performed at screening, 
Day 1 of each cycle before infusion and EOT and 40-Day Follow-up Visit. Vital signs will be 
performed at every visit (before infusion and EOI on Day 1 of each cycle). 
Blood pressure and heart rate will be measured after the subject has rested in a semi-recumbent 
position for 5 minutes or more. 
Information will be entered in the CRF on whether or not measured, date of measurement, and 
measurement results for the following items: systolic blood pressure, diastolic blood pressure, 
pulse rate, respiratory rate, body temperature, pulse oximetry, height (at screening), and body 
weight. 
9.11. 
Other Examinations 
ECHO or MUGA scan (the same test must be used for the subject throughout the study) will be 
performed at screening and before infusion on Day 1 of Cycle 5 and then every 4 cycles 
(± 7 days) (e.g., Cycle 5, 9,13…) as well as at EOT.  
Ophthalmologic assessments including visual acuity testing, slit lamp examination and 
fundoscopy will be performed at screening and at EOT only. 


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10. 
OTHER ASSESSMENTS 
Not applicable. 


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11. 
STATISTICAL METHODS 
11.1. 
General Statistical Considerations 
The primary database lock will occur 6 months after the last subject’s first visit or when 80% of 
subjects experience disease progression or discontinue study treatment, whichever occurs first.  
Summary statistics will be presented by cohort.  Continuous variables will be summarized by the 
number of observations, mean, standard deviation, median, minimum, and maximum values. 
Categorical variables will be summarized using frequency counts and percentages. 
Assessment 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 tumor measurements. The 
last non-missing value of a variable taken before the first dose of the study drug will be used as 
the baseline value. In general, missing or dropout data will not be imputed for the purpose of 
data analysis. 
The DLT analysis will be summarized in the DLT Evaluable Analysis Set for assessment of the 
MTD or RDE.  Efficacy analyses will be performed on the Full Analysis Set (FAS) and 
Response Evaluable Set (RES).  Safety analyses will be performed on the Safety Analysis Set 
(SAF). Analysis of PK parameters will be based on the PK Analysis Set.  All other exploratory 
analyses will be performed based on the FAS. 
An interim analysis is planned (Section 11.6) to be initiated for all Breast Cancer subjects in the 
study, including those from Part 1.  Efficacy and safety interim analysis will be performed when 
all subjects enrolled into Cohorts 1 and 2 in Part 2 had at least 12 weeks of follow up after 
initiation of study treatment or have discontinued study treatment. The purpose of this interim 
analysis is to look at preliminary efficacy and safety signals for breast cancer subjects in the 
study. The results from this interim analysis will not be used to change the conduct of the study. 
11.2. 
Analysis Sets 
DLT Evaluable Analysis Set will include all subjects who were able to complete two cycles of 
treatment of both study drugs (trastuzumab deruxtecan and nivolumab) or have discontinued 
from study due to a DLT. 
FAS will include all subjects who signed the main ICF and were enrolled in the study.  
SAF will include all enrolled subjects who have received at least one dose of any of the study 
drugs. 
RES will include all enrolled subjects who received at least 1 dose of both study drugs and had 
measurable disease at baseline per independent ICR Committee. 
PK Analysis Set will include all subjects who received at least one dose of trastuzumab 
deruxtecan plus nivolumab and had measurable serum concentrations.   
11.3. 
Study Population Data 
Subject disposition will be summarized for subjects in the FAS.  The total number of subjects for 
each defined analysis set will also be tabulated.  The demographic and baseline characteristics 


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will be summarized descriptively for the FAS and RES.  Study drug exposure and treatment 
duration will be summarized using descriptive statistics for the FAS. 
11.4. 
Efficacy Analyses 
The primary efficacy analysis will be performed for the FAS.  All efficacy analyses will be 
performed for the FAS and RES. All confidence intervals will be 2-sided 95% confidence 
intervals, unless stated otherwise.  
11.4.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint for Part 2 is ORR, as assessed by Independent ICR Committee 
and defined as the proportion of subjects who achieved a confirmed response (CR or PR) during 
study treatment (from first dose to start of new anticancer treatment) based on specified analysis 
set FAS.   
ORR will be summarized by cohort for FAS (primary analysis).  The 2-sided 95% exact 
confidence interval will be provided. 
11.4.2. 
Secondary Efficacy Analyses 
 The secondary efficacy endpoints based on RECIST version 1.1 are:  DoR, DCR, 
PFS, and TTR, all based on ICR Committee and investigator assessment, as well as 
ORR based on investigator assessment, and OS. DOR, defined as time from first 
documented objective response (CR or PR) to disease progression as per RECIST 1.1. 
DOR will be measured for responding subjects (CR or PR) only.  Detailed censoring 
rules for DOR analysis will be specified in the Statistical Analysis Plan (SAP). 
 DCR, defined as proportion of subjects achieved CR, PR, or SD. 
 PFS, defined as time from the date of first dose to the date of objective disease 
progression as per RECIST 1.1 or death (if no progression) due to any cause. Detailed 
censoring rules for PFS analysis will be specified in the SAP. 
 OS, defined as time from the date of first dose to the date of death due to any cause. 
Subjects alive will be censored at date of last known to be alive.  
 TTR, defined as time from the date of first dose to the date of first documented 
objective response (CR or PR). TTR will be measured for responding subjects only.  
 ORR, as assessed by investigator and defined as the proportion of subjects who 
achieved a confirmed response (CR or PR) during study treatment (from first dose 
until the first documented disease progression as per RECIST v1.1).   
ORR and DCR will be summarized by cohort for FAS and RES, and their 95% exact confidence 
intervals will be provided.  
Summary statistics (n, mean, standard deviation, median, minimum, maximum) will be provided 
for TTR by cohort. 


