Clinical trial NCT03451162
Conditions: Breast Cancer
Sponsor: Genentech, Inc.
Start date: 2018-04-17; Completion date: 2021-07-16
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This first-in-human, Phase 1, open-label, multicenter, dose-escalation study will evaluate the safety, tolerability, and PK of DHES0815A as a single agent in participants with advanced and/or metastatic HER2-positive breast cancer for whom established treatment has proven ineffective or intolerable or is unavailable. The study may include a dose-expansion cohort (based on an ongoing assessment of the totality of data obtained in this study) to further assess safety, tolerability, PK, and preliminary anti-tumor activity.

Detailed description:

Arms: arm 1: Participants will receive DHES0815A in escalating doses in the dose-escalation cohort of the study. Participants will receive additional infusions of DHES0815A on Day 1 of subsequent cycles provided that they meet the protocol specified criteria for acceptable toxicity and ongoing clinical benefit. arm 2: Participants will be treated at or below the Maximum Tolerated Dose (MTD) of DHES0815A (based on the review of the totality of the data) to obtain additional safety, tolerability, PK, and anti-tumor activity data.
Interventions: intervention 1: DHES0815A
Intervention descriptions: intervention 1: DHES0815A will be administered via intravenous (IV) infusion on Day 1 of each 21-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: A Phase I, Open-Label Study Evaluating the Safety, Tolerability, and 
Pharmacokinetics of Escalating Doses of DHES0815A in Patients 
With HER2-Positive Breast Cancer 
NCT Number: NCT03451162 
Document Date: Protocol Version 2: 08-May-2019 
 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
DHES0815A—Genentech, Inc.
Protocol GO39869, Version 2
PROTOCOL
TITLE:
A PHASE I, OPEN-LABEL STUDY EVALUATING 
THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF ESCALATING DOSES 
OF DHES0815A IN PATIENTS WITH 
HER2-POSITIVE BREAST CANCER
PROTOCOL NUMBER:
GO39869
VERSION NUMBER:
2
EUDRACT NUMBER:
To be determined
IND NUMBER:
133077
TEST PRODUCT:
DHES0815A
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
DATE FINAL:
See electronic date stamp below.
 
08-May-2019 17:42:38
Title
Approver's Name
Company Signatory
Date and Time (UTC)


DHES0815A—Genentech, Inc.
2/Protocol GO39869, Version 2
PROTOCOL AMENDMENT, VERSION 2:
RATIONALE
Protocol GO39869 has been amended to limit the highest dose for patients enrolled in 
Cohorts 15 of this study to 2.4 mg/kg of DHES0815A every 3 weeks (Q3W) (see 
Section 3.1).  
 
 
 
 
 
 
 
 
In addition, this amendment provides updated stopping rules for safety for the expansion 
cohort (Section 6.1.2). The revised stopping rules employ a Bayesian posterior 
probability approach (Thall and Simon 1994) to evaluate toxicity in the expansion 
cohorts, including the rate of dose-limiting toxicity (DLT)-equivalent events that occur 
during Cycle 1 of study treatment.  Events that are DLT-equivalent in the expansion 
cohort are defined by the same criteria used to identify DLT events in the 
dose-escalation cohorts (Section 3.1.1.1).
Additional clarifications have been made to the exclusion criteria (Section 4.1.2):

The wash-out period for lapatinib has been qualified to be 14-days, given its short 
half-life.

Examples of medical conditions for exclusion regarding evidence of significant 
uncontrolled concomitant disease 
have 
been included: 
Patients with vascular leak syndrome or with a history of or who have active 
interstitial lung disease or pulmonary fibrosis or other clinically significant lung 
disease are not eligible for the study.
Patients who have any malignancies other than breast cancer are excluded 
from the study with the exception of patients who have a history of localized 
malignancies and were treated with curative intent and whose disease is 
unlikely to recur are eligible for the study.


DHES0815A—Genentech, Inc.
3/Protocol GO39869, Version 2

The following qualification has been included in the exclusion criterion for clinically 
significant history of liver disease to reflect the lower safety risk for asymptomatic 
hepatitis B carriers:
Patients who are asymptomatic hepatitis B virus (HBV) carriers based on 
serologic studies, with no history of clinically significant hepatitis, may be 
eligible if peripheral blood HBV viral load is undetectable by polymerase chain 
reaction (PCR). HBV carriers should receive prophylactic anti-viral therapy and 
be monitored for active HBV replication during trial participation per local 
standard of care.
Other minor revisions have been made to improve clarity and consistency:

Names of countries in which study will be conducted have been removed from 
Section 3.1, as changes to this list may evolve with the ongoing needs of the study.

It has been clarified that absolute counts are required for neutrophils and 
lymphocytes, but that percentages can be reported for other cell counts 
(Section 4.5.6.1 and Appendix 1, footnote "o").

The number of ECGs required at screening has been aligned with language in 
Sections 4.1.2 and 4.5.7 (Appendix 1, footnote "k").

Anti-drug antibody (ADA) and pharmacokinetic (PK) sample collection in footnotes 
"d" and "e" of Appendix 2 has been aligned with information provided in the table of 
Appendix 2.

The Genentech Medical Monitor name and contact information has been updated 
(Protocol Cover Page, Protocol Amendment Acceptance Form, and Section 5.4.1).
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.




DHES0815A—Genentech, Inc.
5/Protocol GO39869, Version 2
3.3.8
Rationale for Collection of Anti-Drug Antibody 
Samples................................................................................. 36
4.
MATERIALS AND METHODS .................................................................... 36
4.1
Patients.................................................................................. 36
4.1.1
Inclusion Criteria.................................................................... 36
4.1.2
Exclusion Criteria................................................................... 38
4.2
Method of Treatment Assignment.......................................... 41
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 41
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 41
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 41
4.3.3
Investigational Medicinal Product Accountability ................... 43
4.3.4
Continued Access to DHES0815A ........................................ 43
4.4
Concomitant Therapy ............................................................ 44
4.4.1
Permitted Therapy................................................................. 44
4.4.2
Cautionary Therapy ............................................................... 45
4.4.2.1
Medications Given with Precaution due to Effects 
Related to Cytochrome P450 Enzymes................................. 45
4.4.3
Prohibited Therapy ................................................................ 45
4.5
Study Assessments ............................................................... 46
4.5.1
Informed Consent Forms and Screening Log........................ 46
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 46
4.5.3
Physical Examinations........................................................... 47
4.5.4
Vital Signs.............................................................................. 47
4.5.5
Tumor and Response Evaluations......................................... 47
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 48
4.5.6.1
Local Laboratory Analyses .................................................... 48
4.5.6.2
Central Laboratory Analyses ................................................. 49
4.5.6.3
Sponsor or Designee for Analysis ......................................... 50
4.5.7
Electrocardiograms................................................................ 51


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6/Protocol GO39869, Version 2
4.5.8
Cardiac Assessments with Echocardiography or 
MUGA.................................................................................... 52
4.5.9
Ocular Assessments with BCVA and Anterior 
Slitlamp Examination ............................................................. 52
52
4.5.11
Optional Samples for Research Biosample 
Repository ............................................................................. 53
4.5.11.1
Overview of the Research Biosample Repository.................. 53
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 53
4.5.11.3
Sample Collection.................................................................. 54
4.5.11.4
Confidentiality........................................................................ 54
4.5.11.5
Consent to Participate in the Research 
Biosample Repository............................................................ 55
4.5.11.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 55
4.5.11.7
Monitoring and Oversight....................................................... 56
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 56
4.6.1
Study Treatment Discontinuation........................................... 56
4.6.2
Patient Discontinuation from Study........................................ 56
4.6.3
Study Discontinuation............................................................ 57
4.6.4
Site Discontinuation............................................................... 57
5.
ASSESSMENT OF SAFETY....................................................................... 57
5.1
Safety Plan ............................................................................ 57
5.1.1
Potential Risks Associated with DHES0815A........................ 58
5.1.1.1
Left Ventricular Dysfunction................................................... 58
5.1.1.2
Dermatologic Toxicity ............................................................ 58
5.1.1.3
Hematological Toxicity........................................................... 59
5.1.1.4
Nephrotoxicity........................................................................ 59
5.1.1.5
Hepatic Toxicity ..................................................................... 59
5.1.1.6
Ocular Toxicity....................................................................... 59
5.1.1.7
Pulmonary Toxicity ................................................................ 60
5.1.1.8
Vascular Leak Syndrome....................................................... 60
5.1.1.9
Gastrointestinal Toxicity......................................................... 61


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5.1.1.10
Infusion-Related Reactions, Hypersensitivity, 
Anaphylaxis ........................................................................... 61
5.1.1.11
Immunogenicity ..................................................................... 61
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 62
5.1.2.1
Dose and Schedule Modifications ......................................... 62
5.1.2.2
Management Guidelines for Patients Who 
Experience Adverse Events................................................... 62
5.1.2.3
Management Guidelines for Patients Who 
Experience Specific Adverse Events ..................................... 63
5.2
Safety Parameters and Definitions ........................................ 67
5.2.1
Adverse Events ..................................................................... 67
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 67
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 68
5.2.4
Dose-Limiting Toxicities (Immediately Reportable 
to the Sponsor)...................................................................... 69
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 69
5.3.1
Adverse Event Reporting Period ........................................... 69
5.3.2
Eliciting Adverse Event Information....................................... 69
5.3.3
Assessment of Severity of Adverse Events ........................... 70
5.3.4
Assessment of Causality of Adverse Events ......................... 70
5.3.5
Procedures for Recording Adverse Events............................ 71
5.3.5.1
Infusion-Related Reactions.................................................... 71
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 71
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 72
5.3.5.4
Persistent or Recurrent Adverse Events................................ 72
5.3.5.5
Abnormal Laboratory Values ................................................. 73
5.3.5.6
Abnormal Vital Sign Values ................................................... 73
5.3.5.7
Abnormal Liver Function Tests.............................................. 74
5.3.5.8
Deaths ................................................................................... 74
5.3.5.9
Preexisting Medical Conditions.............................................. 75
5.3.5.10
Lack of Efficacy or Worsening of Breast Cancer ................... 75


DHES0815A—Genentech, Inc.
8/Protocol GO39869, Version 2
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 75
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 76
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 76
5.4.1
Emergency Medical Contacts................................................ 77
5.4.2
Reporting Requirements for Serious Adverse 
Events, Adverse Events of Special Interest and 
Dose-Limiting Toxicities......................................................... 77
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 77
5.4.2.2
Events That Occur after Study Drug Initiation........................ 78
5.4.3
Reporting Requirements for Pregnancies.............................. 78
5.4.3.1
Pregnancies in Female Patients............................................ 78
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 78
5.4.3.3
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 79
5.5
Follow-Up of Patients after Adverse Events .......................... 79
5.5.1
Investigator Follow-Up........................................................... 79
5.5.2
Sponsor Follow-Up ................................................................ 79
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 79
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 80
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 80
6.1
Determination of Sample Size ............................................... 81
6.1.1
Dose Escalation..................................................................... 81
6.1.2
Dose Expansion .................................................................... 81
6.2
Summaries of Conduct of Study............................................ 83
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 83
6.4
Safety Analyses..................................................................... 83
6.4.1
Adverse Events ..................................................................... 83
6.4.2
Clinical Laboratory Results.................................................... 84
6.5
Pharmacokinetic Analyses..................................................... 84


DHES0815A—Genentech, Inc.
9/Protocol GO39869, Version 2
6.6
Activity Analyses.................................................................... 85
6.7
Immunogenicity Analyses...................................................... 85
6.8
Biomarker Analyses............................................................... 86
7.
DATA COLLECTION AND MANAGEMENT ............................................... 86
7.1
Data Quality Assurance......................................................... 86
7.2
Electronic Case Report Forms............................................... 86
7.3
Source Data Documentation.................................................. 87
7.4
Use of Computerized Systems .............................................. 87
7.5
Retention of Records............................................................. 87
8.
ETHICAL CONSIDERATIONS.................................................................... 88
8.1
Compliance with Laws and Regulations ................................ 88
8.2
Informed Consent.................................................................. 88
8.3
Institutional Review Board or Ethics Committee.................... 89
8.4
Confidentiality........................................................................ 90
8.5
Financial Disclosure .............................................................. 90
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 90
9.1
Study Documentation ............................................................ 90
9.2
Protocol Deviations................................................................ 91
9.3
Site Inspections ..................................................................... 91
9.4
Administrative Structure......................................................... 91
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 91
9.6
Protocol Amendments ........................................................... 92
10. REFERENCES ........................................................................................... 93
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 25
Table 2
Administration of First and Subsequent Infusions of 
DHES0815A................................................................................ 43
Table 3
Guidelines for Management of Patients Who Experience 
Specific Adverse Events ............................................................. 63


DHES0815A—Genentech, Inc.
10/Protocol GO39869, Version 2
Table 4
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 70
Table 5
Causal Attribution Guidance ....................................................... 71
Table 6
Probability of Escalation to the Next Dose .................................. 81
Table 7
Probability of Failing to Observe Toxicity .................................... 81
Table 8
Examples of Early Stopping Rules Based on DLT-Equivalent 
Event Rate in an Expansion Cohort............................................ 83
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 27
Figure 2
Left Ventricular Dysfunction Management Guidelines ................ 65
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 96
Appendix 2
Schedule of Pharmacokinetic and Immunogenicity Samples.... 101
Appendix 3
Response Evaluation Criteria in Solid Tumors (RECIST):  
Modified Excerpt from Original Publication ............................... 102
Appendix 4
ECOG Performance Status Scale............................................. 114
Appendix 5
New York Heart Association Classification ............................... 115
Appendix 6
Recommended Anaphylaxis Management ............................... 116


DHES0815A—Genentech, Inc.
11/Protocol GO39869, Version 2
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE I, OPEN-LABEL STUDY EVALUATING 
THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF ESCALATING DOSES 
OF DHES0815A IN PATIENTS WITH 
HER2-POSITIVE BREAST CANCER
PROTOCOL NUMBER:
GO39869
VERSION NUMBER:
2
EUDRACT NUMBER:
To be determined
IND NUMBER:
133077
TEST PRODUCT:
DHES0815A
MEDICAL MONITOR:
, M.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor and/or CRO.


DHES0815A—Genentech, Inc.
12/Protocol GO39869, Version 2
PROTOCOL SYNOPSIS
TITLE:
A PHASE I, OPEN-LABEL STUDY EVALUATING THE SAFETY, 
TOLERABILITY, AND PHARMACOKINETICS OF ESCALATING 
DOSES OF DHES0815A IN PATIENTS WITH HER2-POSITIVE
BREAST CANCER
PROTOCOL NUMBER:
GO39869
VERSION NUMBER:
2
EUDRACT NUMBER:
To be determined
IND NUMBER:
133077
TEST PRODUCT:
DHES0815A
PHASE:
Phase I
INDICATION:
HER2-Positive Breast Cancer
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will evaluate the safety, pharmacokinetics, and activity of DHES0815A in patients 
with advanced and/or metastatic HER2-positive breast cancer (BC).  Specific objectives and 
corresponding endpoints for the study are outlined in the table below. 
Safety Objective
(Primary Study Objective)
Corresponding Endpoints
To evaluate the safety and tolerability 
of escalating doses of DHES0815A 
administered by IV infusion every 
3 weeks to patients with advanced or 
metastatic HER2-positive BC 
including estimation of the MTD, 
determination of the RP2D, and 
characterization of DLTs
Occurrence and severity of adverse events 
including DLTs, with severity determined according 
to NCI CTCAE v4.0
Change from baseline in targeted vital signs 
Change from baseline in targeted clinical laboratory 
test results, including ECGs
Number of cycles received and dose intensity
LVEF as assessed by ECHO or MUGA scan
Pharmacokinetic Objective
Corresponding Endpoints
To characterize the DHES0815A 
pharmacokinetics when administered by 
IV infusion
Concentration of three key PK analytes of 
DHES0815A (i.e., DHES0815A Total Antibody, 
acPBD-MA, and unconjugated PBD-MA) at 
specified timepoints
PK parameters of DHES0815A Total Antibody, 
acPBD-MA, and unconjugated PBD-MA
Activity Objective
Corresponding Endpoints
To make a preliminary assessment of the 
anti-tumor activity of DHES0815A
Objective response, defined as a complete response 
or partial response on two consecutive occasions 
4 weeks apart, as determined by the investigator 
according to RECIST v1.1






DHES0815A—Genentech, Inc.
15/Protocol GO39869, Version 2

Histologically or cytologically documented HER2-positive BC (see American Society of 
Clinical Oncology-College of American Pathologists 2013 HER2 testing guidelines).  Based 
on review of the available data, enrollment into the expansion cohort may be restricted to 
patients with HER2-positive BC prospectively confirmed by central HER2 testing.

Locally advanced or metastatic BC that has relapsed or is refractory to established 
therapies and for which there is no available established therapy or the therapy is 
contraindicated 

Availability of formalin-fixed, paraffin-embedded (FFPE) tumor specimen obtained at the 
time of the original diagnosis of HER2-positive BC and the most recent available metastatic 
biopsy (if applicable), accompanied by associated pathology reports, with adequate viable 
tumor tissue to establish HER2 status.  Patients who only have available tumor tissue from 
one biopsy may still be eligible for participation in this Phase I study upon discussion with 
the Medical Monitor. 
o
Tumor specimen may consist of 

Either a tissue block (preferred) or at least 
 slides

Fewer than 
 slides may be acceptable upon discussion with the Medical 
Monitor
o
Cytologic or fine-needle aspiration samples are not acceptable.  

Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 2 weeks prior to initiation of study treatment:
o
ANC 1500/L without growth factor support within 28 days prior to Cycle 1, Day 1
o
Platelet count 100,000/L without transfusion support or thrombopoeitin mimetic 
agents within 28 days prior to Cycle 1, Day 1
o
Hemoglobin 9.0 g/dL without transfusion or erythropoiesis stimulating agent 
support within 28 days prior to Cycle 1, Day 1
o
Total bilirubin 1.5 ULN
o
AST and ALT1.5 ULN in the absence of liver metastases.  In patients with 
documented liver metastases: AST and/or ALT 2.5 ULN
o
Serum creatinine 1.5 ULN or creatinine clearance 65 mL/min on the basis of 
either 24-hour urine collection or the Cockroft-Gault glomerular filtration rate 
estimation
o
INR 1.5 and PT/aPTT 1.5 ULN in the absence of anticoagulation therapy.  
If patients are on anticoagulation therapy, INR and PT/aPTT should be within the 
therapeutic range for the medical indication

All acute, clinically significant treatment-related toxicity from prior therapy, except for 
alopecia and anorexia, resolved to Grade 1 prior to study entry

For women of childbearing potential, a negative serum pregnancy test within 7 days prior to 
commencement of dosing. In patients whose BC produces hCG, documentation of an 
evaluation by an obstetrical specialist will be required to confirm that the patient is not 
pregnant within 7 days prior to starting DHES0815A dosing.