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For time to event endpoints (DOR, PFS, OS), Kaplan-Meier estimates of medians and 95% 
confidence intervals for medians using Brookmeyer and Crowley method will be provided by 
cohort. Kaplan-Meier estimates of survival curves will be plotted. 
These analyses will be repeated for pooled Part 1 and Part 2 subjects by cancer type (breast 
cancer and urothelial cancer) and HER2 status. 
11.4.3. 
Other Secondary Efficacy Analyses 
11.4.4. 
Exploratory Efficacy Analyses 
Exploratory efficacy endpoints include: 
 ORR by iRECIST guidelines by study investigator (part 2) 
 CBR for breast cohorts, defined as proportion of subjects achieved CR, PR, or SD for 
at least 6 months per RECIST Version 1.1.  
11.4.5. 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses 
PK and biomarker endpoints include: 
 Pharmacokinetics: Serum concentrations of trastuzumab deruxtecan, MAAA-118a, 
total anti-HER2 antibody and nivolumab.  Nivolumab samples may not be analyzed.  
 Exploratory biomarkers related to understand the mechanism of response and 
resistance 
 Immune biomarkers such as PD-L1, tumor mutation burden, and microsatellite 
instability (MSI).   
11.4.5.1. Pharmacokinetic Analyses 
Descriptive statistics will be provided for serum concentration data of trastuzumab deruxtecan, 
MAAA-1181a, total anti-HER2 antibody and nivolumab (if analyzed) at each time point for each 
dose level of trastuzumab deruxtecan. Serum concentration data of trastuzumab deruxtecan, 
MAAA-1181a and nivolumab (if necessary and analyzed) from this study may be analyzed using 
population PK modeling and results reported separately from the clinical study report. For the 
population PK modeling, data from this study may be combined with other trastuzumab 
deruxtecan studies. Additional analyses maybe done if appropriate and useful for the 
interpretation of data.   
11.4.5.2. Pharmacodynamic Analyses 
Pharmacodynamic analyses will be described in a separate SAP. 
11.4.5.3. Biomarker Analyses 
Biomarkers (HER2 IHC, PD-L1 IHC, TMB, and MSI) will be summarized by cohort using 
descriptive statistics. Summaries and analyses for exploratory biomarkers will be documented in 
a separate analysis plan and will be reported outside the CSR in a separate report.  


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11.4.5.4. Pharmacogenomic Analyses 
Pharmacogenomic analyses will be described in a separate SAP. 
11.4.5.5. Immunogenicity (Anti-Drug Antibody) Analyses 
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 after drug 
treatment as positive.  The ADA titer values and change from baseline for ADA titers will be 
summarized by time point and by cohort using descriptive statistics.  The treatment-emerging 
ADA incidence will be calculated. Treatment-emergent ADA positive subject will be defined as 
subjects who are ADA negative at baseline and become ADA positive post-treatment, or who are 
ADA positive at baseline and post-treatment, but have an increase in ADA titer from baseline to 
post-treatment, or those who have missing ADA data at baseline but become ADA positive 
post-treatment. The number and percentage of subjects positive for NAB of trastuzumab 
deruxtecan, if analyzed, will also be determined. 
11.5. 
Safety Analyses 
DLT data will be summarized for DLT evaluable subjects enrolled in Part 1.  The subjects will 
be considered DLT evaluable if they were able to complete 2 cycles of treatment of both study 
drugs (trastuzumab deruxtecan and nivolumab) or have discontinued from study due to a DLT.  
A subject will be replaced if discontinued from the study during the DLT period due to any other 
reason than DLT (refer to Section 5.8.4).  
Safety analysis for subjects enrolled in each part will be performed using the Safety Analysis Set.  
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics. Listings of safety data will be provided and details will be 
specified in the SAP. 
11.5.1. 
Adverse Event Analyses 
AEs (Section 9.4.1) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and graded using NCI-CTCAE Version 5.0.  The number and percentage of subjects 
reporting TEAEs will be tabulated by system organ class, preferred term, relationship to the 
individual study drug and to any study drug, the worst NCI-CTCAE grade, and cohort.  
Similarly, the number and percentage of subjects reporting serious TEAEs will be tabulated by 
cohort, as well as TEAEs leading to discontinuation of the study drugs. 
The AE (including TEAE) data listing including but not limited to the verbatim terms, system 
organ class, preferred term, NCI-CTCAE grade, and relationship to study drug will be provided.  
Deaths, other SAEs, AESIs, and other significant AEs, including those leading to discontinuation 
of the study drugs, will be listed. 
Non-serious AEs or non-related SAEs occurring 48 days or more after the last dose will not be 
included in the analysis of TEAE but will be summarized separately. 


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11.5.2. 
Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory test results and changes from 
baseline by cohort at each scheduled time of evaluation. 
Abnormal clinical laboratory results will be graded according to NCI-CTCAE version 5.0, if 
applicable, and the grade will be presented in a by-subject data listing.  A shift table, presenting 
2-way frequency tabulation for baseline and the worst post-treatment value according to 
NCI-CTCAE grade, will be provided for clinical laboratory tests. 
All clinical laboratory test results and abnormal clinical laboratory test results deemed of clinical 
significance or of Grade 3 or 4 will be listed. 
11.5.3. 
Vital Sign Analyses 
Descriptive statistics will be provided by cohort for vital sign measurements and changes from 
baseline by scheduled time of evaluation.  All vital sign data will also be listed. The baseline 
value is defined as the last non-missing value before the initial administration of study treatment. 
11.5.4. 
Electrocardiogram Analyses 
Descriptive statistics will be provided by cohort for ECG parameters and changes from baseline 
by scheduled time of evaluation.  In addition, the number and percentage of subjects with ECG 
interval values meeting the criteria will be tabulated (QTcF ≤450 ms, >450 to ≤480 ms, >480 ms 
to ≤500 ms, and >500 ms). QTcF change from baseline will be tabulated (≤30 ms, >30 to 
≤60 ms, >60 ms) where QTcF intervals are the QT corrected for heart rate by Fredericia’s 
formula.  ECG data will also be listed. 
11.5.5. 
Physical Examination Analysis 
Physical examination findings will evaluate the following body systems/organs: general 
appearance, dermatological, head and 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. 
11.5.6. 
Exploratory Safety Analyses 
Not applicable. 
11.5.7. 
Other Endpoint Analysis 
Concomitant medications will be coded using the World Health Organization drug dictionary 
(most recent version).  Number and percentage of subjects taking concomitant medications will 
be summarized.  Concomitant medications will also be listed. 
All other safety endpoints (e.g., physical examination findings including ECOG performance 
status, ECHO/MUGA scan, and ophthalmologic findings) will be listed. 