A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no identified 
cause other than menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus). Women who are considered not to be of childbearing potential are 
not required to have a pregnancy test.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of 1% 
per year during the treatment period and for at least 8.5 months after the last dose of
DHES0815A.


DHES0815A—Genentech, Inc.
16/Protocol GO39869, Version 2
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, and established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
1% per year during the treatment period and for 5.5 months after the last dose of 
DHES0815A.  Men must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for at least 42 days after the last dose of DHES0815A to 
avoid exposing the embryo.

For dose-expansion cohorts only:  no more than two prior systemic 
chemotherapy-containing regimens in the advanced/metastatic setting (excluding 
trastuzumab emtansine, which is considered a targeted cytotoxic agent)
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Treatment with chemotherapy, hormonal therapy (except hormone replacement therapy, 
oral contraceptives), immunotherapy, biologic therapy, radiation therapy (except palliative 
radiation to bony metastases), or herbal therapy as cancer therapy within 4 weeks prior to 
initiation of DHES0815A.  
A shorter interval may be acceptable for patients on oral endocrine therapy provided 
that any clinically relevant drug-related toxicity has completely resolved and prior 
approval is obtained from the Medical Monitor.
For lapatinib, a 14-day washout is adequate on the condition that any related 
toxicities have resolved to Grade 1 or baseline prior to initiation of DHES0815A.

Treatment with any other ADC compound containing a DNA-damaging agent 
(i.e., topoisomerase inhibitors, DNA alkylators), including but not limited to DS-8201a, 
SYD-982, and ADCT-502 at any time prior to initiation of DHES0815A
Trastuzumab emtansine is not considered a DNA-damaging agent.

History of exposure to the following cumulative doses of anthracycline as specified below:
Doxorubicin 500 mg/m2
Liposomal doxorubicin 500 mg/m2
Epirubicin 720 mg/m2
Mitoxantrone 120 mg/m2
Idarubicin 90 mg/m2
If another anthracycline or more than one anthracycline has been used, then the 
cumulative dose must not exceed the equivalent of 500 mg/m2 of doxorubicin. 

History of severe allergic or anaphylactic reactions to monoclonal antibody therapies (or 
recombinant antibodyrelated fusion proteins)

Pregnancy, lactation, or breastfeeding

Major surgical procedure within 4 weeks prior to Day 1 


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
Evidence of a significant uncontrolled concomitant disease of the nervous system, 
pulmonary (including obstructive pulmonary disease and history of symptomatic 
bronchospasm), autoimmune, renal, hepatic, endocrine, or gastrointestinal disorders; or a 
serious non-healing wound or fracture
Note:  Patients with vascular leak syndrome or with a history of or who have active 
interstitial lung disease or pulmonary fibrosis or other clinically significant lung
disease are not eligible for the study.
Patients who have any malignancies other than breast cancer are excluded from the 
study.  However, patients who have a history of localized malignancies and were 
treated with curative intent and whose disease is unlikely to recur in the opinion of 
the investigator (e.g., resected cutaneous basal cell carcinoma, cutaneous squamous 
cell carcinoma, etc.) are considered not to have another malignancy at time of study 
entry and are therefore eligible for the study.

Known active bacterial, viral, fungal, mycobacterial, or other infection 

Clinically significant history of liver disease, including active viral or other hepatitis, current 
alcohol abuse, or cirrhosis
Patients who are asymptomatic hepatitis B virus (HBV) carriers based on serologic 
studies, with no history of clinically significant hepatitis, may be eligible if 
peripheral blood HBV viral load is undetectable by PCR.  HBV carriers should 
receive prophylactic anti-viral therapy and be monitored for active HBV replication 
during trial participation per local standard of care.

Untreated or active CNS metastases (progressing or requiring anticonvulsants or 
corticosteroids for symptomatic control). 
Patients with a history of treated CNS metastases are eligible, provided that all of the 
following criteria are met:
-
Presence of evaluable or measurable disease outside the CNS
-
Radiographically demonstrated stabilization or improvement upon completion of 
CNS-directed therapy and no evidence of interim progression between completion 
of CNS-directed therapy and the screening radiographic study.
-
Completion of radiotherapy 8 weeks prior to the screening radiographic study
-
Discontinuation of high-dose corticosteroids and anticonvulsants 4 weeks prior to 
the screening radiographic study (physiologic corticosteroid replacement is allowed)

Cardiopulmonary dysfunction as defined by the following:
-
Uncontrolled hypertension (systolic 150 mmHg and/or diastolic 100 mmHg)
-
Inadequate left ventricular ejection function at baseline, 50% by either ECHO or 
MUGA
-
History of symptomatic congestive heart failure-Grade 3 per NCI CTCAE v4.0 or 
Class II New York Health Association
-
History of a decrease in LVEF to 40% or symptomatic congestive heart failure with 
prior trastuzumab treatment
-
Myocardial infarction or unstable angina within 6 months of randomization
-
Current dyspnea at rest due to complications of advanced malignancy, or other disease 
requiring continuous oxygen therapy
-
Serious cardiac arrhythmia not controlled by adequate medication

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as 
structural heart disease, coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., 
hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained 
death or long QT syndrome


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
QT interval corrected through use of Fridericia’s formula (QTcF) 470 ms demonstrated by 
at least two ECGs 30 minutes apart

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last data point required for statistical analysis or safety follow-up (42 days following
last dose) is received from the last patient, whichever occurs later.  The end of the study is 
expected to occur about 12 months after the last patient is enrolled. 
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 45 months.
Investigational Medicinal Products
The investigational medicinal product (IMP) for this study is DHES0815A with no comparator or 
placebo arm.
Test Product (Investigational Drug)
DHES0815A administration will be performed in a setting with emergency medical facilities and 
access to a critical care unit with staff who are trained to monitor for and respond to potentially 
serious reactions.  The total dose of DHES0815A for each patient will depend on the dose 
assignment and the patient’s weight on Day 1 of each cycle (or within 72 hours prior to Day 1 of 
that cycle). Patients may receive the initial (Cycle 1) dose of DHES0815A unless the patient’s 
body weight has changed by 5% from baseline weight, in which case a new DHES0815A dose 
must be calculated.  This new dose of DHES0815A may be given in subsequent cycles, unless 
the patient experiences another 5% change in body weight, in which case a new DHES0815A 
dose must be calculated.  DHES0815A will be administered once every 21 days. Patients may 
continue to receive treatment with DHES0815A so long as they meet the criteria to do so or until 
they are required or choose to discontinue from study treatment as outlined in the protocol.
DHES0815A will be administered to patients by IV infusion using either a polyvinyl chloride 
(PVC) or polyolefin composed of polyethylene and polypropylene (PO-PE-PP) bag containing 
0.9% NaCl and using an infusion set equipped with a 0.2-m in-line filter.  The final 
DHES0815A concentration will be determined by dose and patient weight.
Statistical Methods
Primary Analysis
The objective of the dose escalation is to determine the MTD/MAD and RP2D of DHES0815A.
If the safety and PK profile seen in the dose-escalation portion of the study is deemed to be 
favorable to justify further continuation of the study, expansion cohorts will be enrolled to further 
confirm safety and tolerability and to assess preliminary evidence of anti-tumor activity and 
exploratory pharmacodynamic markers of response.
The final analysis will be based on patient data collected through patient discontinuation or 
study discontinuation, whichever occurs first.  All analyses will be based on the safety-evaluable 
population.  All summaries will be presented according to the assigned dose level and cohort.  
In general, data will be summarized as warranted, and listings will be used in place of tables 
when the samples sizes are small.  Continuous variables will be summarized using means, 
standard deviations, median, and ranges; categorical variables will be summarized using counts 
and percentages.


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Determination of Sample Size  
Approximately 2430 patients will be enrolled in the dose-escalation stage.  The exact number 
of patients to be enrolled in the study will depend upon the observed safety and 
pharmacokinetic/pharmacodynamic profile according to the dose-escalation rules.
At the RP2D, up to approximately 25 patients will be enrolled to further assess the safety, 
tolerability, and preliminary evidence of anti-tumor activity of DHES0815A.  
This study is intended to obtain preliminary safety, PK, pharmacodynamic, and activity 
information in the safety-evaluable population.  The sample sizes do not reflect any explicit 
power and type I error considerations.
Efficacy analyses will be performed on an ongoing basis in close collaboration with the study 
investigators for the expansion portion of the study to guide potential early stopping of 
enrollment in the event of lack of efficacy.  Decisions to stop enrollment into the expansion 
cohort for futility will be made based on the totality of the available data, taking into account 
both safety and efficacy.  Anti-tumor activity will be summarized by cohorts with an 80% CI.  
For example, in a cohort with 25 patients, if 10 of 25 patients have CR or PR, the objective 
response rate and its 80% CI will be summarized as 40% (27%55%).
Continuous safety monitoring and interim analyses will be performed for the expansion 
portion of the study to guide potential early stopping of enrollment in the event of 
unacceptable toxicity.  The first safety interim analysis will occur after approximately 
6 patients complete 2 cycles in the expansion cohort or every 6 months, whichever occurs first.
A Bayesian posterior probability approach (Thall and Simon 1994) will be used to evaluate 
the toxicity in the expansion cohorts, including the rate of DLT-equivalent events that occur 
during Cycle 1 of study treatments.  Events that are DLT-equivalent in the expansion cohort 
are defined by the same criteria used to identify DLT events in the dose-escalation cohorts.  
During continuous safety monitoring or in an interim analysis, if the number of observed 
DLT-equivalent events indicates that there is an approximately 80% chance that the true 
DLT rate is 25%, accrual to the cohort may be paused.  The Medical Monitor and Safety 
Scientist will determine whether further enrollment in the cohort should be halted and may 
provide other recommendations as described in the protocol.  The final decision will be based 
on the totality of the observed DLT-equivalent events, other safety events, as well as feedback 
from study investigators, Biostatistics, and Clinical Pharmacology.  The protocol provides 
examples that cover scenarios with different true DLT-equivalent event rate assumptions.  
The examples show the number of observed DLT-equivalent events that might lead the 
Sponsor to stop enrollment and the corresponding operating characteristics using the 
posterior probability approach with a non-informative prior beta (1,1) and the stopping 
criteria stated above.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
acPBD-MA
antibody-conjugated pyrrolo[2,1-c][1,4]benzodiazepine-
monoamide
ADA
anti-drug antibody
ADC
antibodydrug conjugate
BC
breast cancer
BCVA
best corrected visual acuity
CR
complete response
CT
computerized tomography
DAR
drug-to-antibody ratio
DDI
drugdrug interactions
DLT
dose-limiting toxicity
DOR
duration of response
EC
Ethics Committee
ECD
extracellular domain
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
FFPE
formalin-fixed, paraffin-embedded
GLP
Good Laboratory Practice
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HNSTD
highest non-severely toxic dose
ICH
International Council for Harmonisation
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRR
infusion-related reaction
IxRS
interactive voice or web-based response system
LVEF
left ventricular ejection fraction
MAb
monoclonal antibody
MAD
maximum administered dose


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Abbreviation
Definition
MBC
metastatic breast cancer
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multiple-gated acquisition scan
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
OS
overall survival
PBD-MA
pyrrolo[2,1-c][1,4]benzodiazepine monoamide
PCR
polymerase chain reaction
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic
PO-PE-PP
polyolefin composed of polyethylene and polypropylene
PR
partial response
PVC
poly-vinyl chloride
Q3W
every three weeks
QTcF
QT interval corrected through use of Fridericia’s formula
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended Phase II dose
ULN
upper limit of normal


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1.
BACKGROUND
1.1
BACKGROUND ON HER2-POSITIVE BREAST CANCER
Breast cancer (BC) is the most common cancer among women in the world, with an 
estimated 1.68 million cases diagnosed globally per year and a mortality rate of 
approximately 520,000 deaths per year (Ferlay et al. 2015). While advances in early 
diagnosis and adjuvant therapy have led to a decrease in mortality rates from BC in 
developed countries, the prevalence of metastatic breast cancer (MBC) is still high and 
MBC is not considered curable, with the main goals of treatment being to improve
patients’ quality of life and prolong survival (Cardoso et al. 2014).
HER2, also known as erbB2/neu and p185HER2, represents a prominent target in BC 
with approximately 15%20% of patients with primary invasive BC overexpressing the 
HER2 receptor (Reese and Slamon 1997; Owens et al. 2004; Wolff et al 2013). In the 
absence of HER2-targeted therapy, primary breast cancers that overexpress HER2 are 
associated with a poorer prognosis, including a greater risk of relapse and shortened 
survival compared with that of HER2-negative tumors (Slamon et al. 1987; Toikkanen et 
al. 1992; Andrulis et al. 1998; Pauletti et al. 2000; Rubin and Yarden 2001).
Until recently, for patients with HER2-positive MBC, the combination of trastuzumab and 
a taxane was widely accepted as the first-line treatment option of choice on the basis of 
the survival advantage demonstrated in two large pivotal trials (Studies H0648g 
[Slamon et al. 2001] and M77001 [Marty et al. 2005]).  The regimen of pertuzumab, 
which binds HER2 at an epitope that is distinct from trastuzumab, in combination with 
trastuzumab and docetaxel, has shown clear superiority in terms of both progression-
free survival (PFS) and overall survival (OS) with a generally similar safety profile (Study 
WO20698/TOC4129g [Baselga et al. 2012; Swain et al. 2015]) and is the new standard 
of care in many countries. The 5-year median OS of 56.5 months with the 
trastuzumab/pertuzumab/docetaxel regimen compared to 40.8 months with 
trastuzumab/docetaxel (Swain et al. 2015) suggests there may be therapeutic value to 
engagement of HER2 at multiple binding sites. 
In patients with HER2-positive advanced BC previously treated with trastuzumab and 
a taxane, trastuzumab emtansine has significantly prolonged PFS and OS with a more 
favorable safety profile than lapatinib plus capecitabine (Study BO21977/TDM4370g, 
[Verma et al 2012]). Trastuzumab emtansine also improved PFS and OS compared with
physicians' choice of treatment in patients who previously received trastuzumab, 
a taxane, and lapatinib (Study TDM4997g/BO25734 [Krop et al. 2014; Krop et al. 2017]).
Trastuzumab emtansine is considered standard of care in many countries in the 
aforementioned patient population. However, the combination of trastuzumab 
emtansine with pertuzumab in patients with previously untreated MBC, while not inferior
to trastuzumab and docetaxel or paclitaxel, failed to demonstrate superiority 
(Study TDM4788g/BO22589 [Perez et al. 2015]). 


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Although the treatment of MBC is palliative rather than curative in intent, improvement in 
survival is an important treatment goal. There is a significant need for new agents with 
novel mechanisms of action and acceptable toxicity that may be combined with 
established treatments to improve patient outcomes.  Results to date suggest that 
engagement of HER2 at multiple epitopes may confer advantageous clinical benefit and 
that tumor-directed cytotoxic agents may yield a more optimal safety profile over 
systemic chemotherapy.
1.2
BACKGROUND ON DHES0815A
Amplification of HER2 occurs in approximately 20% of patients with BCs and, without 
targeted therapy, is associated with more aggressive disease and shortened survival 
(Slamon et al. 1987; Dawood et al. 2010). High expression of HER2 is also found in a 
subset of other solid tumors, including gastric and esophageal junction cancer 
(Bang et al. 2010; Yan et al. 2015). DHES0815A is a THIOMABantibodydrug
conjugate that consists of MHES0488A, a humanized Ig G1 anti-HER2 (also called 
ERBB2) monoclonal antibody (MAb) (murine clone 7C2), conjugated to the DNA 
alkylating agent, pyrrolo[2,1-c][1,4]benzodiazepine monoamide (PBD-MA) via a disulfide 
linker. The PBD class of naturally occurring anti-tumor agents binds to the minor groove 
of DNA (Antonow and Thurston 2011). Numerous other PBD dimercontaining 
antibodydrug conjugates (ADCs) are currently in clinical trials (Kung Sutherland et al. 
2013; Rudin et al. 2017). The PBD payload on DHES0815A is a monoalkylator, in which
one of the two PBD moieties containing an amide functionality is not involved in DNA 
alkylation, making it less potent than the corresponding bis-alkylator to potentially 
improve tolerability. 
DHES0815A binds domain I of the HER2 extracellular domain (ECD) and has a distinct 
epitope from trastuzumab and pertuzumab, thereby enabling combination therapy with 
these agents.  When bound to HER2, DHES0815A undergoes receptor-mediated 
internalization and is subsequently trafficked to lysosomes where it undergoes 
degradation. Following lysosomal degradation, the disulfide linkage is reduced, resulting 
in self-immolation of the linker and intracellular release of the active PBD-MA
(Zhang et al. 2016). The released payload covalently binds to DNA in a 
sequence-selective manner leading to DNA alkylation but not cross-linking. This DNA 
alkylation ultimately results in cell death. DHES0815A was designed using
THIOMAB antibody technology enabling the conjugation of two PBD-MA linkerdrug 
molecules per antibody to engineered cysteine residues (Junutula et al. 2008).
 
 
. DHES0815A is being developed as a potential therapeutic for 
HER2-expressing cancers either as a single agent or in combination with existing 
treatments for HER2-positive BC.  