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11.6. 
Interim Analysis 
Efficacy and safety interim analysis will be performed when all subjects enrolled into Cohorts 1 
and 2 in Part 2 have had at least 12 weeks of follow up after initiation of study treatment or have 
discontinued study treatment. 
Subjects enrolled in Part 1 will be pooled according to their trastuzumab deruxtecan dose and 
HER2 expressing levels (HER2 positive or HER2 low).  For example, subjects who were dosed 
at 5.4 mg/kg of trastuzumab deruxtecan and have HER2-positive expression Breast Cancer (IHC 
score 3+ or IHC score 2+/ISH+) in Part 1 will be pooled with the same subjects from Part 2 (in 
this case, subjects enrolled in Cohort 1). 
For each dose and HER2 expressing level combination, the primary efficacy endpoint of ORR 
will be summarized using descriptive statistics including 2-sided exact 95% confidence interval 
(Clopper-Pearson). Other efficacy endpoints based on response rates will be summarized by 
cohort using the same methodology as the primary efficacy endpoint. For time to event endpoints 
PFS, Kaplan-Meier estimates of medians and their corresponding 95% CIs using Brookmeyer 
and Crowley method will be provided by each dose and HER2 expressing level combination. 
Safety data related to adverse events will be summarized with descriptive statistics for each dose 
and HER2 expressing level combination.   
11.7. 
The results from this interim analysis will not be used to change the 
conduct of the study. Data Monitoring Committee 
An external Data Monitoring Committee is not planned for this study. DSI has in place a 
multi-layered process for ensuring subject safety through close collaboration of study site 
investigators, the DSI study team, and the DSI Clinical Safety and Pharmacovigilance 
(CSPV)-led Safety Management Team (SMT). This collaborative process constitutes the Data 
Safety Monitoring Plan for the study as detailed below: 
Study safety is evaluated continuously by representatives of DSI CSPV, who operate 
independently from the clinical team and monitor safety across all DSI protocols.  Adverse 
events are monitored continuously by DSI CSPV.  Signal detection is performed at least monthly 
and ad hoc throughout the study by the SMT composed, at a minimum, of the DSI CSPV safety 
physician (chairman of the SMT) and DSI CSPV single case review physician, the study Medical 
Monitor(s), the study biostatistician, and epidemiologist.  The SMT monitors actual or potential 
issues related to subject safety that could result in a significant change in the medical risk-benefit 
balance associated with the use of study drugs.  Furthermore, investigators will be kept updated 
of important safety information by Sponsor.  If appropriate, select safety issues may be escalated 
to a senior level, multidisciplinary, DSI-wide Global Safety Board for further evaluation and 
action. 
To support safety oversight, DSI has established ongoing processes for collection, review, 
analysis, and submission of individual AE reports and their aggregate analyses. Because this is 
an open-label study, the DSI Medical Monitor and the investigators will have access to all data 
necessary for safety evaluation. 
All participants in this study represent individuals with high unmet medical need as the prognosis 
for advanced/metastatic solid tumors is generally very poor. 


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DSI has elected not to use a Data Monitoring Committee for this study. In addition to the 
comprehensive safety monitoring plan outlined above, the following key points were considered 
for this decision: 
 This is an open-label study. 
 Subjects will be observed frequently for clinical evaluation and blood counts during 
dose escalation. 
 The eligibility criteria exclude subjects with disease characteristics that could 
predispose to higher risk of morbidity, including: subjects with pre-existing cardiac 
and lung and autoimmune diseases as specified. 
 Well-defined discontinuation criteria are established in the protocol for individual 
subjects for both safety and treatment futility with clear criteria for treatment 
discontinuation, dose delay, and toxicity management. 
In summary, DSI has determined that, given the study design and the points listed above, an 
independent Data Monitoring Committee is not required for this study. 
11.8. 
Sample Size Determination 
At most, 18 evaluable subjects will be registered for Part 1 following 3+3+3 design (Dose 
Escalation). 
Preliminary results from the dose expansion part of the Phase 1 study of trastuzumab deruxtecan 
monotherapy in a subgroup analysis of HER2-expressing metastatic breast cancer subjects 
pre-treated with trastuzumab emtansine (T-DM1) and pertuzumab demonstrated a 46.7% overall 
response rate (14 of 30 patients).22  Assume that 30 subjects were treated in Cohort 1 and 
observed ORR = 63.3% (19 responders out of 30 subjects), the 80% confidence interval would 
be (50.0%, 75.2%). 
The results of a Phase 2 clinical trial of nivolumab with 270 bladder cancer patients 
demonstrated a 19.6% overall response rate (53 of 270 patients).17,23  Assume that 30 patients 
were treated in Cohort 3 and observed ORR = 30% (9 responders out of 30 subjects), the 80% 
confidence interval would be (19.0%, 43.2%). 
Cohorts 2 and 4 are exploratory cohorts and approximately 15 subjects will be registered into 
Cohorts 2 and 4, respectively. 
All confidence intervals are based on Clopper-Pearson (Exact) approach (SAS 9.4). 
11.9. 
Statistical Analysis Process 
The clinical study data will be analyzed by the designated CRO. 
The detailed 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 will be specified in the study SAP.   
All statistical analyses will be performed using SAS® Version 9.2 or higher (SAS Institute, 
Cary, NC 27513).   


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
12.1. 
Monitoring and Inspections 
The CRO Monitor, Sponsor, 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 (e.g., 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 study 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, standard operating procedures, 
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 study site facilities (e.g., 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 
DS or a designee will supply eCRFs.  An eCRF must be completed for each subject who signs an 
ICF and undergoes any screening procedure.  If a subject is not treated, the reason must be 
recorded on the eCRF.  All data collected during the study will be recorded in this individual, 
subject-specific eCRF.  Instructions will be provided for the completion of the eCRF and any 
corrections made will be automatically documented via the EDC software’s “audit trail.” 
Completion of the eCRF should be kept current to enable the Medical Monitor to review the 
subject’s status throughout the course of the study.  All information and other material to be used 
by subjects and investigative staff must use vocabulary and language that are clearly understood.  
The eCRF will be completed, reviewed and signed off or e-signed by the investigator.  The 
investigator will sign and date the indicated places on the eCRF via the EDC system’s electronic 
signature.  These signatures will indicate that the investigator inspected or reviewed the data on 
the eCRF, the data queries, and the study site notifications, and agrees with the content. 


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12.3. 
Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by the 
Sponsor. 
To ensure the quality of clinical data across all subjects and study sites, a Clinical Data 
Management review will be performed on subject data according to specifications given to 
Sponsor or designee.  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 EDC application.  During this 
review, subject data will be checked for consistency, completeness and any apparent 
discrepancies.  CRF queries will be raised and resolved within the EDC application. 
Demographic data received from external sources such as central laboratories will be reconciled 
to the clinical database. 
Serious AEs in the clinical database will be reconciled with the safety database. 
All AEs will be coded using MedDRA.  Concomitant medications, prior and additional 
anticancer therapy will be coded using World Health Organization Drug Reference 
(WHODRUG) List. 
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 registered 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, CT and MRI scans, and 
correspondence. 
Records of subjects, source documents, monitoring visit logs, data correction forms, CRFs, 
inventory of study drug, regulatory documents (e.g., protocol and amendments, IRB/EC 
correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, clinical 
supplies receipts, distribution and return records), and other Sponsor correspondence pertaining 
to the study must be kept in appropriate study files at the 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 


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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 (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities.  Essential documents contained in the Trial Master File include: 
 Subject files containing completed CRFs, ICFs, and supporting copies of source 
documentation (if kept). 
 Study files containing the protocol with all amendments, IB, copies of relevant 
essential documents required prior to commencing a clinical study, and all 
correspondence to and from the IRB/EC and the Sponsor. 
 Records related to the study drug(s) including acknowledgment of receipt at study 
site, accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
All study-related essential documentation will be retained by the investigator until at least 
3 years after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 3 years have lapsed 
since the formal discontinuation of clinical development of the 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 the Sponsor or the 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 


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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 (1996, § 42, paragraph 1, clause 1), the ICH 
consolidated Guideline E6 for GCP (CPMP/ICH/135/95), and applicable regulatory 
requirement(s) including the following: 
 European Commission Directive (2001/20/EC Apr 2001) and/or; 
 European Commission Directive (2005/28/EC Apr 2005) and/or; 
 US Food and Drug Administration GCP Regulations: Code of Federal Regulations 
Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or; 
 Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 of 27 March 1997 
and/or; 
 The Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical 
Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and 
Cosmetics No. 1 of 25 November 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 identifier as designated by the Sponsor.  Documents that are not for submission to the 
Sponsor or the CRO (e.g., 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 
procedures or any study drugs are administered.  Subjects should be given the opportunity to ask 
questions and receive satisfactory answers to their inquiries, and should have adequate time to 
decide whether or not to participate in the study.  The written ICF should be prepared in the local 
language(s) of the potential subject population. 


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In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  The consent form and any revision(s) should be 
approved by the EC or 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 CRF. 
Suggested model text for the ICF for the study and any applicable subparts (genomic, PK, etc.) 
are provided in the Sponsor’s ICF template for the investigator to prepare the documents to be 
used at his or her study site.  Updates to applicable forms will be communicated via letter from 
the Sponsor. 
For study sites in the US, an additional consent is required for the Health Insurance Portability 
and Accountability Act (HIPAA).  Also, a separate special consent will be required for 
pharmacogenomic testing for this protocol. 
15.4. 
Regulatory Compliance 
The study protocol, subject information and consent form, the IB, any subject written 
instructions to be given to the subject, available safety information, subject recruitment 
procedures (e.g., advertisements), information about payments and compensation available to the 
subjects, and documentation evidencing the investigator’s qualifications should be submitted to 
the EC or IRB for ethical review and approval according to local regulations, prior to the study 
start.  The written approval should identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The Sponsor will appoint a Coordinating Investigator.  Among other possible duties, the 
Coordinating Investigator will be responsible for reviewing and approving the final clinical study 
report and testifying to the accuracy of the description of the study conduct.  Because the 
Coordinating Investigator should have personal knowledge of the conduct of the study, he or she 
will normally be chosen from among those investigators who have registered and treated at least 
1 subject.  However, where an investigator has special knowledge of the field or of the trial, the 
Coordinating Investigator can be chosen prior to enrollment of the first subject.  In all cases, the 
Coordinating Investigator must be chosen prior to locking the database.   
The investigator and/or Sponsor must submit and, where necessary, obtain approval from the EC 
or IRB for all subsequent protocol amendments and changes to the ICF.  The investigator should 
notify the EC or IRB of deviations from the protocol or SAEs occurring at the study site and 
other AE reports received from the Sponsor/CRO, in accordance with local procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group or representative 
to whom this responsibility has been delegated will ensure all legal aspects are covered, and 
approval from the appropriate regulatory bodies obtained, prior to study initiation.  If changes to 


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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.  Please note that in EU, minor changes to the protocol do not need 
to be submitted and in some cases even cannot be submitted to health authorities.  Instead these 
changes need to be notified with any substantial amendment submitted. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Regulatory Authority(ies) in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
drug, the Sponsor should be informed immediately.   
In addition, the investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of any 
suspected/actual serious GCP non-compliance that the investigator becomes aware of. 
15.5. 
Protocol Deviations 
The investigator should conduct the study in compliance with the protocol agreed to by Sponsor 
and, if required, by the regulatory authority(ies), and which was given approval/favorable 
opinion by the IRBs/ECs. 
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 EC or 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 


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information even if subjects were already informed of the relevant information.  The investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised ICF. 
15.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses will 
be communicated to the investigator by DSI or the CRO.  Also, the Sponsor will ensure the 
timely submission of amendments to regulatory authorities. 
A global protocol amendment will affect study conduct at all study sites in all regions of the 
world.  Such amendments will be incorporated into a revised protocol document.  Changes made 
by such 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 local protocol amendment will affect study conduct at a particular study site(s) and/or in a 
particular region/country.  Sponsor approval of local amendments will be clearly documented. 
A protocol amendment may be implemented after it has been approved by the IRB/EC and by 
regulatory authorities (please note that this is not applicable in the EU; non-substantial protocol 
amendments may be implemented without IRB/EC and regulatory approval) where appropriate, 
unless immediate implementation of the change is necessary for subject safety. 
15.8. 
Study Termination 
The Sponsor has the right to terminate the study at any time and study termination may also be 
requested by (a) competent authority(ies). 
15.9. 
Data and Safety Monitoring Board 
Not applicable. 
15.10. 
Address List 
A list of key study personnel (including personnel at the Sponsor, CRO, laboratories, and other 
vendors) and their contact information (address, telephone, fax, email) will be kept on file and 
regularly updated as necessary.  The addresses are also included in the Study Site Manual. 