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Nonclinically, DHES0815A shows potent anti-tumor activity in murine xenograft models 
of HER2-positive breast and gastric cancer as a single agent and in combination, has 
acceptable pharmacokinetic (PK) properties, and has an acceptable safety profile that 
supports its clinical development in patients with HER2-positive cancers. Collectively, 
data from the nonclinical program with DHES0815A support DHES0815A entry into 
clinical trials and provide adequate safety factors to enable a starting dose of 0.6 mg/kg 
in humans. Refer to the DHES0815A Investigator's Brochure for details on nonclinical 
studies.
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
Metastatic HER2-positive BC remains an incurable disease with a median OS of less 
than 5 years reported for patients with previously untreated disease who received a 
combination of a taxane, pertuzumab, and trastuzumab (Swain et al. 2015). Therefore,
novel treatments that can further improve patient outcomes are needed. DHES0815A is 
being developed for treatment of HER2-positive malignancies, including metastatic 
HER2-positive BC. In nonclinical models, DHES0815A demonstrated anti-tumor efficacy 
in HER2-positive models of breast and gastric cancer, including in models insensitive to 
trastuzumab emtansine.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This Phase I trial will enroll patients with locally advanced or metastatic HER2-positive
BC to assess safety, tolerability, and pharmacokinetics and to make a preliminary 
assessment of anti-tumor activity of DHES0815A. Given the relatively poor prognosis 


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and limited treatment options for these patients, this population is considered 
appropriate for early-stage trials of novel therapeutic candidates, and the benefitrisk 
ratio of a clinical study of DHES0815A is considered acceptable.
Once preliminary DHES0815A safety data are available and a recommended Phase II
dose (RP2D) has been determined for DHES0815A, a combination of DHES0815A with 
trastuzumab emtansine is planned to evaluate the safety, tolerability, pharmacokinetics, 
and preliminary efficacy of this combination treatment.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety, pharmacokinetics, and activity of DHES0815A in 
patients with advanced and/or metastatic HER2-positive BC.  Specific objectives and 
corresponding endpoints for the study are outlined below (see Table 1). In this protocol, 
"study treatment" refers to DHES0815A.
Table 1
Objectives and Corresponding Endpoints
Safety Objective
(Primary Study Objective)
Corresponding Endpoints
To evaluate the safety and 
tolerability of escalating doses 
of DHES0815A administered by 
IV infusion every 3 weeks to 
patients with advanced or 
metastatic HER2-positive BC
including estimation of the MTD, 
determination of the RP2D, and 
characterization of DLTs
Occurrence and severity of adverse events
including DLTs, with severity determined 
according to NCI CTCAE v4.0
Change from baseline in targeted vital signs
Change from baseline in targeted clinical 
laboratory test results, including ECGs
Number of cycles received and dose intensity
LVEF as assessed by ECHO or MUGA scan
Pharmacokinetic Objective
Corresponding Endpoint
To characterize the DHES0815A
pharmacokinetics when 
administered by IV infusion
Concentration of three key PK analytes of 
DHES0815A (i.e., DHES0815A Total Antibody,
acPBD-MA, and unconjugated PBD-MA, see 
Section 6.5) at specified timepoints
PK parameters of DHES0815A Total Antibody, 
acPBD-MA, and unconjugated PBD-MA
Activity Objective
Corresponding Endpoints
To make a preliminary assessment of 
the anti-tumor activity of DHES0815A
Objective response, defined as a complete 
response or partial response on two consecutive 
occasions 4 weeks apart, as determined by the 
investigator according to RECIST v1.1
Duration of response, defined as the time from 
the first occurrence of a documented objective 
response to disease progression or death from 
any cause, whichever occurs first, as determined 
by the investigator according to RECIST v1.1




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Figure 1
Study Schema
DLT dose-limiting toxicity; MADmaximum administered dose; MTDmaximum tolerated dose; 
RP2Drecommended Phase II dose; TBDto be determined; Q3W every three weeks.
Notes:  Dose escalation will begin at 0.6 mg/kg and may proceed with 100% dose increases 
until a safety signal has been observed, defined as a DLT in 1 patient or 2 patients with a 
Grade 2 DHES0815A-related major organ adverse event (unless present at baseline) in DLT 
window (Cycle 1: Study Days 121).
Dose escalation may proceed with 50% increases after safety signal has been observed.
Approximately 2430 patients may be enrolled in the dose-escalation cohort of the study 
to examine the safety, tolerability, and pharmacokinetics of increasing doses of 
DHES0815A administered by IV infusion on Day 1 of a 21-day cycle.  Alternative 
DHES0815A dosing schedules may also be explored based on an ongoing review of the 
totality of the data.
The dose-expansion cohort of this Phase I study may include up to approximately 
25 patients with HER2-positive BC at the dose and schedule proposed for future studies
(the RP2D). The decision on whether to open this expansion cohort will be based on an 
ongoing assessment of the totality of data obtained in this study. 
The exact sample size for this trial will be determined by the number and size of the 
cohorts needed per the dose-escalation and cohort expansion rules.  This number is 
estimated to be 55 patients, but the number of patients and cohorts may decrease or 
increase if fewer cohorts are required, patients need to be replaced, or additional cohorts 
are enrolled.


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Patients in this study will be initially assessed for eligibility during the screening period 
(lasting 28 days).  Following confirmation of eligibility, patients will receive DHES0815A 
by IV infusion on the first day of every cycle.  A detailed PK evaluation will be performed 
during Cycle 1 and more limited PK assessments thereafter. Patients will be evaluated 
weekly by physical examination and by blood collections for routine hematologic and 
metabolic laboratory assessments for the first four cycles of DHES0815A treatment
during dose escalation, the first two cycles during dose expansion, and less frequently 
thereafter. Cardiac ejection fraction (left ventricular ejection fraction [LVEF]) will be 
monitored by transthoracic echocardiogram (ECHO) or multiple-gated acquisition scan
(MUGA) at baseline and in the last week (Days 1521) of Cycles 1, 2, 4, and 6, and then 
after every four cycles thereafter. Ophthalmic examinations (best corrected visual acuity 
[BCVA] and anterior segment slit lamp examination with fluorescein) to monitor for visual 
and/or corneal changes will occur at baseline and during the last week (Days 1521) of 
Cycles 2, 4, and 6, and every four cycles thereafter.  Tumor assessment will occur at 
baseline and during the last week (Days 1521) of every even-numbered cycle until 
Cycle 8 (i.e., at Cycles 2, 4, 6, and 8) and at every three cycles thereafter (i.e., at 
Cycles 11, 14, 17, etc.) until discontinuation or study termination. 
Adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Patients 
deriving clinical benefit may be offered continued treatment with DHES0815A until 
disease progression or intolerable toxicity at the discretion of the investigator (see 
Section 3.1.1.4).
Disease status will be assessed using the Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) (Eisenhauer et al. 2009; see Appendix 3). Tumor status will 
be categorized as a complete response (CR), partial response (PR), stable disease, or 
progressive disease (PD), per RECIST v1.1. Objective response should be confirmed 
by repeat physical examination or image-based evaluation 4 weeks after the initial 
documentation, per RECIST v1.1 (see Appendix 3). 
Blood samples will be collected for assessment of molecular and genetic biomarkers at 
baseline and end of study.
A detailed schedule of activities is provided in Appendix 1 and Appendix 2.
 
 
.  Patients enrolled in Cohorts 15 
(0.6 mg/kg Q3W, 1.2 mg/kg Q3W, 2.4 mg/kg Q3W, 4.0 mg/kg Q3W, and 6.0 mg/kg 
Q3W, respectively) may not receive a dose higher than 2.4 mg/kg Q3W, 
 


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3.1.1
Dose-Escalation Stage
Approximately 2430 patients will be enrolled in the dose-escalation stage. Cohorts of 
36 patients each will be treated at escalating doses of DHES0815A in accordance with 
the dose-escalation rules described below. The starting dose of DHES0815A is based 
on nonclinical safety assessments and will be no higher than 0.6 mg/kg IV Q3W (see 
Section 3.3.2 for more details). For added safety during dose escalation, treatment will 
be staggered such that the first patient treated at each dose level will receive his or her 
first infusion at least 1 day prior to subsequent patients in that cohort.  In addition, 
cohorts may be expanded even in the absence of dose-limiting toxicities (DLTs) in order 
to evaluate non-DLT adverse events further or to collect additional safety or PK data.  
Intrapatient dose escalation as per Section 3.1.1.3 will be allowed.  
Patients will be closely monitored for adverse events during the DLT assessment 
window, defined as Days 121 of Cycle 1. Adverse events identified as DLTs, as 
defined in Section 3.1.1.1, will be reported to the Sponsor within 24 hours (see
Section 5.3.1).
Patients who discontinue from the study prior to completing the DLT assessment window 
for reasons other than a DLT will be considered non-evaluable for dose-escalation 
decisions and maximum tolerated dose (MTD) assessments and will be replaced by an 
additional patient at that same dose level. Patients who receive supportive care during 
the DLT assessment window that confounds the evaluation of DLTs may be replaced at 
the discretion of the Medical Monitor.
3.1.1.1
Definition of Dose-Limiting Toxicity
For dose-escalation purposes, any one of the following events will be considered a DLT 
if it occurs during the DLT assessment window, unless clearly attributed to another 
identified etiology by the investigator (e.g., cancer progression):

15% decrease from baseline in LVEF or 10% decrease to less than a 50% LVEF

Grade 3 non-hematologic toxicity with the following exceptions:
–
Grade 3 nausea, vomiting, or diarrhea that resolves to Grade 1 with 
standard-of-care therapy in 7 days
–
Grade 3 fatigue that resolves to Grade 2 in 7 days
–
Grade 3 elevation of serum hepatic transaminase (ALT or AST) without an 
increase in direct bilirubin 2upper limit of normal (ULN) or clinical jaundice 
and lasting 7 days
–
Grade 3 laboratory abnormalities that are asymptomatic and considered by the 
investigator not to be clinically significant

Grade 4 neutropenia (ANC 500 cells/L) lasting 7 days 

Grade 3 febrile neutropenia 

Grade 4 anemia


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
Grade 4 thrombocytopenia

Grade 3 thrombocytopenia associated with clinically significant bleeding

Any increase in hepatic transaminase (ALT or AST) 3baseline in combination 
with either an increase in direct bilirubin 2ULN or clinical jaundice, in the 
absence of cholestasis or other contributory factors (e.g., worsening of metastatic 
disease, concomitant exposure to known hepatotoxic agent, or documented 
infectious etiology).
This is suggestive of potential drug-induced liver injury (according to 
Hy’s Law) and will be considered a DLT.
3.1.1.2
Starting Dose, Dose-Escalation Rules, and Determination of 
the Maximum Tolerated Dose
The starting dose of DHES0815A is 0.6 mg/kg administered by IV infusion Q3W to 
patients in the first cohort.  The dose may be increased by up to 100% of the preceding 
dose level for each successive cohort until a safety signal (defined as a DLT in 1 patient 
or study drugrelated Grade 2 major organ adverse events (unless present at baseline)
in at least 2 patients during the DLT assessment window in a given cohort) is observed.  
Once a safety signal has been observed in a given cohort, the dose may be increased 
by up to 50% of the preceding dose level for each successive cohort.  Intrapatient dose 
escalation may be allowed for some patients (see Section 3.1.1.3).
Dose escalation of DHES0815A will occur in accordance with the rules listed below.

A minimum of 3 patients will initially be enrolled in each cohort.

If none of the first 3 DLT-evaluable patients experiences a DLT, enrollment of the 
next cohort at the next highest dose level may proceed.

If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will 
be expanded to 6 patients.  If there are no further DLTs in the first 6 DLT-evaluable 
patients, enrollment of the next cohort at the next highest dose level may proceed.

If 2 or more DLT-evaluable patients in a cohort experience a DLT, the MTD will have 
been exceeded and dose escalation will stop.  An additional 3 patients will be 
evaluated for DLTs at the preceding dose level, unless 6 patients have already been 
evaluated at that level.  However, if the dose level at which the MTD is exceeded is 
15% higher than the preceding dose level, 6 patients may be evaluated at an 
intermediate dose level.

If the MTD is exceeded at any dose level, the highest dose at which fewer than 2 of 
6 DLT-evaluable patients (i.e., 33%) experience a DLT will be declared the MTD.

If the MTD is not exceeded at any dose level, the highest dose administered in this 
study will be declared the maximum administered dose (MAD).

As long as the MTD has not been exceeded, additional patients may be enrolled at 
a given dose level in a given arm to explore factors influencing adverse events or to 
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Relevant demographic, adverse event, laboratory, dose administration, and PK (if 
available) data will be reviewed prior to dose-escalation decisions, which will be made by 
the Sponsor Medical Monitor in consultation with the Principal Investigators and a 
committee composed of the following Sponsor representatives:  Medical Monitor and 
clinical safety scientist, with consultation from the statistician, clinical pharmacologist, 
and clinical trial leader.  On the basis of a review of real-time safety data and available 
preliminary PK data, dose escalation may be halted or modified by the Sponsor as 
deemed appropriate.
3.1.1.3
Intrapatient Dose Escalation
To minimize the exposure of patients to suboptimal doses and to maximize the collection 
of information at relevant doses, patients may progressively escalate from their current 
dose of DHES0815A to the highest dose level tolerated by completed cohorts. Patients 
will need to complete at least three cycles at their originally assigned DHES0815A dose 
level, as well as at each of the subsequent dose levels, prior to any further dose 
escalation.
Once the MTD is declared and the RP2D is determined, patients who remain in the 
study and continue to tolerate the study drug may escalate their dose to the RP2D level 
or the dose level below the RP2D under their current dosing schedule.  The RP2D will 
be at or below the MTD (or MAD) and determined by the totality of data, including DLTs, 
safety, activity, and PK data (see Section 3.1.1.2).
All intrapatient dose-escalation decisions will be made by the Sponsor in consultation 
with the participating investigators and will include assessment of safety data within the 
treatment cohorts, as well as the totality of the safety data.
For patients in Cohorts 15, please also refer to Section 3.1.
3.1.1.4
Continuation of DHES0815A (Cycles 2)
Patients without a DLT during the DLT assessment window will be eligible to receive 
additional infusions of DHES0815A at the same dose level at which they were enrolled 
or at an increased dose as detailed in Section 3.1.1.3 (the day of infusion being Day 1 of 
each cycle), provided that they meet the following criteria for acceptable toxicity and 
ongoing clinical benefit:

Acceptable toxicity:  All adverse events experienced with prior infusions that were 
not attributed to constitutional symptoms of the patient’s cancer or intercurrent
illness must have decreased to Grade 1 or baseline grade on or before the day of 
the next infusion.  
Exceptions on the basis of ongoing clinical benefit may be allowed after a careful 
assessment and discussion of benefit versus risk with the patient by the 
investigator and approval from the Medical Monitor.  In addition, delay of therapy 
because of toxicities not attributed to study drug may not require discontinuation 


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from the study but must be approved by the Medical Monitor.  Dose modifications 
are described in Section 5.1.2.1.

Ongoing clinical benefit:  Patients must demonstrate improvement/stabilization in 
tumor burden, according to the RECIST v1.1 (Appendix 3) or demonstrate clinical 
signs or symptoms of benefit, as judged by the investigator, independent of RECIST.
All tumors assessed at screening must be documented and re-assessed at 
each subsequent tumor evaluation (see Appendix 1 for tumor assessment 
schedule).  For each patient, the same imaging modality should be used 
throughout the study.
For patients in Cohorts 15, please also refer to Section 3.1.
Women of childbearing potential will need to undergo a urine pregnancy test prior to 
each DHES0815A cycle (patients whose breast tumor produces human chorionic 
gonadotropin [hCG] and were confirmed not be pregnant prior to enrollment should be 
monitored with serum pregnancy tests rather than urine pregnancy tests prior to 
each cycle of study treatment). If a urine pregnancy test result is positive, patient dosing 
will be postponed until the result is confirmed by a serum pregnancy test. Patients who 
are pregnant must permanently discontinue study treatment.
DHES0815A administration will be discontinued in patients who experience a DLT 
during the DLT assessment window (Days 121 of the first cycle) if this toxicity does not 
return to baseline grade within 14 days. Patients who experience a DLT during the first 
cycle (Days 121) and whose toxicity returns to baseline within 14 days may be 
restarted at a dose level tolerated by the prior cohort following discussion with the 
Medical Monitor. A treatment delay beyond 14 days may be acceptable upon discussion 
with the Medical Monitor (see Section 5.1.2.1).
3.1.2
Expansion Stage
After dose escalation has been completed, up to approximately 25 patients may be 
enrolled in the expansion stage. Patients may be treated at or below the MTD or MAD 
to obtain additional safety, tolerability, and PK data, as well as preliminary evidence of 
anti-tumor activity. 
If the frequency of Grade 3 or 4 toxicities or other unacceptable toxicities at the initial 
expansion-stage dose level suggest that the MTD has been exceeded, accrual at that 
dose level of DHES0815A will be halted. Consideration will then be given to enrolling 
patients in an expansion cohort at a lower dose level.
Patients in the dose-expansion cohort will be eligible to receive DHES0815A treatment
after Cycle 1 provided that they meet the same criteria for acceptable toxicity and 
ongoing clinical benefit as outlined for the dose-escalation cohorts in Section 3.1.1.4.


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3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which the last data point required for statistical analysis or safety follow-up
(42 days following last dose) is received from the last patient, whichever occurs later.  
The end of the study is expected to occur about 12 months after the last patient is 
enrolled. The total length of the study, from screening of the first patient to the end of 
the study, is expected to be approximately 45 months.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Patient Population
Patients with HER2-positive MBC can derive significant clinical benefit from 
HER2-directed therapies. Despite advances in treatment options for patients with 
HER2-positive MBC that include trastuzumab, pertuzumab, trastuzumab emtansine, 
lapatinib, and chemotherapy, HER2-positive MBC remains an incurable disease. Nearly 
all patients with HER2-positive MBC will eventually suffer disease progression and die 
from their disease (Verma et al. 2012; Swain et al. 2015). Given the relatively poor 
prognosis for patients with HER2-positive MBC and limited treatment options, this 
patient population is considered appropriate for early-stage trials of novel therapeutic 
candidates. DHES0815A is a novel ADC designed to target HER2-positive tumor cells, 
providing a rationale for studying this investigational agent in patients with HER2-positive
BC.
3.3.2
Rationale for Starting Dose and Schedule of DHES0815A
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
.


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Refer to the DHES0815A Investigator’s Brochure for additional details of the nonclinical 
studies described above.
3.3.3
Rationale for Evaluating Patients in the Dose-Expansion 
Cohort
It is expected that the small number of patients in each cohort during the dose-escalation 
stage will limit the extent to which the relationships between dose, drug exposure, and 
adverse events related to DHES0815A can be evaluated.  Therefore, a total of 
approximately 25 patients with HER2-positive advanced and/or metastatic breast cancer
may be enrolled at the proposed RP2D to further characterize the pharmacokinetics of 
DHES0815A, collect additional safety data, and assess for evidence of anti-tumor 
activity. 
3.3.4
Rationale for Pharmacokinetic Sampling Schedule
The PK sampling schedule that follows the DHES0815A administration is designed to 
capture DHES0815A exposure data at a sufficient number of timepoints to provide a 
detailed profile of the concentrationtime curve for DHES0815A total antibody 
(all drug-to-antibody ratios [DARs] including fully conjugated, partially deconjugated, and 
fully deconjugated anti-HER2 antibody), antibody-conjugated PBD-MA (acPBD-MA), and 
unconjugated PBD-MA. 
DHES0815A is designed to be structurally stable in circulation.  However, it is possible 
that catabolism could occur, resulting infor exampledeconjugation of the cytotoxic 
drug and changes in the overall DAR.  Exploratory structural data (e.g., changes in DAR 
distribution) may provide additional insight on the safety and efficacy of DHES0815A.
3.3.5
Rationale for Biomarker Assessments
HER2 status is routinely assessed on tumor tissue using approved assays 
 
 in patients with BC 
to assess whether they may benefit from currently approved HER2-directed therapies.
The possible relationship between HER2 expression and DHES0815A anti-tumor activity 
will be explored in this Phase I trial. HER2 expression in available tumor tissue will be 


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analyzed 
.  
 
 
 
 
3.3.6
Rationale for Collecting Blood Samples to Identify
 
 
 
 
  
 
 
 
 
 
3.3.7
Rationale for Collection of Pre-treatment Paraffin-Embedded 
Tumor Samples for Tumor Marker Assessment and Optional 
Tumor Tissue Biopsy on Progression
Paraffin-embedded tumor samples (either blocks [preferred] or at least 
 
slides) will be required from all patients for the central laboratory evaluation of HER2 
expression and other biomarker assessments (see Section 4.5.6.2). Tumor tissue 
obtained at the time of the original diagnosis of HER2-positive BC and the most recent 
available metastatic biopsy (if applicable) should be submitted. Patients who only have
available tumor tissue from one timepoint may still be eligible for participation in this 
Phase I study upon discussion with the Medical Monitor.
For patients who consent, an additional optional biopsy may be collected per investigator 
discretion, preferably at the time of radiographic progression. Biopsies should be 
minimally invasive, defined as requiring only local anesthesia, and in general, exclude
brain, lungs, or any internal organs that may subject patients to significant risk as 
referenced in Section 4.5.6.2.
The tumor tissues will be evaluated for HER2 and other biomarkers that are potentially 
relevant to study disease evolution, impact of prior treatments, and DHES0815A anti-tumor 
activity. Associations between biomarkers with outcomes measures will be explored. 
Tissue may be analyzed using molecular assays including, but not limited to, 
,
immunofluorescence,
. 


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Central review of HER2 status in patient tumor samples will be performed on an ongoing 
basis
 
.  Based on a review of the data, enrollment into the expansion cohort 
may be restricted to patients with centrally confirmed HER2-positive MBC. 
3.3.8
Rationale for Collection of Anti-Drug Antibody Samples
As with any recombinant antibody, DHES0815A may elicit an immune response and 
patients may develop antibodies against DHES0815A.  Anti-drug antibody (ADA) 
response and potential correlation of response to relevant clinical safety endpoints will 
therefore be assessed for all treated patients.  This could include ADA to the antibody, 
linker, drug, or epitopes involving multiple ADC components.  Although ADAs directed 
against DHES0815A are not expected to result in significant clinical sequelae, patients 
will be monitored for any potential immune response to DHES0815A in the Phase I 
clinical trial.  Validated screening and confirmatory assays will be employed to detect 
ADAs at multiple timepoints before, during, and after treatment with DHES0815A (see 
analysis Section 5.1.1.11). Serum samples will be collected from all patients prior to 
their first dose of DHES0815A and at several additional timepoints (see Appendix 1 and 
Appendix 2). 
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 55 patients with HER2-positive advanced and/or metastatic BC will be 
enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed written informed consent approved by the institution’s independent Ethics
Committee (EC) or Institutional Review Board (IRB). 

Age 18 years at time of signing Informed Consent Form

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Life-expectancy 12 weeks at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator’s judgment

Measurable disease by RECIST v1.1 with at least one measurable target lesion

Histologically or cytologically documented HER2-positive BC (see Wolff et al. 2013
for American Society of Clinical Oncology-College of American Pathologists 2013 
HER2 testing guidelines). Based on review of the available data, enrollment into the 
expansion cohort may be restricted to patients with HER2-positive BC prospectively 
confirmed by central HER2 testing.

Locally advanced or metastatic BC that has relapsed or is refractory to established 
therapies and for which there is no available established therapy or the therapy is 
contraindicated


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
Availability of formalin-fixed, paraffin-embedded (FFPE) tumor specimen obtained at 
the time of the original diagnosis of HER2-positive BC and the most recent available 
metastatic biopsy (if applicable), accompanied by associated pathology reports, with 
adequate viable tumor tissue to establish HER2 status. Patients who only have 
available tumor tissue from one biopsy may still be eligible for participation in this 
Phase I study upon discussion with the Medical Monitor. 
o
Tumor specimen may consist of 

Either a tissue block (preferred) or at least 
 
slides

Fewer than 
 slides may be acceptable upon discussion 
with the Medical Monitor
o
Cytologic or fine-needle aspiration samples are not acceptable.  

Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 2 weeks prior to initiation of study treatment:
o
ANC1500/L without growth factor support within 28 days prior to Cycle 
1, Day 1
o
Platelet count100,000/L without transfusion support or thrombopoeitin 
mimetic agents within 28 days prior to Cycle 1, Day 1
o
Hemoglobin 9.0 g/dL without transfusion or erythropoiesis stimulating 
agent support within 28 days prior to Cycle 1, Day 1
o
Total bilirubin 1.5 ULN
o
AST and ALT1.5ULN in the absence of liver metastases.  In patients 
with documented liver metastases: AST and/or ALT2.5ULN
o
Serum creatinine1.5ULN or creatinine clearance65 mL/min on the 
basis of either 24-hour urine collection or the Cockroft-Gault glomerular 
filtration rate estimation
o
INR 1.5 and PT/aPTT 1.5 ULN in the absence of anticoagulation 
therapy.  If patients are on anticoagulation therapy, INR and PT/aPTT 
should be within the therapeutic range for the medical indication

All acute, clinically significant treatment-related toxicity from prior therapy, except for 
alopecia and anorexia, resolved to Grade 1 prior to study entry

For women of childbearing potential, a negative serum pregnancy test within 7 days 
prior to commencement of dosing. In patients whose BC produces hCG,
documentation of an evaluation by an obstetrical specialist will be required to 
confirm that the patient is not pregnant within 7 days prior to starting DHES0815A 
dosing.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical 


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sterilization (removal of ovaries and/or uterus). Women who are considered not to 
be of childbearing potential are not required to have a pregnancy test.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of 1% per year during the treatment period and for at least 8.5 months after the 
last dose of DHES0815A.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, and established proper use of 
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of 1% per year during the treatment period and for 5.5 months
after the last dose of DHES0815A.  Men must refrain from donating sperm 
during this same period.
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 42 days after the last dose of 
DHES0815A to avoid exposing the embryo.

For dose-expansion cohorts only: no more than two prior systemic 
chemotherapy-containing regimens in the advanced/metastatic setting (excluding 
trastuzumab emtansine, which is considered a targeted cytotoxic agent)
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Treatment with chemotherapy, hormonal therapy (except hormone replacement 
therapy, oral contraceptives), immunotherapy, biologic therapy, radiation therapy 
(except palliative radiation to bony metastases), or herbal therapy as cancer therapy 
within 4 weeks prior to initiation of DHES0815A.
A shorter interval may be acceptable for patients on oral endocrine therapy 
provided that any clinically relevant drug-related toxicity has completely 
resolved and prior approval is obtained from the Medical Monitor.
For lapatinib, a 14-day washout is adequate on the condition that any related 
toxicities have resolved to Grade 1 or baseline prior to initiation of 
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
Treatment with any other ADC compound containing a DNA-damaging agent 
(i.e., topoisomerase inhibitors, DNA alkylators), including but not limited to
DS-8201a, SYD-982, and ADCT-502 at any time prior to initiation of DHES0815A
Trastuzumab emtansine is not considered a DNA-damaging agent.

History of exposure to the following cumulative doses of anthracycline as specified 
below:
Doxorubicin500 mg/m2
Liposomal doxorubicin500 mg/m2
Epirubicin720 mg/m2
Mitoxantrone120 mg/m2
Idarubicin90 mg/m2
If another anthracycline or more than one anthracycline has been used, then the 
cumulative dose must not exceed the equivalent of 500 mg/m2 of doxorubicin. 

History of severe allergic or anaphylactic reactions to monoclonal antibody therapies 
(or recombinant antibodyrelated fusion proteins)

Pregnancy, lactation, or breastfeeding

Major surgical procedure within 4 weeks prior to Day 1

Evidence of a significant uncontrolled concomitant disease of the nervous system, 
pulmonary (including obstructive pulmonary disease and history of symptomatic 
bronchospasm), autoimmune, renal, hepatic, endocrine, or gastrointestinal disorders; 
or a serious non-healing wound or fracture
Note:  Patients with vascular leak syndrome or with a history of or who have 
active interstitial lung disease or pulmonary fibrosis or other clinically 
significant lung disease are not eligible for the study.
Patients who have any malignancies other than breast cancer are excluded 
from the study.  However, patients who have a history of localized 
malignancies and were treated with curative intent and whose disease is 
unlikely to recur in the opinion of the investigator (e.g., resected cutaneous 
basal cell carcinoma, cutaneous squamous cell carcinoma, etc.) are considered 
not to have another malignancy at time of study entry and are therefore 
eligible for the study. 

Known active bacterial, viral, fungal, mycobacterial, or other infection 

Clinically significant history of liver disease, including active viral or other hepatitis, 
current alcohol abuse, or cirrhosis
Patients who are asymptomatic hepatitis B virus (HBV) carriers based on 
serologic studies, with no history of clinically significant hepatitis, may be 
eligible if peripheral blood HBV viral load is undetectable by PCR. HBV 
carriers should receive prophylactic anti-viral therapy and be monitored for 
active HBV replication during trial participation per local standard of care.


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
Untreated or active CNS metastases (progressing or requiring anticonvulsants or 
corticosteroids for symptomatic control). 
Patients with a history of treated CNS metastases are eligible, provided that all 
of the following criteria are met:
–
Presence of evaluable or measurable disease outside the CNS
–
Radiographically demonstrated stabilization or improvement upon 
completion of CNS-directed therapy and no evidence of interim progression 
between completion of CNS-directed therapy and the screening 
radiographic study.
–
Completion of radiotherapy 8 weeks prior to the screening radiographic 
study
–
Discontinuation of high-dose corticosteroids and anticonvulsants 4 weeks 
prior to the screening radiographic study (physiologic corticosteroid 
replacement is allowed)

Cardiopulmonary dysfunction as defined by the following:
–
Uncontrolled hypertension (systolic 150 mmHg and/or diastolic 100 mmHg)
–
Inadequate left ventricular ejection function at baseline, 50% by either ECHO 
or MUGA
–
History of symptomatic congestive heart failure-Grade 3 per NCI CTCAE v4.0 
or Class II New York Health Association (see Appendix 5)
–
History of a decrease in LVEF to 40% or symptomatic congestive heart failure
with prior trastuzumab treatment
–
Myocardial infarction or unstable angina within 6 months of randomization
–
Current dyspnea at rest due to complications of advanced malignancy, or other 
disease requiring continuous oxygen therapy
–
Serious cardiac arrhythmia not controlled by adequate medication

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such 
as structural heart disease, coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing), clinically significant electrolyte abnormalities 
(e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden 
unexplained death or long QT syndrome

QT interval corrected through use of Fridericia’s formula (QTcF) 470 ms 
demonstrated by at least two ECGs 30 minutes apart

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment 
complications


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4.2
METHOD OF TREATMENT ASSIGNMENT
This is an open-label study.  Patients will be assigned to dose levels in the order in 
which they are enrolled and in accordance with the DLT review and dose-escalation and
expansion plan.  
After signed informed consent has been obtained and preliminary eligibility has been 
established for a patient, the study site will submit documentation supporting eligibility to 
the Sponsor and obtain the Sponsor’s approval to enroll the patient.  Once the Sponsor 
reviews and approves the patient for enrollment, the Sponsor will provide the dose group 
assignment.  No pre-planned protocol deviations or waivers will be allowed.
During the dose-escalation stage of the study, when the last patient in a cohort has 
completed the 21-day DLT assessment window, a dose-escalation meeting will be held 
to review whether DLTs were observed in any patients in that cohort, as well as to 
review available cumulative safety data for the current and prior cohorts.  
Dose-escalation decisions will be made and communicated to the sites in writing prior to 
the opening of the next cohort.
Treatment assignment will be conducted using an interactive voice or web-based 
response system (IxRS).  After written informed consent has been obtained, all patients 
will receive a screening number, which will be assigned by the IxRS.  Following 
completion of the screening period and after all patient eligibility requirements are 
confirmed, the Sponsor will provide the dose group assignment and patients will be 
assigned an identification number by the IxRS. 
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is DHES0815A.
4.3.1
Study Treatment Formulation, Packaging, and Handling
DHES0815A will be supplied by the Sponsor as sterile liquid in 20-mL glass vials.  
DHES0815A vials must be refrigerated at 2C8C (36F46F) until use. DHES0815A
should not be used beyond the expiration date provided by the manufacturer.
Vial contents should not be frozen or shaken and should be protected from light during 
storage. Vials are intended for single use only; therefore, any remaining solution should 
be discarded. For additional information on the formulation and handling of DHES0815A,
see the pharmacy manual.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any overdose or incorrect administration of DHES0815A should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 


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associated with an overdose or incorrect administration of any of the study treatments 
should be recorded on the Adverse Event eCRF.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.2.
DHES0815A administration will be performed in a setting with emergency medical 
facilities and access to a critical care unit with staff who are trained to monitor for and 
respond to potentially serious reactions.  The total dose of DHES0815A for each patient 
will depend on the dose assignment and the patient’s weight on Day 1 of each cycle (or 
within 72 hours prior to Day 1 of that cycle). Patients may receive the initial (Cycle 1) 
dose of DHES0815A unless the patient’s body weight has changed by 5% from 
baseline weight, in which case a new DHES0815A dose must be calculated.  This new 
dose of DHES0815A may be given in subsequent cycles, unless the patient experiences 
another 5% change in body weight, in which case a new DHES0815A dose must be 
calculated. DHES0815A will be administered once every 21 days. Patients meeting the 
criteria outlined in Section 3.1.1.4 may continue to receive treatment with DHES0815A 
until they meet criteria for study treatment discontinuation (see Section 4.6.1), 
discontinue the study (see Section 4.6.2), or the Sponsor terminates the study.
DHES0815A will be administered to patients by IV infusion using either a polyvinyl 
chloride (PVC) or polyolefin composed of polyethylene and polypropylene 
(PO-PE-PP) bag containing 0.9% NaCl and using an infusion set equipped with a
0.2-m in-line filter.  The final DHES0815A concentration will be determined by dose and 
patient weight. Compatibility testing has shown that DHES0815A is stable and does not 
adsorb to the IV bags or IV administration sets when diluted in 0.9% NaCl solution in 
PVC or PO-PE-PP bags at expected concentrations.  For additional information on the 
dose solution preparation and handling of DHES0815A, see the pharmacy manual and 
the DHES0815A Investigator's Brochure.
The initial infusion (i.e., Cycle 1) should be administered over 90 (10) minutes. The 
DHES0815A infusion may be slowed or interrupted for patients experiencing 
infusion-related adverse events (see Table 3 in Section 5.1.2.3 for management 
guidelines for infusion-related adverse events). If no infusion-related reactions (IRRs)
are observed for Cycle 1, the time for subsequent infusions (Cycle 2 and beyond) may 
be reduced to 30 (10) minutes. Patients will be observed for 2 hours for fever, chills, 
rigors, hypotension, nausea, or other infusion-related adverse events following the first 
two infusions of DHES0815A at Cycle 1 and Cycle 2. Patients who experience 
infusion-related adverse events following any given infusion should be observed for 
2 hours following the next subsequent infusion. In the absence of infusion-related 
adverse events, infusions of DHES0815A subsequent to Cycle 2 may be administered 
over 30 (10) minutes followed by a 30-minute observation period after the infusion.
DHES0815A infusions will be administered per the instructions outlined in Table 2.


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Table 2
Administration of First and Subsequent Infusions of DHES0815A
Cycle 1
Cycle 2
Cycle 3 and Beyond
Infusion time
90 minutes
30 minutes
30 minutes
Observation time
2 hours
2 hours
30 minutes
Notes:  
Infusion and observation times assume that no infusion-related adverse events occurred during
the prior infusion.  If no infusion-related adverse event occurred during the first infusion, the 
infusion time for Cycle 2 can be shortened to 30 minutes, but the observation time should 
remain at 2 hours.  If no infusion-related adverse events have occurred after the first two cycles, 
both the infusion time and the observation time can be shortened to 30 minutes.
If a patient experiences an infusion-related reaction, refer to Section 5.1.1.10 for details on 
management.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (DHES0815A) will be provided by the 
Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to confirm the 
shipment condition and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to DHES0815A
The Sponsor (Genentech, a member of the Roche Group) will offer continued access to 
Genentech IMP (DHES0815A) free of charge to eligible patients in accordance with the 
Roche Global Policy on Continued Access to Investigational Medicinal Product, as 
outlined below.
A patient will be eligible to receive Genentech IMP (DHES0815A) after completing the 
study if all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Genentech IMP treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them


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A patient will not be eligible to receive Genentech IMP (DHES0815A) after completing 
the study if any of the following conditions are met:

The Genentech IMP is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's insurance or 
wouldn't otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP
is not effective for advanced and/or metastatic HER2-positive BC

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
advanced and/or metastatic HER2-positive BC

Provision of the Genentech IMP is not permitted under the laws and regulations of 
the patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study drug to the study completion/discontinuation visit. All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives, hormone-replacement therapy, or other maintenance therapy 

Hematopoietic growth factors such as erythropoietin, granulocyte colony-stimulating 
factor (filgrastim, pegfilgrastim), and granulocyte-macrophage colony-stimulating 
factor (sargramostim) as clinically indicated and when used in accordance with 
instructions provided in the package inserts. 
Any use of these agents during the DLT assessment window must be 
discussed with the Medical Monitor.

Bisphosphonates and denosumab for prevention of skeletal-related events as
clinically indicated and when used in accordance with instructions provided in the 
package inserts

Biologic agents (other than those listed above and not intended for the treatment of 
cancer) as clinically indicated and when used in accordance with instructions 
provided in the package inserts
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice. 