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16. 
REFERENCES 
1. Global Burden of Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, et al. 
Global, regional, and national cancer incidence, mortality, years of life lost, years lived 
with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a 
systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017; 
3(4):524-48. 
2. Santa-Maria CA, Nye L, Mutonga MB, et al. Management of metastatic HER2-positive 
breast cancer: where are we and where do we go from here? Oncology (Williston Park). 
2016; 30(2):148-55. 
3. Bartsch R, Wenzel C, Altorjai G, et al. Capecitabine and trastuzumab in heavily 
pretreated metastatic breast cancer. J Clin Oncol. 2007; 25(25):3853-8. 
4. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive 
advanced breast cancer. N Engl J Med. 2006; 355 (26):2733-43. 
5. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or 
in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory 
metastatic breast cancer. J Clin Oncol. 2010; 28(7):1124-30. 
6. Krop IE, Kim SB, González-Martín A, et al. Trastuzumab emtansine versus treatment of 
physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a 
randomised, open-label, phase 3 trial. Lancet Oncol. 2014; 15(7):689-99. 
7. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 
2015; 65(2):87-108. 
8. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017; 67(1):7-
30. 
9. Marcos-Gragera R, Mallone S, Kiemeney LA, et al. Urinary tract cancer survival in 
Europe 1999-2007: results of the population-based study EUROCARE-5. Eur J Cancer. 
2015; 51(15):2217-30. 
10. Láe M, Couturier J, Oudard S, et al. Assessing HER2 gene amplification as a potential 
target for therapy in invasive urothelial bladder cancer with a standardized methodology: 
results in 1005 patients. Ann Oncol. 2010; 21(4):815-9.  
11. NIH National Cancer Institute: FDA Approves Nivolumab for Bladder Cancer[Internet] 
National Cancer Institute. 2017 Mar 01 [cited 2017 Oct 12]. Available from: 
https://www.cancer.gov/news-events/cancer-currents-blog/2017/fda-nivolumab-bladder. 
12. Goldhirsch A, Wood WC, Gelber RD, et al. Progress and promise: highlights of the 
international expert consensus on the primary therapy of early breast cancer 2007. Ann 
Oncol. 2007; 18(7):1133-44. 
13. Trastuzumab deruxtecan IB. Version 6.0. 09 Sep 2019. 
14. Postow MA, Harding J, Wolchok JD. Targeting immune checkpoints: releasing the 
restraints on anti-tumor immunity for patients with melanoma. Cancer J. 2012; 
18(2):153-9. 


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15. Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009; 
15(23):7412-20. 
16. Nakayama-Iwata T, Ishii C, Ogitani Y, et al. DS-8201a, a HER2-targeting antibody-drug 
conjugate, elicits immune responses and shows benefits in combination with an anti-PD-1 
antibody. Poster presented at: Annual Meeting of American Society of Clinical 
Oncology; 2017 Jun 02-06; San Francisco, CA.   
17. Nivolumab IB. Version 16.0. 23 Jun 2017. 
18. Brahmer J, Redkamp KL, Baas P, et al. Nivolumab verus docetaxel in advanced 
squamous-cell non-small-cell lung cancer. N Engl J Med. 2015; 373(2):123-35. 
19. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab verses docetaxel in advanced 
nonsquamous non-small-cell lung cancer. N Engl J Med. 2015; 373(17):1627-39. 
20. Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and safety outcomes in patients 
with advanced melanoma who discontinued treatment with nivolumab and ipilimumab 
because of adverse events: a pooled analysis of randomized Phase II and III trials. J Clin 
Oncol. 2017; 35(34):3807-14.  
21. International Council for Harmonisation (ICH) ICH E2A Guideline. Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, 1994 Oct [cited 2017 
Dec 03]. Available from: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A
/Step4/E2A_Guideline.pdf. 
22. Daiichi Sankyo Inc. New precision medicine data on DS-8201 in HER2-expressing breast 
cancer revealed at 2017 American Society of Clinical Oncology (ASCO) annual meeting. 
2017 Jun 06 [cited 2017 Nov 22]. Available from: 
http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/00
6641.html. 
23. OPDIVO (nivolumab) US prescribing information. 2017 Feb [cited 2017 Nov 22]. 
Available from:  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s024lbl.pdf. 


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17. 
APPENDICES 
17.1. 
Appendix 1: Schedule of Events 
Table 17.1: 
Schedule of Events 
Visit/Cycle 
Tissue 
Screen 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
Subsequent 
Cycles 
Q6W 
EOCTa 
EOTa 
Follow-up 
 
 
 
Study Day 
 
 
1 
8 
15 
1 
1 
1 
 
 
 
40-
dayb 
LTFUp 
(Q6W/Q3M) 
100-
Day 
Window (d) 
 
-14 to -1 
BI 
EOI 
-3 
-3  
BI 
EOI 
BI 
EOI 
BI 
EOI 
± 7 
 
 
+ 7 
± 7/± 14 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent  
X 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign SID 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drugc 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Tumor Biopsyd 
Exploratory Biomarkersd 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
 
 
Medical History, including Target 
Disease 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinatione 
 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
Weighte 
 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
Vital Signse 
 
X 
X 
Xn 
X 
X 
X 
Xn 
X 
Xn 
X 
Xn 
 
 
X 
X 
 
 
SpO2e 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
Hematology, Coagulation, & 
Chemistry, Urinalysise 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 


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Visit/Cycle 
Tissue 
Screen 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
Subsequent 
Cycles 
Q6W 
EOCTa 
EOTa 
Follow-up 
 
 
 
Study Day 
 
 
1 
8 
15 
1 
1 
1 
 
 
 
40-
dayb 
LTFUp 
(Q6W/Q3M) 
100-
Day 
Window (d) 
 
-14 to -1 
BI 
EOI 
-3 
-3  
BI 
EOI 
BI 
EOI 
BI 
EOI 
± 7 
 
 
+ 7 
± 7/± 14 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGA scan (LVEF)f 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Ophthalmologic Assessmentsg 
 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Tumor Assessment (CT/MRI of the 
chest, abdomen, pelvis, and any other 
sites of disease) 
 
Xm 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Troponinh 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
Pregnancy Test (Urine or Serum)i 
 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
PK Blood (Serum) Samplej 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
PK Sampling in case of for CQ/HCQ 
Administration 
 
 
 
If CQ or HCQ is administered for SARS-CoV-2 infection, 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 trastuzumab deruxtecan resumption, after the CQ/HCQ washout 
periodw, (within 8h BI of trastuzumab deruxtecan) 
 
 
 
 
ADA Blood Samplek 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
HER2ECD Biomarker Blood (serum) 
Samplel 
 
 
X 
 
 
 
 
 
X* 
 
 
 
 
X 
X 
 
 
 
cfDNA Biomarker Blood (plasma) 
Samplesl 
 
 
X 
 
 
 
 
 
X* 
 
 
 
 
X 
X 
 
 
 
Pharmacogenomics Blood Sample 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Visit/Cycle 
Tissue 
Screen 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
Subsequent 
Cycles 
Q6W 
EOCTa 
EOTa 
Follow-up 
 