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4.4.2
Cautionary Therapy
4.4.2.1
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes
DHES0815A consists of a human monoclonal IgG1 antibody, a cleavable disulfide-linker, 
and PBD-MA.  There is a low risk of PK drugdrug interactions (DDI) between the 
MAb component and small molecules due to different metabolic pathways that each 
undergo. In vitro data also suggest there is low risk of DDI specifically with the released 
payload from DHES0815A, unconjugated PBD-MA. PBD-MA was found to be a weak 
competitive inhibitor of CYP2C8 and CYP3A4/5 and a time-dependent inhibitor for 
CYP3A4/5 as well as CYP2B6 at concentrations much higher than expected to be 
reached given the projected administered clinical doses of DHES0815A. Given that the 
expected liver concentration of the PBD-MA will likely be low at the administered clinical 
dose, the DDI potential for the unconjugated PBD-MA as a perpetrator is likely low. In
human and animal liver microsomes the unconjugated PBD-MA was extensively
metabolized by oxidation pathways, which are catalyzed mainly by CYP3A4/5 as well as 
CYP2J2 (minor). However, in vivo contribution of CYP3A to the total clearance of 
unconjugated PBD-MA following administration of DHES0815A is not known at this time.  
Therefore, the DDI potential for unconjugated PBD-MA is unclear as a victim and the 
use of strong CYP3A inhibitors should be avoided in patients who are administered 
DHES0815A.  Patients should be closely monitored for adverse reactions if taking strong 
CYP3A inhibitors cannot be avoided; these include, but are not limited to, boceprevir, 
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, mibefradil, 
lopinavir/ritonavir, nefazodone, nelfinavir, ritonavir, posaconazole, saquinavir, telaprevir,
telithromycin, or voriconazole.  Investigators may also consult the Drug Development 
and Drug Interactions: Table of Substrates, Inhibitors, and Inducers web site for a 
non-exhaustive list of CYP3A:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm
4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited during the study:

Cytotoxic chemotherapy

Radiotherapy for progressive disease except for cases where localized radiotherapy 
is indicated and approval of the Medical Monitor is obtained

Immunotherapy for the treatment of cancer

Hormone therapy (other than contraceptives, hormone-replacement therapy, or 
megestrol acetate)

Biologic agents for the treatment of cancer

Herbal therapy

Any therapies intended specifically for the treatment of advanced cancer, whether 
approved by regulatory authorities or investigational


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Patients who require the use of any of these agents will be discontinued from 
DHES0815A treatment. Questions about whether specific medications are prohibited 
therapy during this Phase I study should be discussed with the Medical Monitor.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
Collection of any nonsafety-related data or patient samples may be terminated by the 
Sponsor at any time if further collection of such data or samples is also not related to the 
study's primary objective(s). The decision to discontinue any data collection will be 
communicated to sites (IRBs and ECs) by means of a memorandum and will not require 
a protocol amendment.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, and smoking 
history will be recorded at baseline.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 7 days prior to screening visit will be recorded.  
At the time of each follow-up physical examination, an interval medical history should be 
obtained and any changes in medications and allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.


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4.5.3
Physical Examinations
A complete physical examination will be done at screening and should include an 
evaluation of the head, eyes, ears, nose, and throat and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, genitourinary, gastrointestinal, and 
neurologic systems.  
Weight will be measured at each cycle within 72 hours prior to administration of 
study drug.  Height will be measured during the screening period only.
Targeted physical examinations should be limited to systems of primary relevance 
(i.e., cardiovascular, respiratory, skin, and any system that might be associated with 
tumor assessment) and systems associated with symptoms.
Changes from baseline abnormalities should be recorded at each subsequent physical 
examination.  New or worsened abnormalities should be recorded as adverse events if 
appropriate.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, heart rate, systolic and diastolic 
blood pressures while the patient is in a seated position, pulse oximetry, and 
temperature.
On Day 1 of Cycle 1 and on Day 1 of Cycle 2 and on any day of infusion where a 2-hour 
post-infusion observation period is warranted (see Section 4.3.2), vital signs will be 
assessed prior to infusion, every 15 (5) minutes during infusion, at the end of infusion 
(5 minutes), and every 30 (10) minutes after the infusion for 2 hours.  For all other 
days of infusion where a 30-minute post-infusion observation period is allowed (see 
Section 4.3.2), vital signs will be assessed prior to infusion, every 15 (5) minutes 
during infusion, at the end of infusion (5 minutes), and at 30 (10) minutes after 
infusion.  Oxygen saturation via pulse oximetry will be monitored at a minimum every 
15 (5) minutes during infusion from pretreatment to the end of the observation period.  
Additional monitoring should be performed if clinically indicated.  Vital signs will be 
monitored at the timepoints specified in Appendix 1.
4.5.5
Tumor and Response Evaluations
All measurable disease must be documented at screening and reassessed at each 
subsequent tumor evaluation.  Response will be assessed using RECIST v1.1 
(see Appendix 3). Assessments should include an evaluation of all sites of disease.
Computed tomography (CT) scans should include the chest, abdomen, and pelvis; CT 
scans of the neck should be included if clinically indicated. Magnetic resonance imaging
(MRI) scan may be used instead of CT scans in patients for whom CT scans are 
contraindicated or in circumstances in which MRI is the preferred imaging modality.  


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The same method of assessment and the same technique should be used at baseline 
and for all on-study assessments.
If at any time during the treatment phase there is suspicion of disease progression 
based on clinical or laboratory findings before the next scheduled assessment, an 
unscheduled tumor assessment should be performed. 
Objective responses using RECIST v1.1 should be confirmed by repeat assessments 
performed 4 weeks after initial documentation of response. 
4.5.6
Laboratory, Biomarker, and Other Biological Samples
4.5.6.1
Local Laboratory Analyses
Local laboratory (i.e., non-central laboratory) assessments may be performed up to
72 hours preceding DHES0815A administration unless otherwise specified.  Pre-infusion 
laboratory samples should be drawn within 04 hours before the start of infusion.  
Post-infusion laboratory samples should be drawn within 030 minutes after the end of 
infusion, unless otherwise specified.  Results from predose assessments must be 
reviewed by the investigator and the review documented prior to DHES0815A 
administration.
Samples for the following laboratory tests will be sent to the study site's local laboratory
for analysis:

Hematology:  complete blood count, including hemoglobin, hematocrit, platelet 
count, RBC count, WBC count, and absolute differential count for neutrophils and 
lymphocytes; percentage or absolute count is acceptable for all other cell types 
(e.g., eosinophils, monocytes, basophils, bands, and other cells)  

Serum chemistry panel: sodium, potassium, chloride, bicarbonate, glucose, BUN or 
urea, creatinine, calcium, phosphorus, magnesium, total and direct 
bilirubin, total protein, albumin, LDH, ALT, AST, and ALP.  

Coagulation:  INR, aPTT, PT

Pregnancy test: serum and urine pregnancy tests

Urinalysis, including macroscopic analysis (specific gravity, protein, pH, glucose, 
ketones, blood, bilirubin, leukocyte esterase, urobilinogen, and nitrite) and, if any 
abnormalities, microscopic analysis (RBCs, WBCs, epithelial cells, casts, crystals, 
bacteria, and yeast).


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4.5.6.2
Central Laboratory Analyses
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis:

Archival Tumor Tissue
Patients will provide the following tumor tissue samples:
1.
Tumor tissue sample collected at time of initial diagnosis
2.
The most recent available metastatic tumor biopsy tissue
Archival tissue will be used for determination of HER2 status and for 
exploratory biomarker research.
Availability of a representative FFPE tumor specimen in a paraffin block (preferred) 
or at least 
 sections with an 
associated pathology report must be confirmed prior to study enrollment. If less 
than 
slides are available, the patient may still be eligible for the study after 
Medical Monitor approval has been obtained.
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples must contain a minimum of 50 viable tumor cells that preserve cellular 
context and tissue architecture regardless of needle gauge or retrieval method. 
Samples collected via resection, core-needle biopsy (at least three cores, 
embedded in a single paraffin block), or excisional, incisional, punch, or forceps 
biopsy are acceptable.  Fine-needle aspiration (defined as samples that do not 
preserve tissue architecture and yield cell suspension and/or smears), brushing, 
cell pellets from pleural effusion, and lavage samples are not acceptable.  
In the event that enrollment into the expansion cohort of the study is restricted to 
patients with HER2-positive tumors as prospectively assessed 
 
(see Section 3.3.7), tumor samples will need to be submitted and assessed for 
HER2 expression prior to the first dose of DHES0815A.

Optional Tumor Biopsy
An additional optional minimally invasive biopsy may be collected per investigator 
discretion, preferably at the time of radiographic progression. The suitability and 
timing of biopsy collection for individual patients will be based on discussion with 
and the approval of the Sponsor’s Medical Monitor.  Patients who agree to undergo 
these additional biopsies will be asked to sign an optional Informed Consent Form.

Blood for Biomarker Analysis
 
 


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4.5.6.3
Sponsor or Designee for Analysis
The following samples will be sent to the Sponsor or a designee for analysis:

Blood samples for PK analysis of DHES0815A: serum DHES0815A total antibody 
(all DAR species, including DAR 0 and DAR 1), plasma acPBD-MA, and 
unconjugated PBD-MA concentrations with the use of validated methods.  

Plasma samples for assessment of DHES0815A catabolism

A baseline serum sample (Cycle 1, Day 1 only) may be used, depending upon 
review of DHES0815A PK/ADA data, to measure HER2 ECD, pertuzumab, 
trastuzumab, and/or trastuzumab emtansine levels in order to better 
understand potential drug interferences or impact on pharmacokinetics.

Serum samples for ADA
A validated antibody-bridging ELISA will be used to screen for and confirm the 
presence of anti-DHES0815A antibodies in patient samples as well as to 
characterize domain specificity and titer of ADA in positive samples.
At the discretion of the Sponsor, these samples may also be used for exploratory 
analyses related to DHES0815A, if considered necessary.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.11), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Samples collected for PK and immunogenicity (ADA) analysis may be needed for 
additional method development, validation, biomarker assays, and characterization.
These samples, if not used up, will be destroyed within 15 years after the final 
clinical study report has been completed.

Blood samples collected for 
will be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements).

Blood and tumor tissue samples collected for biomarker research will be destroyed 
no later than 15 years after the final Clinical Study Report has been completed.

For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or 18 months after final closure of the study database, whichever 
occurs first.  For patients who are not enrolled, remaining archival tissue blocks will 
be returned to the site upon request.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal will still be analyzed, unless the patient specifically requests that the samples 
be destroyed or local laws require destruction of the samples. However, any data 
collected prior to patient request for destruction of samples will still be used for analysis. 


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Data arising from sample analysis, including data on germline mutations, will be subject 
to the confidentiality standards described in Section 8.4.
 
 The aggregate results of any conducted research will be available in accordance 
with the effective Sponsor policy on study data publication.
4.5.7
Electrocardiograms
Triplicate ECG recordings will be obtained at specified timepoints, as outlined in the
schedule of activities (see Appendix 1).  ECGs acquired on different days should be as 
closely time-matched as feasible. Three interpretable ECG recordings (e.g., without 
artifacts) must be obtained at each timepoint (5 minutes).  The average of the 
three readings will be used to determine ECG intervals (e.g., PR, QRS, QT).  
Single ECG recordings may be obtained at unscheduled timepoints as indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation), should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings will be stored at a central location.  If considered 
appropriate by the Sponsor, ECGs may be analyzed retrospectively at a central 
laboratory.
If at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms longer 
than the baseline value, another triplicate ECG must be recorded, ideally within the next 
5 minutes, and triplicate ECG monitoring should continue until QTcF has stabilized on 
two successive ECGs.  The Medical Monitor should be notified.  Standard-of-care 
treatment may be instituted per the discretion of the investigator.  If a PK sample is not 
scheduled for that timepoint, an unscheduled PK sample should be obtained.  A decision 
on study drug discontinuation should be made, as described in Section 4.6.1.  The 
investigator should also evaluate the patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, co-medications known to prolong the QT interval, severe 
bradycardia).


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4.5.8
Cardiac Assessments with Echocardiography or MUGA
ECHO is the preferred method of assessment of LVEF, although MUGA scan is also 
accepted.  All efforts should be made to use the same method and the same facilities 
throughout the entire study for each patient and to have the same assessor for each.
LVEF is to be assessed at screening, during the last week (Days 1521) of Cycles 1, 2,
4, and 6, and then every four cycles thereafter, or as clinically indicated.  Please refer to 
Appendix 1 for the schedule of cardiac assessments.
4.5.9
Ocular Assessments with BCVA and Anterior Slitlamp 
Examination
Ophthalmic examinations will include assessment of BCVA and an anterior segment slit 
lamp examination with fluorescein. Ophthalmic examinations must be conducted during 
the screening period, during the last week (Days 1521) of even-numbered cycles until 
Cycle 6 (i.e., at Cycles 2, 4, and 6) and every four cycles thereafter (i.e., at Cycles 10, 14, 
18, etc.), at the study discontinuation visit (unless the most recent ophthalmic 
examination has occurred within the past 4 weeks) and at unscheduled time points if 
clinically indicated.
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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4.5.11
Optional Samples for Research Biosample Repository
4.5.11.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research. RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.11.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body. 
If a site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.5.11) will not be applicable at that site.


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4.5.11.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to DHES0815A or 
HER2-positive BC:

Blood plasma samples collected at baseline and disease progression

Tumor tissue samples from biopsies performed at the investigator's discretion 
during the study at time of progression, if deemed clinically feasible, for exploratory 
research on biomarkers
Biopsies at the time of progression should be performed within 40 days after 
progression or prior to the next anti-cancer therapy, whichever is sooner.  
Samples collected via resection, core-needle biopsy (at least three cores 
preferred), or excisional, incisional, punch, or forceps biopsy are preferred.

Leftover serum, plasma, and tumor tissue samples (with the exception of remaining 
archival tissue blocks, which will be returned to sites) and any derivatives thereof 
(e.g., DNA, RNA, proteins, peptides), including leftover tissue samples from 
medically indicated procedures (e.g., bronchoscopy, esophagogastroduodenoscopy, 
colonoscopy) performed at the investigator's discretion during the course of the 
study
The above samples may be sent to one or more laboratories for testing, which may 
include, but are not limited to, analysis of germline or somatic mutations via 
, whole 
exome sequencing, 
, or other genomic and molecular analysis methods. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
 and WES provide a comprehensive characterization of the genome and exome,
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.  Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.11.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.


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Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.11.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.11.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  However, if RBR specimens have been tested prior 
to withdrawal of consent, results from those tests will remain as part of the overall 
research data.  If a patient wishes to withdraw consent to the testing of his or her 
specimens, the investigator must inform the Medical Monitor in writing of the patient's 
wishes through use of the appropriate RBR Subject Withdrawal Form and, if the trial is 
ongoing, must enter the date of withdrawal on the RBR Research Sample Withdrawal of 
Informed Consent eCRF.  The patient will be provided with instructions on how to 
withdraw consent after the trial is closed.  A patient's withdrawal from Study GO39869


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does not, by itself, constitute withdrawal of specimens from the RBR.  Likewise, a 
patient's withdrawal from the RBR does not constitute withdrawal from Study GO39869.
4.5.11.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Pregnancy

Use of an anti-cancer therapy other than DHES0815A

Symptomatic deterioration attributed to disease progression

Confirmed disease progression per investigator assessment according to 
RECIST v1.1 unless a patient continues to demonstrate signs and symptoms of 
clinical benefit from DHES0815A treatment that is independent of RECIST v1.1, as 
judged by the investigator and upon discussion with the Medical Monitor (see
Appendix 3)
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced unless enrolled in the dose-escalation cohorts and they discontinue prior to 
completion of the 21-day DLT window.
Patients will return to the clinic for a treatment discontinuation visit within 42 days after 
the last dose of study drug (see Appendix 1 for additional details).
4.6.2
Patient Discontinuation from Study
Patients will return to the clinic for a study discontinuation visit at treatment
discontinuation.


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Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. Patients 
who withdraw from the study will not be replaced.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
DHES0815A is not approved, and clinical development is ongoing.  This is the first study 
in which DHES0815A will be administered to humans.  The safety plan for patients in 
this study is based on nonclinical experience with DHES0815A, clinical experience with 
HER2-targeting molecules (i.e., trastuzumab, pertuzumab, and trastuzumab emtansine),
and published clinical data of rovalpituzumab tesirine (DLL3-targeting ADC linked to a 


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PBD dimer; Rudin et al. 2017) and SJG-136 (PBD dimer; Hochhauser et al. 2009).  The 
anticipated important potential safety risks for DHES0815A are outlined below.  Please 
refer to the DHES0815A Investigator's Brochure for a complete summary of safety 
information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below.
5.1.1
Potential Risks Associated with DHES0815A
5.1.1.1
Left Ventricular Dysfunction
Patients treated with DHES0815A may be at risk of developing left ventricular 
dysfunction.  Significant cardiac events, including LVEF of 40%, have been observed 
with HER2-targeting molecules (i.e., trastuzumab, pertuzumab, and trastuzumab 
emtansine).
Patients must meet specified LVEF requirements to be included in this study (see 
Section 4.1.2).
Left ventricular function will be monitored by measurement of ejection fraction using 
ECHO (or MUGA) scans as described in Section 4.5.8 and the schedule of activities
(see Appendix 1).
Guidelines for management of patients who develop left ventricular dysfunction are 
provided in Table 3.
5.1.1.2
Dermatologic Toxicity
Skin disorders, including hyperpigmentation, erythema, and rash may occur in patients 
treated with DHES0815A.  In nonclinical studies, hyperpigmentation has been observed 
in cynomolgus monkeys and did not reverse during the recovery period.  HER2-targeting 
molecules can cause skin disorders, including erythema, rash, and pruritus.  Skin 
disorders have also been observed with rovalpituzumab tesirine, including Grade3 
events of rash, erythema, and photosensitivity (Rudin et al 2017).
Patients should be monitored closely for skin toxicity.  Patients are advised to prevent 
exposure to UV light and apply sunscreen to exposed areas of the skin when outside in 
the sun.  If skin toxicity occurs, patients should be evaluated by a dermatologist, and a 
proper dermatologic diagnosis should be established and recorded on the eCRF.  For 
Grade 2 dermatologic events, photographs of the affected area should be obtained if 
possible and submitted to the sponsor to document the type and course of the skin 
toxicity.  The photographs will be taken in such a manner as not to create any risk of 


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identifying the patient; photographs will be thoroughly de-identified at the sites prior to 
providing them to the Sponsor.
5.1.1.3
Hematological Toxicity
In nonclinical studies, mild decreases in lymphocytes, eosinophils, and reticulocytes 
have been observed in cynomolgus monkeys.  In addition, minimal lymphoid depletion 
was noted in spleen and lymph nodes.  Thrombocytopenia has been reported in patients 
in clinical trials of trastuzumab emtansine and cases of severe bleeding events, some 
with a fatal outcome, have been observed (KadcylaU.S. Package Insert).  Declines in 
other hematopoietic lineages were less frequent with the use of trastuzumab emtansine 
than that observed for platelets.  Thrombocytopenia also occurred in 12% of patients 
treated with rovalpituzumab tesirine (including two Grade 4 and one fatal event; 
Rudin et al. 2017).
Hematologic laboratory parameters will be monitored as described in Section 4.5.6 and 
the schedule of activities (see Appendix 1).  Guidelines for management of DHES0815A 
in patients who develop hematologic toxicity are provided in Table 3.
5.1.1.4
Nephrotoxicity
No renal findings or changes in urinalysis were observed in GLP toxicology studies with 
DHES0815A in cynomolgus monkeys.  However, tubular degeneration had been seen in 
nonclinical studies at higher doses of DHES0815A than were tested in the GLP 
toxicology studies. 
Patients with a baseline serum creatinine level higher than 1.5ULN or creatinine 
clearance 65 mL/min will be excluded from this study.  To address potential renal 
toxicity, BUN and creatinine will be measured frequently and urinalysis will be done at 
each cycle.
5.1.1.5
Hepatic Toxicity
No pathological liver findings and no changes in liver function tests were observed in 
GLP toxicology studies in cynomolgus monkeys.  Hepatic toxicity (including liver failure 
and death) and nodular regenerative hyperplasia of the liver are identified risks for 
trastuzumab emtansine and elevated transaminases (Grades 24) were observed with 
both SJG-136 (Hochhauser et al. 2009) and rovalpituzumab tesirine (Rudin et al. 2017).
Patients must meet specified hepatic laboratory test requirements to be included in this 
study (see Section 4.1.2).  Hepatic laboratory parameters will be monitored as described 
in Section 3.1.1.1 and the schedule of activities (see Appendix 1).
5.1.1.6
Ocular Toxicity
In GLP toxicology studies in cynomolgus monkeys, corneal pigmentation was observed 
after administration of DHES0815A.  Ocular toxicity is therefore a potential risk for 
patients treated with DHES0815A and may present with impaired vision.  


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Ophthalmic examinations will include assessment of BCVA and an anterior segment 
slitlamp examination with fluorescein. Ophthalmic examinations must be conducted 
during the screening period, during the last week (Days 1521) of even-numbered 
cycles until Cycle 6 (i.e., at Cycles 2, 4, and 6) and every four cycles thereafter (i.e., at 
Cycles 10, 14, 18, etc.), and at the study discontinuation visit (unless the most recent 
ophthalmic examination has occurred within the past 4 weeks). Patients who experience 
ocular symptoms, including but not limited, to eye pain, dry eyes, blurred vision, or a 
decline in visual acuity, will be required to undergo an ophthalmic examination at an 
unscheduled visit as soon as practical.  Such visits should include the same 
assessments as those described above, along with any additional assessments deemed 
clinically indicated per standard of care.  
If no study drugrelated ophthalmic adverse events Grade 2 are reported during dose 
escalation, ophthalmic examinations may not be required for patients enrolled in the
expansion cohort.
5.1.1.7
Pulmonary Toxicity
In GLP toxicology studies in cynomolgus monkeys, an increase in alveolar macrophages 
was observed after the administration of DHES0815A.  Mild alveolar degeneration and 
fibroplasia was observed in nonclinical studies when cynomolgus monkeys received 
DHES0815A at dose levels higher than those given in the GLP toxicology studies.
Cases of interstitial lung disease, including pneumonitis, some leading to acute 
respiratory distress syndrome or death, have been reported in patients receiving 
HER2-targeting drugs (i.e., trastuzumab, pertuzumab, trastuzumab emtansine).  Signs 
and symptoms may include dyspnea, cough, fatigue, and pulmonary infiltrates.  Patients 
with dyspnea at rest due to complications of advanced malignancy and comorbidities 
may be at risk of pulmonary events. Therefore, patients with clinically significant 
pulmonary symptoms or disease will be excluded from this study (see Section 4.1.2). 
Patients who develop new respiratory symptoms or imaging findings suggestive of 
pulmonary toxicity should be evaluated by a pulmonologist.
5.1.1.8
Vascular Leak Syndrome
GLP studies in cynomolgus monkeys receiving DHES0815A did not reveal indications
for vascular leak, edema, or serosal effusion.  In clinical trials with SJG-136 
(Hochhauser et al. 2009) and rovalpituzumab tesirine (Rudin et al. 2017), vascular leak 
syndrome, serosal effusions, and edema were observed.
Patients treated with DHES0815A will be closely monitored for clinical signs and 
symptoms indicating vascular leak.  As part of scheduled tumor assessment, CT or MRI 
imaging of chest and abdomen will be performed that may also be assessed for 
evidence of internal effusions.


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5.1.1.9
Gastrointestinal Toxicity
Gastrointestinal toxicity (watery diarrhea, mucosal atrophy in small and large intestine 
and stomach) was observed in nonclinical studies when cynomolgus monkeys received 
DHES0815A at dose levels higher than those given in the GLP toxicity study. 
Patients will be closely monitored for clinical signs of gastrointestinal toxicity, and 
supportive treatment will be initiated at the investigator's discretion.
5.1.1.10
Infusion-Related Reactions, Hypersensitivity, Anaphylaxis
Some MAbs may be associated with the development of allergic or anaphylactic 
reactions to either the active protein or excipients.  True allergic/anaphylactic reactions 
are rare with the first dose of a product, because they require prior sensitization.  
Patients with true allergic/anaphylactic reactions should not receive further doses of the 
product. 
MAbs may also be associated with reactions that are clinically indistinguishable from 
true allergic/anaphylactic reactions but that are mediated through direct release of 
cytokines or other pro-inflammatory mediators.  Such reactions are often termed IRRs.  
IRRs typically occur with the first infusion of a MAb product and are generally less 
frequent and/or less severe with subsequent infusions.  They can often be managed by 
slowing the infusion rate and/or pretreatment with various medications.
Despite the different pathophysiology of IRRs (reactions involving cytokine release) and 
hypersensitivity (allergic) reactions, the clinical manifestations are the same and include 
flushing, chills, pyrexia, dyspnea, hypotension, wheezing, bronchospasm, and 
tachycardia.  Allergic/anaphylactic reactions and IRRs typically begin during or within 
several hours after completing the infusion.  The onset of symptoms may be rapid, and 
some reactions may be life threatening.
Patients with a history of allergic/anaphylactic reactions to MAbs, including trastuzumab, 
pertuzumab, or trastuzumab emtansine, will be excluded from this study (see 
Section 4.1.2).
Administration of DHES0815A will be performed in a setting with access to emergency 
facilities and staff who are trained to monitor and respond to medical emergencies.  
Patients should be closely monitored for IRRs during and after each infusion of 
DHES0815A, as described in Section 4.3.2.
Guidelines for management of patients who experience IRRs or hypersensitivity 
reactions are provided in Table 3. Please see Appendix 6 for guidance on anaphylaxis 
precautions.
5.1.1.11
Immunogenicity
As with any recombinant antibody, DHES0815A may elicit an immune response and 
patients may develop antibodies against DHES0815A.  ADA response and potential 


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correlation of response to relevant clinical safety endpoints will therefore be assessed for 
all treated patients. Validated screening and confirmatory assays with appropriate 
sensitivity and therapeutic tolerance will be employed to detect ADAs at multiple 
timepoints before, during, and after treatment with DHES0815A.  Serum samples will be 
collected from all patients prior to their first dose of DHES0815A and at several 
additional timepoints (see Appendix 2).
5.1.2
Management of Patients Who Experience Adverse Events
5.1.2.1
Dose and Schedule Modifications
The dose of DHES0815A can be reduced by one dose level up to two times for 
management of drug-related toxicities. If further dose reduction is indicated after 
two dose reductions, the patient must discontinue DHES0815A.  Dose increases after 
prior dose reduction for drug-related toxicities will not be permitted.
DHES0815A treatment may be temporarily suspended in patients who experience 
toxicity considered to be related to study drug.  Dose delays for 14 days because of 
toxicity have to be discussed with and approved by the Medical Monitor; otherwise, the 
patient should be discontinued from DHES0815A.  DHES0815A treatment may be 
suspended for reasons other than toxicity (e.g., surgical procedures) with 
Medical Monitor approval.  The investigator and the Medical Monitor will determine the 
acceptable length of treatment interruption.
5.1.2.2
Management Guidelines for Patients Who Experience Adverse 
Events
Guidelines for managing DHES0815A-related toxicities other than the ones specified in 
Table 3 are as follows:

For Grade 3 adverse events:  DHES0815A treatment should be withheld for 
Grade 3 DHES0815A-related toxicities that have not recovered to Grade 1 or 
baseline prior to planned dosing.  The next scheduled dose may be delayed by 
up to14 days.  Longer dose interruptions are only allowed upon discussion with the 
Medical Monitor.  If improvement to Grade 1 or baseline does not occur within 
14 days (or a longer interval approved by the Medical Monitor), DHES0815A 
treatment should be discontinued.  If the DHES0815A-related toxicity improves to 
Grade 1 or baseline, DHES0815A may be restarted at a reduced dose.  
The DHES0815A dose in subsequent cycles should be reduced to either the next 
lowest dose level tested in dose escalation for patients in the dose escalation cohort, 
or by approximately 25%50% (upon discussion with the Medical Monitor) for 
patients in the expansion cohort.  No more than two dose reductions are permitted 
on study.

For Grade 2 adverse events:  DHES0815A treatment should be withheld for 
Grade 2 DHES0815A-related toxicities that have not recovered to Grade 1 or 
baseline prior to planned dosing.  The next scheduled dose may be delayed by 
14 days.  Longer dose interruptions may be allowed upon discussion with the 
Medical Monitor.  If improvement to Grade 1 or baseline does not occur within 


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14 days (or a longer interval approved by the Medical Monitor), DHES0815A 
treatment should be discontinued.  If the DHES0815A-related toxicity improves to 
Grade 1 or baseline, DHES0815A may be restarted at the current dose.
5.1.2.3
Management Guidelines for Patients Who Experience Specific 
Adverse Events
Guidelines for management of specific adverse events (hematologic toxicity and 
IRRs/hypersensitivity) are outlined in Table 3. Additional guidelines are provided 
in Figure 2 (left ventricular dysfunction) and below for increases in QT interval and ocular 
toxicities. 
Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events
Event
Action to Be Taken
Hematologic toxicity as 
manifested in any one of 
the below laboratory
abnormalities:
Absolute 
neutrophils 1500/mm3
Hemoglobin8 g/dL
Platelets 100,000/mm3

Withhold all study treatment up to 14 days; longer dose 
interruption may be allowed upon discussion with the Medical 
Monitor.

Give supportive treatment as clinically indicated per local 
practice.

Resume DHES0815A treatment if ANC1500/mm3, 
platelets 100,000/mm3, and hemoglobin8 g/dL.

If hematologic toxicity leading to dose hold recurs in consecutive 
cycles, resume DHES0815A treatment at a reduced dose if 
ANC1500/mm3, platelets 100,000/mm3, and 
hemoglobin8 g/dL.

If hematologic toxicity leading to dose hold occurs in 
two consecutive cycles at the reduced dose, discontinue 
DHES0815A.


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Table 3
Guidelines for Management of Patients Who Experience Specific 
Adverse Events (cont.)
Event
Action to Be Taken
Infusion-related reaction or 
hypersensitivity
Grades 12
Reduce DHES0815A infusion rate or interrupt infusion.  Administer 
supportive care with oxygen, -agonists, antihistamines, 
antipyretics, or corticosteroids, as appropriate or according to local 
standard of care, at the investigator’s discretion.  
Monitor patient until complete resolution of symptoms.
Patient may continue DHES0815A infusion (in same cycle and 
subsequent cycles) at the same dose level but at a decreased 
infusion rate at the investigator’s discretion.  

Premedication for infusion reactions (e.g., antihistamines such 
as diphenhydramine, acetaminophen/paracetamol or 
corticosteroids) may be given at the investigator’s discretion for 
subsequent infusions.
In the event of a true hypersensitivity reaction (in which severity of 
reaction increases with subsequent infusions), discontinue 
DHES0815A permanently.
Infusion-related reaction or
hypersensitivity
Grade 3
Stop DHES0815A infusion.  
Administer supportive care with oxygen, -agonists, antihistamines, 
antipyretics, or corticosteroids, as appropriate, at the investigator’s 
discretion.  
Monitor patient until complete resolution of symptoms.  
Note: If Grade 3 symptoms included wheezing, hypoxia, 
generalized urticaria, angioedema or other signs and symptoms 
indicating anaphylactic reaction, discontinue DHES0815A
permanently. For other Grade 3 events, patients may continue 
DHES0815A (in same cycle and subsequent cycles) at the same 
dose level but reduced infusion rate at the investigator’s discretion.  

Premedication for infusion reactions (e.g., antihistamines such 
as diphenhydramine, acetaminophen/paracetamol or 
corticosteroids) should be given for subsequent infusions.
In the event of a true hypersensitivity reaction (in which severity of 
reaction increases with subsequent infusions), discontinue 
DHES0815A permanently.
Infusion-related reaction or 
hypersensitivity
Grade 4
Stop DHES0815A infusion.  
Administer supportive care with oxygen, -agonists, antihistamines, 
antipyretics, or corticosteroids, as appropriate, at the investigator’s 
discretion.
Monitor patient until complete resolution of symptoms.
Discontinue DHES0815A.


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Figure 2
Left Ventricular Dysfunction Management Guidelines
EFejection fraction; LVEF left ventricular ejection fraction.
a Patient may continue study treatment after up to a maximum of two study drug holds for 
reduction in LVEF. DHES0815A should be permanently discontinued if a third dose hold 
would be required per algorithm above. 
Management of Increases in QT Interval
Study drug should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes:

Sustained (at least two ECG measurements 30 minutes apart) QTcF that is 
500 ms and 60 ms longer than the baseline value

Sustained absolute QTcF that is 515 ms

An episode of torsades de pointes or a new ECG finding of clinical concern
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, because this represents an 
increase in QTcF unrelated to alterations in repolarization.  Also of note, it is not 
uncommon to record arrhythmias such as non-sustained ventricular tachycardia, 
supraventricular tachycardia, pauses, or atrial fibrillation in healthy volunteers receiving 
placebo during periods of extended ECG monitoring.  Therefore, it is critical that expert 
cardiology advice be sought to confirm any ECG changes and to ascertain the likelihood 


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of a drug-induced arrhythmia versus the background occurrence of this arrhythmia.  
In such a situation, saving all available ECG data is highly suggested.
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the 
QT interval.  Consultation with a cardiologist or electrophysiologist is recommended to 
help in the management of such patients.
In rare circumstances, it may be acceptable to resume study drug at a lower dose, 
provided that any ECG abnormalities have resolved and the patient is appropriately 
monitored.  Clinical judgment should be applied.
Management of Ocular Toxicities
At the first occurrence of asymptomatic ocular findings on ophthalmologic examination 
that are considered related to DHES0815A, the patient may be re-treated with 
DHES0815A as per study schedule (i.e., dose hold or dose reduction not required) but 
needs to undergo ophthalmic examinations before each additional dose to reassess the 
ocular finding.  

If the ocular finding does not worsen and does remain asymptomatic in 
four consecutive cycles, the patient may continue dosing and resume the standard 
ophthalmic examination schedule (even-numbered cycles until Cycle 6, and every 
four cycles thereafter as described in Section 4.5.9).  

If the ocular finding worsens or if the patient develops ocular symptoms, study drug 
must be held until resolution or clear improvement.  Re-treatment may be initiated 
upon discussion with the Medical Monitor.
At the first occurrence of symptomatic ocular findings considered related to study drug, 
DHES0815A must be held until resolution of visual symptoms and resolution or clear 
improvement of the ocular finding on ophthalmologic exam.  The patient should undergo 
ophthalmic examinations at least every 3 weeks, or more often as clinically indicated for 
reassessment.  

Once visual symptoms resolve and ocular findings resolve or improve, re-treatment 
may be initiated upon discussion with the Medical Monitor.
In the case of first re-occurrence of asymptomatic or symptomatic ocular findings
considered related to study drug, DHES0815A must be held until resolution of visual 
symptoms and resolution or clear improvement of the ocular finding.  The patient should 
undergo ophthalmic examinations at least every 3 weeks, or more often as clinically 
indicated for reassessment.  


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Once visual symptoms resolve and ocular finding resolve or improve, re-treatment may 
be initiated upon discussion with the Medical Monitor at a reduced dose of DHES0815A.
If asymptomatic or symptomatic ocular findings re-occur for a second time, DHES0815A 
must be permanently discontinued.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10 for worsening of BC

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)


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This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

All DLTs

Cases of potential drug-induced liver injury that include any increase in hepatic 
transaminase (ALT or AST) 3baseline in combination with either an increase in 
direct bilirubin 2ULN or clinical jaundice, in the absence of cholestasis or other 
contributory factors (consistent with Hy’s Law; Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.


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5.2.4
Dose-Limiting Toxicities (Immediately Reportable to the 
Sponsor)
During the DLT assessment window, adverse events identified as DLTs, as defined in 
Section 3.1.1.1, are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 or 
reporting instructions).
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 42 days after the 
last dose of study drug or until the patient is lost to follow-up, withdraws consent, initiates 
another anti-cancer therapy, or until study discontinuation/termination, whichever occurs 
first.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"


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5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 4
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v 4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also
Table 5):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study


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
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 5
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during study drug administration or within 24 hours after 
study drug administration and are judged to be related to study drug infusion should be 
captured as a diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF.  
If possible, avoid ambiguous terms such as "systemic reaction."  Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.  If a 
patient experiences both a local and systemic reaction to the same dose of study drug, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs 
and symptoms also recorded separately on the dedicated Infusion-Related Reaction
eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than IRRs, a diagnosis (if known) should be recorded on the 
Adverse Event eCRF rather than individual signs and symptoms (e.g., record only liver 


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failure or hepatitis rather than jaundice, asterixis, and elevated transaminases).  
However, if a constellation of signs and/or symptoms cannot be medically characterized 
as a single diagnosis or syndrome at the time of reporting, each individual event should 
be recorded on the Adverse Event eCRF.  If a diagnosis is subsequently established, 
all previously reported adverse events based on signs and symptoms should be nullified 
and replaced by one adverse event report based on the single diagnosis, with a starting 
date that corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
Another exception is symptomatic ocular events.  In such cases, the symptoms reported 
by the patient and any abnormal findings observed on ophthalmologic examination 
should be recorded separately on the Adverse Event eCRF.  
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 


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to "serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia" and a decreased 
neutrophil count of 500/mm3 should be recorded as "neutropenia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms


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
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total 
bilirubin 2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Sections 5.2.2 and 5.2.3).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
This includes death attributed to progression of BC.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 


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reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of breast cancer, "breast cancer progression" 
should be recorded on the Adverse Event eCRF and the details (e.g., clinical course, 
clinical findings, cause of death as per the death certificate) should be recorded in the 
Serious Adverse Event detail field.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Breast Cancer
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease (e.g., new lesion, increase in target- or non-target-lesions) should not
be recorded as adverse events.  These data will be captured as efficacy assessment 
data only.  In most cases, the expected pattern of progression will be based on RECIST 
v1.1.  In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration.  However, every effort should be made to document 
progression through use of objective criteria.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care


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
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer (e.g. tumor pain or 
failure to thrive that require in-patient care)
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).
No safety data related to overdosing of DHES0815A are available.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

DLTs during the DLT assessment window (defined in Section 5.2.4; see 
Section 5.4.2 for details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)


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The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Genentech Medical Monitor contact information:
Medical Monitor:
, M.D.
Telephone No.:
(mobile)
Alternate Telephone No.:
5.4.2
Reporting Requirements for Serious Adverse Events, Adverse 
Events of Special Interest and Dose-Limiting Toxicities
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event) by faxing the form using the fax number provided to investigators.
Serious adverse events should be reported by fax to PPD.
North America
Telephone No.: 1 800 201 8725
Fax No.: 1 888 488 9697 
EMEA and Asia Pacific 
Telephone No.: 44 1223 374 240
Fax No.: 44 1223 374 102
Once the electronic data capture (EDC) system is available, all information will need to 
be entered and submitted via the EDC system.