 
 
Study Day 
 
 
1 
8 
15 
1 
1 
1 
 
 
 
40-
dayb 
LTFUp 
(Q6W/Q3M) 
100-
Day 
Window (d) 
 
-14 to -1 
BI 
EOI 
-3 
-3  
BI 
EOI 
BI 
EOI 
BI 
EOI 
± 7 
 
 
+ 7 
± 7/± 14 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Antibody Test (as required by 
local regulations)m 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/C Serology m 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 infection sampleu 
 
 
X 
 
 
 
 
 
 
 
Xv 
 
 
 
X 
 
 
 
AEso  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Prior/Concomitant 
Medications/Additional Anticancer 
Treatment 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Hospitalization-related Records 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
CT/MRI of the Brain (as needed 
clinically)q 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Thyroid panel (T3 or FT3, FT4, 
TSH)r 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Serum Amylase and Lipases 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
12-lead ECG t 
 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Survival Follow-up (every 3 months) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Schedule of Events – Legend 
ADA = anti-drug antibody; AE = adverse event; BI = before infusion, cfDNA = cell-free DNA; CQ = chloroquine; CT = computed tomography; d = days; ECG 
= electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; EOT = End of Treatment; HBsAg = 
hepatitis B surface antigen; HCQ = hydroxychloroquine; HER2 = human epidermal growth factor receptor 2; HER2ECD = HER2 extracellular domain; HIV = 
human immunodeficiency virus; LTFU = Long-term Follow-up; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = 
multigated acquisition; NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; PK = pharmacokinetic; Q3M = every 
3 months; Q6W = every 6 weeks; SARS-CoV-2 = Severe Acute Respiratory Syndrome Coronavirus 2; SID = subject identifier; SpO2 = peripheral oxygen 
saturation. 


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a End of Treatment (EOT) on a subject level is defined as the date investigator decides to discontinue study treatment (+7 days).  End of Combination Treatment 
(EOCT) is the date the investigator decides to discontinue one of the study drugs. In the event combination treatment is discontinued, optional tumor biopsy 
and biomarker blood samples assessments should be collected. 
b 40 days (+ 7 days) after the last study drug administration or before starting new anticancer treatment, whichever comes first. In cases where EOT and 40-Day 
follow-up Visit fall within 7 days then both of these visit requirements can be completed during the same visit. 
c Trastuzumab deruxtecan and nivolumab to be administered every 3 weeks ± 2 days unless discontinued or delayed per protocol (Section 5.5.1, Section 5.8.1). 
Nivolumab will be administered prior to trastuzumab deruxtecan. 
d At tissue pre-screening (Section 6.1.1), collect adequate, archived tumor tissue sample for central laboratory HER2 testing.  If an archived tissue sample is not 
available or is inadequate, a new tumor biopsy is required for HER2 screening.  The sample must be a formalin-fixed paraffin embedded (FFPE) block and not 
stored slides cut previously from such an FFPE block.  
 Collection of a new tumor biopsy is optional at Screening (Section 6.1.2), Cycle 3, Day 1, and at the end of combination treatment, (i.e the discontinuation of 
trastuzumab deruxtecan or nivolumab). Additional exploratory biomarker testing may be conducted on tissue and/or liquid biopsy samples collected during the 
study.  
e Within 3 days before administration.  Urinalysis test is to be performed at screening and as clinically indicated throughout the study. Coagulation tests are to be 
performed at baseline, Cycle l, Day 1, EOT, and as clinically indicated.  
 Total bilirubin testing also includes direct bilirubin and indirect bilirubin. 
f ECHO/MUGA scan will be performed at screening and before infusion on Day 1 of Cycle 5 and then every 4 cycles (± 7 days [eg, Cycles 5, 9, 13, etc)].  The 
same test must be used for a given subject throughout the study.  
g Ophthalmologic assessments including visual acuity testing, slit lamp examination, and fundoscopy at screening and EOT only and as clinically indicated. 
h Collect blood samples for troponin testing (preferably high-sensitivity troponin-T) by local (for eligibility) AND central labs at screening and EOT.  During 
the study, local troponin testing should only be performed if clinically indicated (i.e. a subject reports signs or symptoms suggestive of congestive heart failure, 
myocardial infarction, or other causes of myocyte necrosis). Whenever a local troponin testing is performed (during the study treatment period), an additional 
sample will be submitted for central lab troponin-T testing, and ECG performed in triplicate. If ECG is abnormal, follow institutional guidelines. Blood 
samples will also be collected on Day 1 of each cycle, 2-3 hours post infusion for retrospective central lab analysis of troponin. 
i Within 72 hours before enrollment for all female subjects of childbearing potential; a positive urine pregnancy test result must immediately be confirmed using 
a serum test. Perform repeat pregnancy tests (urine or serum test per institutional guideline) 72 hours before infusion of each cycle and at EOT.   
j Timing of blood samples for PK analysis is shown in Table 8.1. 
k ADA samples will be obtained prior to study treatment on Day 1 of Cycles, 1, 2, and 3 and thereafter every 4 cycles, and 40-Day Follow-up (Section 8.3. For 
subjects with positive ADA at the 40-Day F/U Visit, additional serum ADA samples may be collected at the Long-term F/U visits as follows: 
• 
Every 3 months (± 14 days) up to 1 year after the last dose of the study drug, or until the ADA becomes negative, or until the ADA titer becomes less 
than baseline (applicable when pre-existing ADA was observed), or until the subject starts another anti-cancer therapy or withdraws consent from the 
study, whichever occurs first.  
l Biomarker sampling time points are shown in Table 8.3. * Every 4 cycles starting on Cycle 3 (eg, Cycle 3, 7, 11...). 
m Within 28 days (+7 days) before enrollment. 
n Within 30 minutes of completing infusion of each study drug. 
o Part I subjects should be assessed for dose-limiting toxicities on Cycles 1 and 2 (through Cycle 3, Day 1). Grade 3 or Grade 4 AEs ongoing at the 
discontinuation of study drug(s) will be monitored (including local laboratory tests when appropriate) at intervals no greater than 7 days until the AE is 
determined to be resolving or back to baseline. Refer to Section 9.2.  
p Subjects who discontinue study treatment for any reason other than disease progression will be followed every 6 weeks (± 7 days) during first year and every 
12 weeks (± 14 days) the year after for tumor assessment until disease progression or start of new anticancer therapy.  Subjects who discontinue study treatment 


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due to disease progression will be followed every 3 months (± 14 days) from the date of the 40-Day Follow-up Visit until death, withdrawal of consent, loss to 
follow-up, or study closure, whichever occurs first.  
q At baseline, brain MRI/CT is required if the subject has a history of brain metastases and/or symptoms suggestive of brain metastases.  If there is no brain 
metastases at the time of screening, brain CT or MRI during the study treatment should only be performed if symptoms associated with brain metastases appear 
during the study period.  If no clinical symptoms are observed, brain CT or MRI is not mandatory at screening or during the study period.  At EOT, brain 
MRI/CT is required when subject has stable baseline brain metastases.  
r Thyroid function tests: While on nivolumab, the subject must have a thyroid panel including TSH testing every 6 weeks.  
 Thyroid panel should include: 
• 
Triiodothyronine (T3) or free triiodothyronine (FT3) 
• 
Free thyroxine (FT4)  
• 
Thyroid stimulating hormone (TSH) 
If TSH <0.5 × LLN or TSH >2 × ULN, or consistently out of range in 2 subsequent measurements: FT4 is required to be tested at subsequent cycles as 
clinically indicated, and an endocrinology consult should be considered. 
s Serum amylase and lipase testing every 3 weeks (sampling before treatment).  Amylase and lipase testing before infusion on the first day of each treatment 
cycle and at EOT. 
t ECG will be taken in triplicate at screening. Subsequent ECGs will be performed in triplicate, in close succession if an abnormality is noted. ECGs will be 
taken while in a supine/semi-recumbent position. 
u If subject provides consent, samples should be collected prior to study drug infusion.  See Section 9.11.  For subjects with suspected or confirmed 
SARS-CoV-2 infections (ie, COVID-19), follow the dose modifications in Section 17.8   
v Starting at Cycle 5, Day 1 and every 4 cycles thereafter. 
w a washout period of no less than14 d since last dose of CQ/HCQ is required before restarting trastuzumab deruxtecan.  See Table 8.2  
For suspected interstitial lung disease (ILD)/pneumonitis, treatment with study drug should be interrupted pending evaluation.  
Evaluations should include: 
 
high resolution CT  
 
pulmonologist consultation (Infectious Disease consultation as clinically indicated)  
 
Blood culture and CBC. Other blood tests could be considered as needed 
 
Consider bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible 
 
pulmonary function tests and pulse oximetry (SpO2) 
 
arterial blood gases if clinically indicated  
 
one blood sample collection for PK (central) analysis as soon as ILD/pneumonitis is suspected, if feasible.  


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17.2. 
Appendix 2: Eastern Cooperative Oncology Group Performance Status (ECOG Performance 
Status) 
Table 17.2: 
Eastern Cooperative Oncology Group Performance Status Scale 
GRADE 
DESCRIPTION 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., 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 h 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking h 
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 


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17.3. 
Appendix 3: Response Evaluation Criteria in Solid Tumors 
Version 1.1 
17.3.1. 
Measurability of Tumor at Baseline 
17.3.1.1. Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
17.3.1.1.1.  
Measurable 
 Tumor lesions: Must be accurately measured in at least one 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 (i.e., 
screening for this study) and in follow-up (i.e., all measurements past screening for 
this study), only the short axis will be measured and followed.  See also notes below 
on “Baseline documentation of target and non-target lesions” for information on 
lymph node measurement.  
17.3.1.1.2.  
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. 
17.3.1.1.3.  
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment. 
17.3.1.1.3.1. Bone Lesions 
 Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 


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 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
17.3.1.1.3.2. 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.  
17.3.1.1.3.3. 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. 
17.3.1.2. Specifications by Methods of Measurements 
17.3.1.2.1.  
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 before enrollment. 
17.3.1.2.2.  
Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation should 
always be performed rather than clinical examination unless the lesion(s) being followed cannot 
be imaged but are assessable by clinical exam. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (eg, for body scans). 
17.3.2. 
Tumor Response Evaluation 
17.3.2.1. 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. 


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In this study, only subjects with measurable disease at baseline should be included. 
17.3.2.2. Baseline Documentation of “Target” and “Non-target” Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five 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 one 
or two organ sites involved a maximum of two and four 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 two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥10 mm 
but <15 mm) should be considered non-target lesions.  Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression.”  In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg, “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”). 
17.3.2.3. Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 


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17.3.2.3.1.  
Evaluation of Target Lesions 
Complete response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note: the appearance of 1 or more new lesions is also 
considered progression). 
Stable disease (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. 
17.3.2.3.2.  
Special Notes on the Assessment of Target Lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study.  This means that when lymph nodes are 
included as target lesions, the “sum” of lesions may not be zero even if CR criteria are met, since 
a normal lymph node is defined as having a short axis of <10 mm.  For PR, SD, and PD, the 
actual short axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become “too small to measure”: While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes lesions or lymph 
nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
“too small to measure.”  When this occurs, it is important that a value be recorded on the eCRF.  
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned.  (Note: It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well).  This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness).  The 
measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error.  To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if 
it is below 5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum.  
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 


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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.” 
17.3.2.3.3.  
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. 
Complete response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Progressive disease (PD): Unequivocal progression (see comments below) of existing non-target 
lesions (Note: the appearance of 1 or more new lesions is also considered progression). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
17.3.2.3.4.  
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 one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the subject has only non-measurable disease: The same general concepts apply here as 
noted above, however, in this instance there is no measurable disease assessment to factor into 
the interpretation of an increase in non-measurable disease burden.  Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly non-
measurable) a useful test that can be applied when assessing subjects for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease (i.e., 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. 
17.3.2.3.5.  
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 


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identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e., 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 follow-up 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 
follow-up 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. 
17.3.2.4. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study drug until the 
EOT.   
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. 
17.3.2.4.1.  
Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 17.3 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, see Table 17.3. 
Table 17.3: 
Overall 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 = in-evaluable; PD = progressive disease; PR = partial response; SD = stable disease 


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17.3.2.4.2.  
Missing Assessments and Inevaluable Designation 
When no imaging/measurement is performed at all at a particular timepoint, the subject is not 
evaluable (NE) at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that timepoint, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response.  This would be most likely to happen in the case of PD.  For 
example, if a subject had a baseline sum of 50 mm with three measured lesions and at follow-up 
only two 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. 
17.3.2.4.3.  
Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject is known. 
Best response is defined as the lesser of the two best responses across two consecutive scans 
(eg, a subject who has PR at first assessment, SD at second assessment, and PD on last 
assessment; this would report as 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. 
17.3.2.4.4.  
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. 
17.3.2.5. Frequency of Tumor Re-evaluation 
In this study, tumor measurement will be conducted every 6 week (± 7 days) while the subject 
remains on study until progression of disease, withdrawal of consent, death, or loss to follow-up.  
Scan dates should not be adjusted or rescheduled due to dose interruption of any type. 