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5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 42 days after the last dose of study drug or until the patient 
is lost to follow-up, withdraws consent, initiates another anti-cancer therapy, or study 
discontinuation/termination, whichever occurs first.  DLTs will be reported during the DLT 
assessment window. Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the EDC system.  A report will be generated and sent to Safety 
Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event) by faxing the form using the fax number 
provided to investigators in Section 5.4.2.1. Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system.  
Instructions for reporting serious adverse events that occur after the adverse event 
reporting period are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 8.5 months after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy) by faxing the form using the fax number provided to 
investigators in Section 5.4.2.1.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
5.5 months after the last dose of study drug.  A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy) by faxing the form using the 
fax number provided to investigators in Section 5.4.2.1.  Attempts should be made to 


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collect and report details of the course and outcome of any pregnancy in the partner of a 
male patient exposed to study drug.  When permitted by the site, the pregnant partner 
would need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  If the authorization has been signed, 
the investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  An 
investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Congenital Anomalies/Birth Defects and Abortions
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see
Section 5.4.2).  Any abortion should be reported in the same fashion (as the Sponsor 
considers abortions to be medically significant).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events that are considered to be related to study drug or trial-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 


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42 days after the last dose of study drug or until the patient is lost to follow-up, withdraws 
consent, initiates another anti-cancer therapy, or study discontinuation/termination, 
whichever occurs first) if the event is believed to be related to prior study drug treatment.  
These events should be reported through use of the Adverse Event eCRF.  However, if 
the EDC system is not available, the investigator should report these events directly to 
the Sponsor or its designee, by faxing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number provided 
to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the DHES0815A Investigator's Brochure
as a reference document.
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The objective of the dose escalation is to determine the MTD/MAD and RP2D of 
DHES0815A.
If the safety and PK profile seen in the dose-escalation portion of the study is deemed to 
be favorable to justify further continuation of the study, expansion cohorts will be 
enrolled to further confirm safety and tolerability and to assess preliminary evidence of 
anti-tumor activity and exploratory pharmacodynamic markers of response.
The final analysis will be based on patient data collected through patient discontinuation 
or study discontinuation, whichever occurs first. All analyses will be based on the 
safety-evaluable population. All summaries will be presented according to the assigned 
dose level and cohort. In general, data will be summarized as warranted, and listings 
will be used in place of tables when the samples sizes are small. Continuous variables 
will be summarized using means, standard deviations, median, and ranges; categorical 
variables will be summarized using counts and percentages.


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6.1
DETERMINATION OF SAMPLE SIZE
6.1.1
Dose Escalation
Approximately 2430 patients will be enrolled in the dose-escalation stage. The exact 
number of patients to be enrolled in the study will depend upon the observed safety and 
pharmacokinetic/pharmacodynamic profile according to the dose-escalation rules 
(Section 3.1.1.2).
The operating characteristics of the dose-escalation stage of this study are shown in
Table 6, which provides the probability of escalation to the next higher dose for each 
underlying true DLT rate. For example, for a toxicity that occurs in 5% of patients, there 
is a 95% probability of escalating. Conversely, for a common toxicity that occurs with a 
rate of 70%, the probability of escalating is 5%.
Table 6
Probability of Escalation to the Next Dose
True underlying 
DLT rate
5%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of 
escalating the 
dose
97%
91%
71%
49%
31%
17%
8%
3%
1%
0.10%
DLT dose-limiting toxicity.
Table 7 shows the probability of failing to observe toxicity in a sample size of 3 patients 
given various true underlying toxicity rates.  For example, with 3 patients, the probability 
of failing to observe toxicity occurring at least 60% of the time is less than 7%.
Table 7
Probability of Failing to Observe Toxicity
True underlying 
DLT rate
5%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of
failing to 
observe toxicity
(n3)
86%
73%
51%
34%
22%
13%
6.40% 2.70% 0.80% 0.01%
DLT dose-limiting toxicity.
6.1.2
Dose Expansion
At the RP2D, up to approximately 25 patients will be enrolled to further assess the safety, 
tolerability, and preliminary evidence of anti-tumor activity of DHES0815A.
This study is intended to obtain preliminary safety, PK, pharmacodynamic, and activity 
information in the safety-evaluable population. The sample sizes do not reflect any 
explicit power and type I error considerations.


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Efficacy analyses will be performed on an ongoing basis in close collaboration with the 
study investigators for the expansion portion of the study to guide potential early 
stopping of enrollment in the event of lack of efficacy.  Decisions to stop enrollment 
into the expansion cohort for futility will be made based on the totality of the available 
data, taking into account both safety and efficacy. Anti-tumor activity will be 
summarized by cohorts with an 80% CI.  For example, in a cohort with 25 patients, if 
10 of 25 patients have CR or PR, the objective response rate and its 80% CI will be 
summarized as 40% (27%55%).
Continuous safety monitoring and interim analyses will be performed for the expansion 
portion of the study to guide potential early stopping of enrollment in the event of 
unacceptable toxicity.  The first safety interim analysis will occur after approximately 
6 patients complete 2 cycles in the expansion cohort or every 6 months, whichever 
occurs first.
A Bayesian posterior probability approach (Thall and Simon 1994) will be used to 
evaluate the toxicity in the expansion cohorts, including the rate of DLT-equivalent 
events that occur during Cycle 1 of study treatments.  Events that are DLT-equivalent 
in the expansion cohort are defined by the same criteria used to identify DLT events in 
the dose-escalation cohorts (Section 3.1.1.1). During continuous safety monitoring or 
in an interim analysis, if the number of observed DLT-equivalent events indicates that 
there is an approximately 80% chance that the true DLT rate is 25%, accrual to the 
cohort may be paused.  The Medical Monitor and Safety Scientist will determine 
whether further enrollment in the cohort should be halted and may provide other 
recommendations as described in Section 3.1.1.  The final decision will be based on the 
totality of the observed DLT-equivalent events, other safety events, as well as feedback 
from study investigators, Biostatistics, and Clinical Pharmacology. Table 8 provides 
examples that cover scenarios with different true DLT-equivalent event rate 
assumptions.  The examples show the number of observed DLT-equivalent events that 
might lead the Sponsor to stop enrollment and the corresponding operating 
characteristics using the posterior probability approach with a non-informative prior 
beta (1,1) and the stopping criteria stated above.


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Table 8
Examples of Early Stopping Rules Based on DLT-Equivalent 
Event Rate in an Expansion Cohort
Number 
of 
patients
Number of events 
to recommend
stopping 
enrollment
Probability of early stopping for DLT
If true DLT 
rate 40%
If true DLT 
rate 30%
If true DLT 
rate 20%
6
3
46%
26%
10%
12
5
56%
28%
7%
18
6
79%
47%
13%
DLT dose-limiting toxicity (equivalent events).
Note:  Recommend stopping enrollment if there is an approximately 80% chance that the true 
DLT rate is 25%.
6.2
SUMMARIES OF CONDUCT OF STUDY
Summaries of study conduct will include all enrolled patients in the study.  The number 
of patients who enroll, discontinue, or complete the study will be summarized. Reasons 
for discontinuations and premature study withdrawal will be listed and summarized. 
Enrollment and major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results. 
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including, but not limited, to age, 
race/ethnicity, weight, type of malignancy, duration of malignancy, site of metastatic 
disease, baseline ECOG Performance Status, number of prior cancer regimens) will be 
summarized using means, standard deviations, medians, and ranges for continuous 
variables and proportions for categorical variables, as appropriate. Summaries will be 
presented overall and by dose level. 
6.4
SAFETY ANALYSES
For safety analyses, the analysis population will include all enrolled patients who receive 
at least one dose of study medication.
Study treatment discontinuation and reasons for patient discontinuations from the study 
will be described and summarized. Study drug administration data will be listed and any 
dose modifications will be flagged.
6.4.1
Adverse Events
All adverse events occurring on or after treatment on Day 1 will be summarized by 
mapped term, appropriate thesaurus levels, and NCI CTCAE v4.0 toxicity grade.


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All adverse events reported during the adverse event reporting period will be considered
as treatment-emergent adverse events. Incidence rates will be summarized with 
frequency and percentage by mapped term, with all patients treated as the denominator, 
unless otherwise specified. In addition, adverse event incidence rates will also be 
summarized by severity and relationship to study drug. Treatment-related adverse 
events are those judged by the Investigator to be at least possibly related to the study 
drug. 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, and DHES0815A exposure. All patients who receive study treatment on 
Cycle 1, Day 1 will be included in the analyses.
Adverse event data will be listed by patient number and study day. Serious adverse 
events, including deaths, will be listed separately and will be summarized.
Relevant laboratory and vital sign (pulse rate, blood pressure, and temperature) data will 
be displayed by time, with NCI CTCAE v4.0 Grades 3 and 4 values identified, where 
appropriate. Additionally, all laboratory data will be summarized by NCI CTCAE v4.0.
Safety data will be accumulated up to the end of the patient’s treatment period.
6.4.2
Clinical Laboratory Results
Normal ranges will be used to identify values that are outside the normal ranges, and 
abnormal laboratory results will be graded according to the NCI CTCAE v4.0.
A shift summary of baseline grade by maximum postbaseline NCI CTCAE grade will be 
presented, as appropriate. For each laboratory parameter, the baseline laboratory value 
will be defined as the last laboratory value collected on or prior to the date of the 
first dose of study drug.
Patients who develop toxicities of Grade 3 will be summarized. Laboratory test results 
not having NCI CTCAE grade will also be summarized. Parameters that have criteria 
available for both low and high values (e.g., hypocalcaemia vs. hypocalcemia) will be 
summarized for both criteria. Patients will only be counted once for each criterion.
6.5
PHARMACOKINETIC ANALYSES
The pharmacokinetics of DHES0815A will be characterized by measuring DHES0815A 
total antibody (all DARs including fully conjugated, partially deconjugated, and fully 
deconjugated anti-HER2 antibody) by ELISA, acPBD-MA by immunoaffinity LC-MS/MS, 
and unconjugated PBD-MA by LC-MS/MS. Two additional exploratory plasma 
PK samples (see Appendix 2) will be collected for catabolite and 
stability/biotransformation analyses. A baseline serum sample (Cycle 1, Day 1 only) 
may be used, depending upon review of DHES0815A PK/ADA data, to measure HER2 
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understand potential drug interferences or impact on pharmacokinetics.  Individual and 
mean concentration of DHES0815A versus time data will be tabulated and plotted by 
dose level. The following PK parameters will be derived when appropriate as data allow:

Total exposure (area under the concentrationtime curve)

Maximum observed serum concentration 

Minimum observed serum concentration 

Clearance

Volume of distribution at steady state 
Compartmental, non-compartmental, and/or population methods may be considered. 
Estimates for these parameters will be tabulated and summarized (mean, 
standard deviation, coefficient of variation, median, minimum, and maximum). Other 
parameters, such as accumulation ratio, terminal half-life, and dose proportionality, may 
also be calculated.
Additional PK analyses will be conducted as appropriate.
6.6
ACTIVITY ANALYSES
Objective response will be summarized by dose level and cohort. Objective response is 
defined as a CR or PR, as determined by investigator assessment according to 
RECIST v1.1 and confirmed by repeat assessment 4 weeks after initial documentation. 
Patients with missing baseline or no response assessments will be classified as
non-responders.
Among patients with an objective overall response, duration of response (DOR) will be 
defined as the time from the initial CR or PR to the time of disease progression or death, 
whichever occurs first. If a patient has not experienced disease progression or death, 
DOR will be censored at the day of the last tumor assessment showing no disease 
progression.
6.7
IMMUNOGENICITY ANALYSES
Patients are considered to have treatment-induced ADA responses if they are ADA 
negative at baseline and develop an ADA response following DHES0815A 
administration. Patients are considered to have treatment-enhanced ADA if they are 
ADA positive at baseline and the titer of one or more postbaseline samples is at least
4-fold greater than baseline titer (i.e., 0.60 titer units) following study drug 
administration. ADA incidence will be determined from the patients with treatment-
induced and treatment-enhanced ADA. 
Patients are considered to be negative for ADAs if they are ADA negative at all 
timepoints.  Patients are considered to be treatment unaffected if they are ADA positive 
at baseline but do not have any postbaseline samples with a titer that is at least 4-fold 


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greater than the titer of the baseline sample.  ADA prevalence will be determined from 
all patients with ADA-positive responses at baseline.
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned.
The relationship between ADA status and safety, efficacy, PK, activity, and biomarker 
endpoints will be analyzed and reported via descriptive statistics, as data allow.
6.8
BIOMARKER ANALYSES
Potential exploratory biomarkers and changes will be listed by dose, schedule, and 
response status.  Additional biomarker analyses with PK, efficacy, and safety data may 
be conducted as appropriate. 
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.


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7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution 
of IMP, including eCRFs, data (if applicable), Informed Consent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for at least 15 years after completion or discontinuation of the study or for the length of 


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time required by relevant national or local health authorities, whichever is longer.  After 
that period of time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a 
U.S. Investigational New Drug (IND) Application will comply with U.S. Food and Drug 
Administration regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union or European Economic Area will comply with the 
E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.


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The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 


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8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.


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9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by Genentech, Inc.  The Sponsor will provide 
clinical operations management, data management, and medical monitoring.  A contract 
research organization will be responsible for the overall study management.
Approximately 55 patients will be enrolled in this study at global sites.  Enrollment will 
occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in
Section 4.5.6.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 


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an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Rubin I, Yarden Y. The basic biology of HER2. Ann Oncol 2001;12(Suppl 1):S38.
Rudin CM, Pietanza MC, Bauer TM, et al. Rovalpituzumab tesirine, a DLL3-targeted 
antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, 
first-in-class, open-label, phase 1 study. Lancet Oncol 2017;18:4251.
Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and 
survival with amplification of the HER-2/neu oncogene. Science 1987;235:17782.
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal 
antibody against HER2 for metastatic breast cancer that overexpresses HER2. 
N Engl J Med 2001;344:78392.
Swain SM, Baselga J, Kim S-B, et al. Pertuzumab, trastuzumab, and docetaxel in 
HER2-positive metastatic breast cancer. N Engl J Med 2015;372:72434.
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Toikkanen S, Helin H, Isola J, et al. Prognostic significance of HER-2 oncoprotein 
expression in breast cancer: a 30-year follow-up. J Clin Oncol 1992;10:10448.
Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced 
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Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal 
growth factor receptor 2 testing in breast cancer: American Society of Clinical 
Oncology/College of American Pathologists clinical practice guideline update. 
J Clin Oncol 2013;31:39974013.
Yan M, Schwaederle M, Arguello D, et al. HER2 expression status in diverse cancers: 
review of results from 37,992 patients. Cancer Metastasis Rev 2015;34:15764.
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disulfide-linked pyrrolobenzodiazepineaAntibody-drug conjugates. ACS Med Chem 
Lett 2016;7:988993.


DHES0815A—Genentech, Inc.
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Appendix 1 Schedule of Activities
Assessment
Day:
Screening
Cycles 14 a
Cycles 58 a
Cycles 8 a
Study 
Discontinuation 
Visit c
Safety 
Follow-Up d
28 to 1
1 b
(1)
8
(1)
15
(1)
1 b
(1)
8
(1)
15
(1)
1 b
(1)
15
(1)
Informed consent
x
Confirm eligibility criteria
x
Medical history and demographics e
x
Complete physical examination f
x
Limited physical examination g
x
x
x
x
x
x
x
Height (at screening only) and weight
x
x
x
x
x
Vital signs h
x
x
x
x
x
x
x
x
ECOG Performance Status
x
x
x
x
x
x
x
x
Adverse events i
x j
x
x
x j
x
x j
x
x
Concomitant medications
x
x
x
x
x
x
x
x
12-Lead ECG k
x
x
x
Ophthalmic examination l
x
x l
x l
x l
x
Tumor assessmentCT/MRI m
x
x
x
x
x
PK sampling n
x
x
x
x
Serum ADA n
x
x
Hematology o
x
x
x
x
x
x
x
x
Serum chemistry p
x
x
x
x
x
x
x
x
ECHO/MUGA scan q
x
x q
x q
x q
x
Coagulation (aPTT, PT, and INR)
x
As clinically indicated


Appendix 1
Schedule of Activities (cont.)
DHES0815A—Genentech, Inc.
97/Protocol GO39869, Version 2
Day:
Assessment
Screening
Cycles 14 a
Cycles 58 a
Cycles 8 a
Study 
Discontinuation 
Visit c
Safety 
Follow-Up d
28 to 1
1 b
(1)
8
(1)
15
(1)
1 b
(1)
8
(1)
15
(1)
1 b
(1)
15
(1)
Serum/urine pregnancy test r
x
x
x
x
x
Urinalysis s
x
x
x
x
x
Tumor tissue t
x
Optional on-progression tumor tissue u
x
Blood for biomarkers testing v
x
x
x
DHES0815A infusion x
x
x
x
ADAanti-drug antibody; BCVAbest corrected visual acuity; CT computed tomography; DLT dose-limiting toxicity; ECEthics Committee; 
ECOGEastern Cooperative Oncology Group; ECHO echocardiogram; hCGhuman chorionic gonadotropin; IRBInstitutional Review Board; 
LVEFleft ventricular ejection fraction; MUGAmultiple-gated acquisition; MRImagnetic resonance imaging; PKpharmacokinetic; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1;
Notes:  Written informed consent for participation in the study must be obtained before performing any study-specific screening tests or evaluations.  
Screening tests and evaluations will be performed within 28 days prior to the first dose of any study drug, unless otherwise specified.  Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to study entry may be used; such 
tests do not need to be repeated for screening.  Assessments scheduled on a day of study drug administration should be performed prior to study 
drug dosing, unless otherwise specified.
a For patients in the dose-escalation cohort, the following assessments will take place weekly during the first four cycles of DHES0815A 
administration:  limited physical examination, vital signs, ECOG Performance Status, hematology labs, and serum chemistry labs.  Patients in the 
dose-expansion cohort will undergo those same assessments on a weekly basis for only the first two cycles of DHES0815A administration; 
starting with Cycle 3, these patients will be evaluated according to the schedule of assessments outlined for Cycles 58 until they reach Cycle 8.
b Laboratory assessments may be performed up to 72 hours preceding DHES0815A administration unless otherwise specified.  Results from 
predose assessments must be reviewed and the review documented prior to DHES0815A administration.
c Perform within 42 days after the last infusion of DHES0815A or before starting a new treatment regimen, whichever is earlier.  The visit at which 
response assessment shows progressive disease may be used as the study treatment discontinuation visit.


Appendix 1
Schedule of Activities (cont.)
DHES0815A—Genentech, Inc.
98/Protocol GO39869, Version 2
d Patients who have not withdrawn consent or been lost to follow-up will be contacted 42 days after the last dose of study drug for information on 
adverse events and initiation of any subsequent anti-cancer therapies.
e Medical history includes all clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), 
reproductive status, smoking history, and all medications used by the patient within 7 days preceding the screening visit (including prescription
drugs, over-the-counter drugs, and herbal/homeopathic remedies and therapies). Demographic data includes age, sex, and self-reported 
race/ethnicity.
f
Complete physical examination should include evaluation of head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.
g Limited physical examination should include systems of primary relevance (i.e., cardiovascular, respiratory, and any system that might be 
associated with tumor assessment) and systems associated with symptoms.  Patients should be evaluated weekly by limited physical 
examination through Cycle 4, on Day 1 and Day 8 Cycles 58, and at least on Day 1 of each Cycle beyond Cycle 8.
h Vital signs include measurement of respiratory rate, heart rate, systolic and diastolic blood pressure while the patient is in a seated position, 
pulse oximetry, and temperature.  On Day 1 of Cycle 1 and on Day 1 of Cycle 2, and on the day of infusion where a 2-hour post-infusion 
observation period is warranted (Section 4.3.2), vital signs will be assessed prior to infusion, every 15 (5) minutes during infusion, at the end of 
infusion (5 minutes), and every 30 (10) minutes after the infusion for 2 hours.  For all other days of infusion where a 30-minute post-infusion 
observation period is allowed, vital signs will be assessed prior to infusion, every 15 (5) minutes during infusion, at the end of infusion 
(5 minutes), and at 30 (10) minutes after infusion.  Oxygen saturation via pulse oximetry will be monitored at a minimum
every 15 (5) minutes during infusion from pre-treatment to the end of the observation period.
i
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 42 days after the last dose of study drug or 
until the patient is lost to follow-up, withdraws consent, initiates another anti-cancer therapy, or study discontinuation/termination, whichever 
occurs first. After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to 
be related to prior study drug treatment (see Section 5.6). The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  
Every effort should be made to follow all serious adverse events considered to be related to study drug or trial-related procedures until a final 
outcome can be reported.
j
Patients will be monitored for any untoward effects for 2 hours following completion of the first DHES0815A infusion on Day 1 of Cycle 1 and 
Day 1 of Cycle 2.  If infusion-related events occur, manage as per Table 3 in Section 5.1.2.3.  Patients who experience infusion-related adverse 
events following any given infusion should be observed for 2 hours following the subsequent infusion.  In the absence of infusion-related adverse 
events after Cycle 2, subsequent infusions of DHES0815A may be followed by a 30-minute observation period (see Section 4.3.2). 


Appendix 1
Schedule of Activities (cont.)
DHES0815A—Genentech, Inc.
99/Protocol GO39869, Version 2
k Except at screening, digitized, triplicate, 12-lead ECGs will be obtained at the following timepoints: on Cycle 1, Day 1 at 30 (15) minutes before
infusion and 30 (15) minutes after infusion; on Cycle 2, Day 1 at 30 (15) minutes before infusion and 30 (15) minutes after infusion; on 
Cycle 4, Day 1 at 30 (15) minutes before infusion and 30 (15) minutes after infusion; at end of treatment.  Obtain post-screening ECGs as 
close as possible to scheduled serum and plasma PK samples (see Appendix 2).  For screening, to determine eligibility, two ECGs collected
30 minutes apart (Section 4.1.2) are required to assess QT interval through use of Fridericia’s formula (QTcF).
l
Ophthalmic examinations should include assessment of BCVA and an anterior segment slit lamp examination with fluorescein. Ophthalmic 
examinations must be conducted during the screening period, during the last week (Days 1521) of even-numbered cycles until Cycle 6 (i.e., at 
Cycles 2, 4, and 6) and every four cycles thereafter (i.e., at Cycles 10, 14, 18, etc.), and at the study discontinuation visit (unless the most recent 
ophthalmic examination has occurred within the past 4 weeks).  Sites will provide the sponsor with ophthalmic examination clinic notes. Patients 
who experience ocular symptoms, including but not limited to eye pain, dry eyes, blurred vision, or a decline in visual acuity, will be required to 
undergo an ophthalmic examination at an unscheduled visit as soon as practical.  Such visits should include the same assessments as those 
described above, along with any additional assessments deemed clinically indicated per standard of care. If no study drugrelated ophthalmic 
adverse events Grade 2 are reported during dose escalation, ophthalmic examinations may not be required for patients enrolled into the 
expansion cohort. 
m Tumor assessments should be performed at screening, during the last week (Days 1521) of every even-numbered cycle until Cycle 8 (i.e., at 
Cycles 2, 4, 6, and 8) and every three cycles thereafter (i.e., at Cycles 11, 14, 17, etc.) until treatment discontinuation, and at study 
discontinuation visit (unless last prior tumor assessment was performed 4 weeks).  Response should be assessed on the basis of physical 
examinations and image-based evaluations, using RECIST v1.1. CT scans should include the chest, abdomen, and pelvis; CT scans of 
the neck should be included if clinically indicated.  MRI may be used instead of CT scans in patients for whom CT scans are contraindicated or in 
circumstances in which MRI is the preferred imaging modality.  The same method of assessment and the same technique should be used at 
baseline and for all on-study assessments. 
n Please see Appendix 2 for a complete list of PK and ADA blood draws.
o Hematology consists of complete blood count, including hemoglobin, hematocrit, platelet count, RBC count, WBC count, and absolute differential 
count for neutrophils and lymphocytes; percentage or absolute count is acceptable for all other cell types (e.g., eosinophils, monocytes, 
basophils, bands, and other cells).
p Serum chemistry includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, calcium, phosphorus, magnesium, total 
and direct bilirubin, total protein, albumin, LDH, ALT, AST, and ALP.  
q ECHO or MUGA scans to monitor LVEF should be conducted during screening, at the end of the DLT window (i.e., end of Cycle 1), during the 
last week (Days 1521) of even-numbered cycles until Cycle 6 (i.e., at Cycles 2, 4, and 6), every four cycles thereafter (i.e., at Cycles 10, 14, 18, 
etc.), and at the study discontinuation visit (unless no study drug has been given since the last ECHO or MUGA scan).  Other assessments 
should be conducted if clinically indicated.


Appendix 1
Schedule of Activities (cont.)
DHES0815A—Genentech, Inc.
100/Protocol GO39869, Version 2
r
For women of childbearing potential, a serum pregnancy test must be performed within 7 days prior to Day 1. Urine pregnancy tests will be 
performed on the first day of every cycle during the study. If a urine pregnancy test result is positive, patient dosing will be postponed until the 
result is confirmed by a serum pregnancy test.  Patients who become pregnant while on study must permanently discontinue study treatment as 
outlined in Section 4.6.1. Patients of childbearing potential whose tumors produce hCG and were confirmed not be pregnant prior to enrollment 
should be monitored with serum pregnancy tests rather than urine pregnancy tests prior to each cycle of study treatment. 
s Urinalysis includes macroscopic analysis (specific gravity, protein, pH, glucose, ketones, blood, bilirubin, leukocyte esterase, urobilinogen, and 
nitrite) and, if any abnormalities, microscopic analysis (RBCs, WBCs, epithelial cells, casts, crystals, bacteria, and yeast).  A urine pregnancy test 
will be performed on the first day of every cycle in women of childbearing potential (see Section 4.5.6.1).
t
Patients will provide two types of tissue: 1) archival tumor samples collected at the time of initial diagnosis that were used to determine HER2 
status and 2) metastatic tumor tissue obtained between the time of the last dose of the most recent prior anti-cancer therapy and enrollment into 
this study. Archival specimen must be a representative formalin-fixed, paraffin-embedded tumor specimen, accompanied by an associated 
pathology report, with adequate viable tumor tissue.  The tumor specimen may consist of a tissue block (preferred) or at least 
, 
 slides. Cytologic or fine-needle aspiration samples are not acceptable.
u For patients who have signed the optional Informed Consent Form, on-progression tumor tissue biopsies may be collected during the study or at 
the study discontinuation visit.
v Blood samples for biomarker testing will be collected at screening, prior to DHES0815A administration on Cycle 1, Day1, and at the 
end-of-treatment visit.
 
x The infusion on Cycle 1, Day 1 will be administered over at least 90 (10) minutes. In the absence of infusion-related adverse events,
subsequent infusions of DHES0815A may be administered over 30 (10) minutes. The DHES0815A infusion may be slowed or interrupted for 
patients experiencing infusion-related adverse events (Section 5.3.5.1).


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101/Protocol GO39869, Version 2
Appendix 2 Schedule of Pharmacokinetic and Immunogenicity
Samples
Study Visit
Timepoint
DHES0815A
PK a,b,c
Anti-DHES0815A 
Antibody (ADA) d
Cycle 1, Day 1
Pre-infusion
x e
x
30 minutes (15 minutes) 
post-EOI
x
4 hours (15 minutes) post-EOI
x
Cycle 1, Day 2
24 hours (2 hours) post-EOI
x
Cycle 1, Day 3
48 hours (2 hours) post-EOI
x
Cycle 1, Day 8
7 days (1 day) post-EOI
x
Cycle 1, Day11
10 days (1 day) post-EOI
x
Cycle 1, Day 15
14 days (1 day) post-EOI
x
Cycle 1, Day 17
16 days (1 day) post-EOI
x
Cycles 24, Day 1
Pre-infusion
x
x
30 minutes (15 minutes) 
post-EOI
x
Cycles 24, Day 8
7 days (1 day) post-EOI
x
Cycles 24, Day 15
14 days (1 day) post-EOI
x
Study treatment 
discontinuation visit
Within 42 days after last 
infusion
x
x
acPBD-MAantibody-conjugated PBD-MA; ADAanti-drug antibody; ECDextracellular domain; 
EOIend of infusion; NAnot applicable; PBD-MApyrrolo[2,1-c][1,4]benzodiazepine-monoamide;
PKpharmacokinetic; QTcFQT interval corrected through use of Fridericia's formula.
Note:  Samples will be submitted to a central laboratory.  Pre-infusion laboratory samples should be 
drawn within 4 hours before the start of infusion.
a For PK sample collection instructions, please refer to the laboratory manual. In the event that a 
serious adverse event or a dose-limiting toxicity occurs at a time when a PK sample is not 
scheduled, every effort should be made to collect a PK sample as an unscheduled event.
b Clinical plans include measurement of the following analytes for PK assessment of DHES0815A:  
DHES0815A total antibody (serum, SER-PK), acPBD-MA (plasma, PL-PK1), and unconjugated 
PBD-MA (plasma, PL-PK2).  Two additional exploratory PK samples (plasma, PL-PK-EXP1, PL-
PK-EXP2) will be collected for catabolite and stability/biotransformation analyses.
c If an increase in QTcF is observed in an ECG measurement as described in Section 4.5.7 and a 
PK sample is not scheduled at that timepoint, then an unscheduled DHES0815A PK sample should 
be obtained.
d Serum samples for assessment of anti-DHES0815A antibodies (ADA) will be drawn at baseline 
(prior to dosing on Day1, Cycle 1), before dosing on Day 1 of Cycles 24, at study completion/early 
discontinuation visit.
e In addition to PK samples specified in footnote "b," a baseline serum sample (Cycle 1, Day 1
only) may be used, depending upon review of DHES0815A PK/ADA data, to measure HER2 ECD, 
pertuzumab, trastuzumab, and/or trastuzumab emtansine levels to better 
understand potential drug interferences or impact on pharmacokinetics.


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Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
version 1.1 1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity. 2
Measurability of Tumor at Baseline
Definitions
At baseline, tumor lesions/lymph nodes will be categorized as measurable 
or non-measurable as described below.
a)
Measurable Tumor Lesions
Tumor Lesions.  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 
as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, 
a lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement.
b)
Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm 
or pathological lymph nodes with short axis 10 but 15 mm) 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, peritoneal spread, and abdominal 
                                           
1 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;45:22847.
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original Publication (cont.)
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103/Protocol GO39869, Version 2
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
c)
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques for measuring bone lesions.  
However, these techniques can be used to confirm the presence or disappearance 
of bone lesions.

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
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 non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable.


Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original Publication (cont.)
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Target Lesions:  Specifications by Methods of Measurements 
a)
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 4 weeks before the beginning of the treatment.
b)
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 the study.  
Imaging-based evaluation should always be the preferred option.
Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  
For the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
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. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 


Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original Publication (cont.)
DHES0815A—Genentech, Inc.
105/Protocol GO39869, Version 2
and interpretation of non-target disease or new lesions, since the same lesion may 
appear to have a different size using a new modality.
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization 
of these techniques for objective tumor evaluation cannot generally be advised.
Tumor Response Evaluation
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.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above.
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 (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as non-measurable lesions (even if the size is 10 mm by 
CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should 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 that can be measured reproducibly should 
be selected.
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above, 
pathological nodes that 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 


Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original Publication (cont.)
DHES0815A—Genentech, Inc.
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obtained (for CT 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 that 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 of 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 of 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 of diameters will be used as a 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 Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
Response Criteria
a)
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for 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 of 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 (nadir), including baseline
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.


Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original Publication (cont.)
DHES0815A—Genentech, Inc.
107/Protocol GO39869, Version 2

Stable disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study
b)
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 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 complete response criteria are met, since a normal lymph node is defined as 
having a short axis of 10 mm.
Target Lesions That Become Too Small to Measure.  During the study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that 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 CRF, as follows:

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 and BML (below measurable limit) should 
be ticked.  (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 and BML should also be ticked).
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and in that case BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, 
the longest diameters of the fragmented portions should be added together to calculate 
the target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximum 
longest diameter for the coalesced lesion.


Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original Publication (cont.)
DHES0815A—Genentech, Inc.
108/Protocol GO39869, Version 2
c)
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.  Although some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the protocol.

Complete response (CR):  Disappearance of all non-target lesions and (if applicable) 
normalization of tumor marker level
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

Progressive disease (PD):  Unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.
d)
Special Notes on Assessment of Progression of Non-Target Disease
When the Patient 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 in a magnitude that, even in the 
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 Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have 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 patients 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, that is, an increase in tumor burden representing an 
additional 73% increase in volume (which is equivalent to a 20% increase in diameter 
in a measurable lesion).  Examples include an increase in a pleural effusion from “trace” 
to “large” or an increase in lymphangitic disease from localized to widespread, or may 
be described in protocols as “sufficient to require a change in therapy.”  If unequivocal 
progression is seen, the patient should be considered to have had overall PD at that 


Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original Publication (cont.)
DHES0815A—Genentech, Inc.
109/Protocol GO39869, Version 2
point.  Although 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.
e)
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, 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 patient’s baseline lesions show partial or 
complete response.  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 during the study in an anatomical location that was not scanned 
at baseline is considered a new lesion and will indicate disease progression.
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.
Evaluation of Response
a)
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original Publication (cont.)
DHES0815A—Genentech, Inc.
110/Protocol GO39869, Version 2
Table 1:  Timepoint Response:  Patients with Target Lesions
(with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; 
PRpartial response; SDstable disease.
Table 2:  Timepoint Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some trials; thus, assigning “stable disease” 
when no lesions can be measured is not advised.
b)
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless 
a convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned timepoint response.  This would be most likely 
to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm 


Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original Publication (cont.)
DHES0815A—Genentech, Inc.
111/Protocol GO39869, Version 2
with three measured lesions and during the study only two lesions were assessed, but 
those gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, 
the response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess” except where this is clear evidence of 
progression, as this equates with the case being not evaluable at that timepoint.


Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original Publication (cont.)
DHES0815A—Genentech, Inc.
112/Protocol GO39869, Version 2
Table 3:  Best Overall Response When Confirmation Is Required
Overall Response at First 
Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum 
duration for SD was met; 
otherwise, PD
CR
PD
SD, provided minimum 
duration for SD was met; 
otherwise, PD
CR
NE
SD, provided minimum 
duration for SD was met; 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum 
duration for SD was met; 
otherwise, PD
PR
NE
SD, provided minimum 
duration for SD was met; 
otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the 
first timepoint.  Under these circumstances, the original CR should be changed to PR and the 
best response is PR.
c)
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 patients with CR may not have a total sum of “zero” on the CRF.


Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST):  Modified Excerpt from Original Publication (cont.)
DHES0815A—Genentech, Inc.
113/Protocol GO39869, Version 2
Patients 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 patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 1–3.
For equivocal findings of progression (e.g., 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.
In studies for which patients with advanced disease are eligible (i.e., primary disease still or 
partially present), the primary tumor should also be captured as a target or non-target lesion, as 
appropriate.  This is to avoid an incorrect assessment of complete response if the primary tumor 
is still present but not evaluated as a target or non-target lesion.


DHES0815A—Genentech, Inc.
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Appendix 4 ECOG Performance Status Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance 
without restriction
1
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, 
e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 
50% of waking hours
4
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair
5
Dead
ECOGEastern Cooperative Oncology Group.


DHES0815A—Genentech, Inc.
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Appendix 5 New York Heart Association Classification
Class
Description
I
Patients with cardiac disease but without resulting limitations of physical activity.  
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain.
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.
III
Patients with cardiac disease resulting in marked limitation of physical activity.  They 
are comfortable at rest.  Less than ordinary physical activity causes fatigue, palpitation, 
dyspnea, or anginal pain.
IV
Patients with cardiac disease resulting in inability to carry on physical activity without 
discomfort.  Symptoms of cardiac insufficiency or of the anginal syndrome may be 
present event at rest.  If any physical activity is undertaken, discomfort is increased.
Excerpted from Oxford Textbook of Medicine. Vol 2, p. 2228. Oxford Press 1997.


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Appendix 6 Recommended Anaphylaxis Management
The following equipment is needed in the event of a suspected 
anaphylactic reaction during study drug infusion:
Appropriate monitors (electrocardiogram, blood pressure, pulse oximetry)
Oxygen and masks for oxygen delivery

Airway management devices per standard of care

Epinephrine for intravenous, intramuscular, and/or endotracheal administration 
in accordance with institutional guidelines 

Salbutamol (or albuterol or equivalent)

Antihistamines (H1 and H2 blockers)

Corticosteroids

IV infusion solutions, tubing, catheters, and tape
The following are the recommended procedures to follow in the event of a 
suspected anaphylactic reaction during study drug infusion:
Stop the study drug infusion.
Call for additional assistance!
Maintain an adequate airway.

Provide oxygen.

Ensure that appropriate monitoring is in place, with continuous electrocardiogram 
and pulse oximetry monitoring, if possible.

Administer epinephrine first, followed by antihistamines, albuterol, or other 
medications as required by patient status and directed by the physician in charge.

Continue to observe the patient and document observations.