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Baseline tumor assessments must be performed within 28 days of enrollment. 
The first on-study imaging assessment should be performed at 6 weeks (42 days ±7 days) from 
Cycle 1, Day 1.  Subsequent tumor imaging should be performed every 6 weeks (±7 days) or 
more frequently if clinically indicated.  After 52 weeks (365 days ±7 days), subjects who remain 
on treatment will have imaging performed every 12 weeks (±14 days).  Imaging timing should 
follow calendar days.  Imaging time points should not be adjusted for delays in cycle starts.  
Imaging should continue to be performed until disease progression is identified by the 
Investigator or notification by the Sponsor, whichever occurs first.  All supplemental imaging 
must be submitted to the central imaging vendor. 
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 chest, abdomen, and pelvis at 
screening period.  An MRI of the brain is mandatory for all subjects included with baseline 
stable brain metastases.  Any additional suspected sites of disease should also be imaged.  Every 
effort should be made to use the same assessment modality for all assessments for each subject.  
Follow-up evaluations should include all sites of disease identified at screening and any other 
locations if PD is suspected (eg, MRI of the brain if brain metastases are suspected) should also 
be imaged.  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. 
Source: Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (Version 1.1) Eur J Cancer. 2009; 45(2):228-47. 


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17.4. 
Appendix 4: Cockcroft-Gault Equation 
The estimated creatinine clearance rate (CrCl; mL/min) will be calculated using the 
Cockcroft-Gault equation based on actual weight in kilograms (1 kilogram = 2.2 pounds): 
Conventional – serum creatinine in mg/dL: 
Male: 
CrCl (mL/min) = 
 
Female: 
CrCl (mL/min) = 
72
 
 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
  
years)]
(in 
 
age
 - 
[140


  0.85 
 
International System of Units (SI) – serum creatinine in μmol/L: 
Male: 
CrCl (mL/min) = 
 
 
Female: 
CrCl (mL/min) = 
0.0113
 
 
72
 
 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
  
years)]
(in 
 
age
 - 
[140




  0.85 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976; 16(1):31-41. 
72
 
 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
  
years)]
(in 
 
age
 - 
[140


0.0113
 
 
72
 
 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
  
years)]
(in 
 
age
 - 
[140






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17.5. 
Appendix 5: Description of the iRECIST Process for Assessment of 
Disease Progression 
17.5.1. 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment. 
17.5.2. 
Assessment and Decision at RECIST 1.1 Progression 
For subjects who show evidence of radiological PD by RECIST 1.1 as determined by the 
Investigator, the Investigator will decide whether to continue a subject on study treatment until 
repeat imaging is obtained (using iRECIST for subject management (see Table 6.2).  This 
decision by the Investigator should be based on the subject’s overall clinical condition. 
Clinical stability is defined as the following:  
 Absence of symptoms and signs indicating clinically significant progression of 
disease 
 No decline in ECOG performance status  
 No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care 
Any subject deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the subject may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment.  Images should continue to be sent in to the central 
imaging vendor for potential retrospective ICR Committee. 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
 Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir 
 Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology. 
 Unequivocal progression of non-target lesion(s) identified at baseline 
 Development of new lesion(s) 
iRECIST defines new response categories, including unconfirmed progressive disease (iUPD) 
and confirmed progressive disease (iCPD).  For purposes of iRECIST assessment, the first visit 
showing progression according to RECIST 1.1 will be assigned a visit (overall) response of 
iUPD, regardless of which factors caused the progression. 


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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed 
as usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST 1.1.  From measurable new lesions, up to 
5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  The sum of 
diameters of these lesions will be calculated, and kept distinct from the sum of diameters for 
target lesions at baseline.  All other new lesions will be followed qualitatively as New 
Lesions - Non-target. 
17.5.3. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the subject will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
17.5.4. 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
 Any of the factors that were the basis for the initial iUPD show worsening 
 For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point 
 For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1 
 For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD 
time point  
 Visible growth of new non-target lesions  
 The appearance of additional new lesions 
 Any new factor appears that would have triggered PD by RECIST 1.1 
17.5.5. 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
 None of the progression-confirming factors identified above occurs AND 
 The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule.  The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. 


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17.5.6. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
 None of the progression-confirming factors identified above occurs, AND 
 The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion 
for progression is “reset”. This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned. 
17.5.7. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
subject continues to be clinically stable, study treatment may continue and follow the regular 
imaging schedule.  If PD is confirmed, subjects will be discontinued from study treatment. 
If a subject has confirmed radiographic progression (iCPD) as defined above, but the subject is 
achieving a clinically meaningful benefit an exception to continue study treatment may be 
considered following consultation with the Sponsor. In this case, if study treatment is continued, 
tumor imaging should continue to be performed following the intervals as outlined in Table 6.2 
and submitted to the central imaging vendor. 
17.5.8. 
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated by 
any of the following events: 
 Target lesions 
 Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression. 
 Non-target lesions 
 If non-target lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD. 
 If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole. 
 New lesions 
 New lesions appear for the first time 


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 Additional new lesions appear 
 Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum 
 Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. Progression 
must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, with one 
exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory imaging 
the burden of new lesions has increased from its smallest value (for new target lesions, the sum 
of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will 
remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or 
until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication. 


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17.6. 
Appendix 6: New York Heart Association Functional Classification 
Table 17.4: 
New York Heart Association Functional Classification 
Functional Capacity  
Objective Assessment  
Class I. Patients with cardiac disease but without resulting limitation of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
A. No objective evidence 
of cardiovascular disease. 
Class II. Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
B. Objective evidence of 
minimal cardiovascular 
disease. 
Class III. Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
C. Objective evidence of 
moderately severe 
cardiovascular disease. 
Class IV. Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
D. Objective evidence of 
severe cardiovascular 
disease. 
Source: American Heart Association, Inc. Classification of Functional Capacity and Objective Assessment.  1994 
[cited 2017 Oct 12].  Available from: 
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/PreviousYears/Classification-of-
Functional-Capacity-and-Objective-Assessment_UCM_423811_Article.jsp